BR112015021410B1 - MACROCYCLIC INHIBITORS OF PD-1/PD-L1 AND CD80(B7-1)/PD-L1 PROTEIN/PROTEIN INTERACTIONS - Google Patents

Abstract

MACROCYCLIC INHIBITORS OF PD-1/PD-L1 AND CD80(B7-1)/PD-L1 PROTEIN/PROTEIN INTERACTIONS. The present invention provides novel macrocyclic peptides that inhibit PD-1/PD-L1 and PD-L1/CD80 protein/protein interactions, and are therefore useful for the amelioration of various diseases, including cancer and infectious diseases.

Description

[001] This application claims priority to Non-Provisional U.S. Patent Application 14/201977 filed on March 10, 2014, Provisional U.S. Patent Application 61/918184 filed on December 19, 2013 and Provisional U.S. Patent Application 61/794589 filed on March 15, 2013, which are incorporated herein in their entirety by reference.

[002] The present invention provides novel macrocyclic peptides that inhibit the PD-1/PD-L1 and CD80/PD-L1 protein/protein interaction, and are therefore useful for the amelioration of various diseases, including cancer and infectious diseases.

[003] Programmed Death 1 (PD-1) protein is an inhibitory member of the CD28 family of receptors, which also includes CD28, CTLA-4, ICOS, and BTLA. PD-1 is expressed on activated T cells, B cells, and myeloid cells (Agata et al., supra; Okazaki et al., Curr. Opin. Immunol, 14:779-782 (2002); Bennett et al., J. Immunol, 170:711-718 (2003)).

[004] PD-1 protein is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al., Int. Immunol, 8:765-772 (1996)). PD-1 contains a membrane-proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane-distal tyrosine-based switch motif (ITSM) (Thomas, M. L., J. Exp. Med., 181:1953-1956 (1995); Vivier, E. et al., Immunol Today, 18:286-291 (1997)). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is critical for CD80 CD86 (B7-2) binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (b7-DC). Activation of PD-1-expressing T cells has been shown to be downregulated upon interaction with cells expressing PD-L1 or PD-L2 (Freeman et al., J. Exp. Med., 192:1027–1034 (2000); Latchman et al., Nat. Immunol, 2:261–268 (2001); Carter et al., Eur. J. Immunol, 32:634–643 (2002)). Both PD-L1 and PD-L2 are members of the B7 family of proteins that bind to PD-1 but do not bind to other members of the CD28 family. The ligand for PD-L1 is abundant in a variety of human cancers (Dong et al., Nat. Med., 8:787-789 (2002)). The interaction between PD-1 and PD-L1 results in a decrease in tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune evasion by cancer cells (Dong et al., J. Mol. Med., 81:281-287 (2003); Blank et al., Cancer Immunol Immunother., 54:307-314 (2005); Konishi et al., Clin. Cancer Res., 10:5094-5100 (2004)). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked (Iwai et al., Proc. Natl. Acad. Sci. USA, 99: 12293–12297 (2002); Brown et al., J. Immunol, 170: 1257–1266 (2003)).

[005] PD-L1 has also been shown to interact with CD80 (Butte, M. J. et al., Immunity, 27: 111-122 (2007)). The PD-L1/CD80 interaction on expressing immune cells has been shown to be an inhibitory interaction. Blocking this interaction has been shown to abrogate this inhibitory interaction (Paterson, A. M. et al., J. Immunol., 187: 1097-1105 (2011); Yang, J. et al., J /mmrao/., 187(3): 1113-1119 (Aug 1 2011)).

[006] When T cells expressing PD-1 contact cells expressing its ligands, functional activities in response to antigenic stimuli, including proliferation, cytokine secretion, and cytotoxicity, are reduced. PD-1/PD-L1 or PD-L2 interactions downregulate immune responses during resolution of an infection or tumor, or during the development of self-tolerance (Keir, M.E. et al., Annu. Rev. Immunol, 26:Epub (2008)). Chronic antigen stimulation, such as that occurring during tumor disease or chronic infections, results in T cells that express elevated levels of PD-1 and are dysfunctional with respect to activity toward the chronic antigen (reviewed by Kim et al., Curr. Opin. Imm. (2010)). This is termed “T cell exhaustion.” B cells also show suppression and “exhaustion” of ligands for PD-1/PD.

[007] Blocking PD-1/PD-L1 binding using antibodies to PD-L1 has been shown to restore and enhance T-cell activation in many systems. Patients with advanced cancer benefit from therapy with a monoclonal antibody to PD-L1 (Brahmer et al., New Engl J. Med. (2012)). Animal models of preclinical tumors and chronic infections have shown that blocking the PD-1/PD-L1 pathway by monoclonal antibodies can improve the immune response and result in tumor rejection or infection control. Antitumor immunotherapy via PD-1/PD-L1 blockade can enhance the immune response to numerous histologically distinct tumors (Dong, H. et al., "B7-H1 pathway and its role in the evasion of tumor immunity", J. Mol Med., 81(5):281-287 (2003); Dong, H. et al., "Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion", Nat. Med., 8(8):793-800 (2002)).

[008] Interference with PD-1/PD-L1 interaction causes increased T cell activity in chronically infected systems. Blockade of PD-L1 caused enhanced viral clearance and restored immunity in mice infected with chromotic lymphocytic choriomeningitis virus (Barber, D.L. et al., "Restoring function in exhausted CD8 T cells during chronic viral infection", Nature, 439(7077):682-687 (2006)). Humanized mice infected with HIV-1 show enhanced protection against viremia and viral depletion of CD4+ T cells (Palmer et al., J. Immunol. (2013)). Blockade of PD-1/PD-L1 by monoclonal antibodies to PD-L1 can restore antigen-specific functionality in vitro to T cells from HIV patients (Day, Nature (2006); Petrovas, J. Exp. Med. (2006); Trautman, Nature Med. (2006); D'Souza, J. Immunol. (2007); Zhang, Blood (2007); Kaufmann, Nature Imm. (2007); Kasu, J. Immunol. (2010); Porichis, Blood (2011)), HCV patients (Golden-Mason, J. Virol. (2007); Jeung, J. Leuk. Biol. (2007); Urbani, J. Hepatol. (2008); Nakamoto, PLoS Path. (2009); Nakamoto, Gastroenterology (2008)), and HBV patients (Boni, J. Virol. (2007); Fisicaro, Gastro. (2010); Fisicaro et al., Gastroenterology (2012); Boni et al., Gastro. (2012); Penna et al., J. Hep. (2012); Raziorrough, Hepatology (2009); Liang, World J. Gastro. (2010); Zhang, Gastro. (2008)).

[009] Blockade of the PD-L1/CD80 interaction has also been shown to stimulate immunity (Yang, J. et al., J. Immunol, 187(3): 1113-1119 (Aug 1 2011)). Immune stimulation resulting from blockade of the PD-L1/CD80 interaction has been shown to be enhanced by combination with blockade of other PD-1/PD-L1 or PD-1/PD-L2 interactions.

[0010] It has been hypothesized that alterations in immune cell phenotypes are an important factor in septic shock (Hotchkiss et al., Nat. Rev. Immunol. (2013)). These include increased levels of PD-1 and PD-L1 (Guignant, et al., Crit. Care (2011)). Cells from septic shock patients with increased levels of PD-1 and PD-L1 exhibit an increased level of T cell apoptosis. Antibodies targeting PD-L1 can reduce the level of immune cell apoptosis (Zhang et al., Crit. Care (2011)). Furthermore, mice lacking PD-1 expression are more resistant to the symptoms of septic shock than wild-type mice. Yang, J. et al., J. Immunol, 187(3): 1113-1119 (Aug 1 2011)). Studies have already shown that blocking PD-L1 interactions using antibodies can suppress inappropriate immune responses and improve signs of disease.

[0011] In addition to enhancing immune responses to chronic antigens, blockade of the PD-1/PD-L1 pathway has also been shown to improve responses to vaccination, including therapeutic vaccination in the setting of chronic infection (Ha, S. J. et al., "Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection", J. Exp. Med., 205(3):543-555 (2008); Finnefrock, A. C. et al., "PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination", J. Immunol, 182(2):980-987 (2009); Song, M.-Y. et al., "Enhancement of vaccine-induced primary and memory CD8+ t-cell responses by soluble PD-1 ", J. Immunother., 34(3):297- 306 (2011)).

[0012] The molecules described in this invention demonstrate the ability to block the interaction of PD-L1 with PD-1, both in biochemical and cell-based experimental systems. These results are consistent with a potential for therapeutic administration to enhance immunity in cancer or chronic infection, including therapeutic vaccine.

[0013] The macrocyclic peptides described in this invention are capable of inhibiting the interaction of PD-L1 with PD-1 and with CD80. These compounds demonstrated highly effective binding to PD-L1, blocking the interaction of PD-L1 with PD-1 or with CD80, and are capable of promoting increased functional T cell activity, which makes them candidates for parenteral, oral, pulmonary, nasal, buccal and systemic delivery formulations.

[0014] In one embodiment the present invention provides a compound of formula (I) A is selected from a link where: denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom; n is 0 or 1; R14 and R15 are independently selected from hydrogen and methyl; and R16 is selected from hydrogen, -CHR17C(O)NH2, -CHR17C(O)NHCHR18C(O)NH2, and - CHR17C(O)NHCHR18C(O)NHCH2C(O)NH2; where R17 is selected from hydrogen and -CH2OH and where R18 is selected from hydrogen and methyl; Rc, Rf, Rh, Rl, Rm, and Rn are hydrogen; Ra, Re, Rj, and Rk are each independently selected from hydrogen and methyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain or form a ring with the corresponding neighboring R group as described below; Re and Rk can each form a ring with the corresponding neighboring R group and the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy; Rb is methyl or, Rb and R2, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy; Rd is hydrogen or methyl, or, Rd and R4, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; Rg is hydrogen or methyl or Rg and R7, together with the atoms to which they are attached, can form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one to four groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and where the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and R1 is methyl or, R1 and R12, together with the atoms to which they are attached, form a ring selected from azetidine and pyrrolidine, where each ring is optionally substituted with one to four independently selected from amino, cyano, methyl, halo, and hydroxy.

[0015] In another embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is

[0016] In another embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is Rd is methyl or, Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; Rg is methyl or, Rg and R7, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one or two groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and where the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and Rk is methyl or, Rk and R11, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy.

[0017] In another embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy; R8 and R7, together with the atoms to which they are attached, form a pyrrolidine ring, wherein said ring is optionally substituted with one or two groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and wherein the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; and Rk is methyl.

[0018] In another embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy; R8 and R7, together with the atoms to which they are attached, form a pyrrolidine ring, wherein said ring is optionally substituted with one or two groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and wherein the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; Rk is methyl; and R8 is selected from: azaindolylC1-C3alkyl, benzothiazolylC1-C3alkyl, benzothienylC1-C3alkyl, benzyloxyC1-C3alkyl, diphenylmethyl, furanylC1-C3alkyl, imidazolylC1-C3alkyl, naphthylC1-C3alkyl, pyridinylC1-C3alkyl, thiazolylC1-C3alkyl, thienylC1-C3alkyl; and indolylC1-C3alkyl, wherein the indolyl moiety is optionally substituted with a group selected from C1-C3alkyl, cyano, halo, and hydroxy.

[0019] In another embodiment the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, and hydroxy; Rg and R7, together with the atoms to which they are attached, form a pyrrolidine ring, wherein said ring is optionally substituted with one or two groups independently selected from amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and wherein the pyrrolidine and piperidine rings are optionally fused to a cyclohexyl, phenyl, or indole group; Rk is methyl; and R8 is 3-indolylC1-C3alkyl optionally substituted with a group selected from C1-C3alkyl, halo, hydroxy, or cyano.

[0020] In another embodiment the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: A is selected from a bond, and where: denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom; n is 0 or 1; R14 and R15 are independently selected from hydrogen and methyl; and R16 is selected from hydrogen, -CHR17C(O)NH2,- CHR17C(O)NHCHR18C(O)NH2, and -CHR17C(O)NHCH2C(O)NH2; where R17 is selected from hydrogen and -CH2OH and where R18 is selected from hydrogen and methyl; Ra, Rf, Rj, Rk, Rl, and Rm are hydrogen; Rb and Rc are methyl; Rg is selected from hydrogen and methyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are independently selected from a natural amino acid side chain and an unnatural amino acid side chain or form a ring with the corresponding neighboring R group as described below; Rd is selected from hydrogen and methyl, or, Rd and R4, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; Re is selected from hydrogen and methyl, or, Re and R5, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; Rh is selected from hydrogen and methyl, or, Rh and R8, together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; and Ri is selected from hydrogen and methyl, or, Ri and R9, together with the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; where each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy.

[0021] In another embodiment the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein A is

[0022] In another embodiment the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein A is Rd is methyl, or, Rd and R4, together with the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; Rg is methyl; and Ri is methyl, or, Ri and R9, together with the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy.

[0023] In another embodiment the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein A is Rd is methyl, or, Rd and R4, together with the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; R8 is methyl; Ri is methyl, or, Ri and R9, together with the atoms to which they are attached are selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with one or two groups independently selected from amino, cyano, methyl, halo, halomethyl, and hydroxy; and R7 is phenylC1-C3alkyl optionally substituted with a fluorine group.

[0024] In another embodiment the present invention provides a method for enhancing, stimulating, and/or increasing the immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of at least one macrocyclic peptide described in this invention. In another embodiment the method further comprises administering an additional agent before, after, or simultaneously with the macrocyclic peptide or peptides described in this invention. In another embodiment the additional agent is an antimicrobial agent, an antiviral agent, a cytotoxic agent, and/or an immune response modifier.

[0025] In another embodiment the present invention provides a method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of one or more macrocyclic peptides described in this invention. In another embodiment the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract, and breast, and a hematologic malignancy.

[0026] In another embodiment the present invention provides a method for treating an infectious disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one macrocyclic peptide described in this invention. In another embodiment the infectious disease is caused by a virus. In another embodiment the virus is selected from HIV, Hepatitis A, Hepatitis B, Hepatitis C, herpes virus, and influenza.

[0027] In another embodiment the present invention provides a method for treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of one or more macrocyclic peptides described in this invention.

[0028] In another embodiment the present invention provides a method for blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, said method comprising administering to the subject a therapeutically effective amount of at least one macrocyclic peptide described in this invention.

[0029] In compounds of formula (I) and (II) where the R side chains are part of a ring that is substituted with methyl, it is understood that the methyl group may be on any substitutable carbon atom in the ring, including the carbon that is part of the parent macrocyclic structure.

[0030] In the compounds of formula (I), preferred R1 side chains are: phenylalanine, tyrosine, 3-thien-2-yl, 4-methylphenylalanine, 4-chlorophenylalanine, 3-methoxyphenylalanine, isotryptophan, 3-methylphenylalanine, 1-naphthylalanine, 3,4-difluorophenylalanine, 4-fluorophenylalanine, 3,4-dimethoxyphenylalanine, 3,4-dichlorophenylalanine, 4-difluoromethylphenylalanine, 2-methylphenylalanine, 2-naphthylalanine, tryptophan, 4-pyridinyl, 4-bromophenylalanine, 3-pyridinyl, 4-trifluoromethylphenylalanine, 4-carboxyphenylalanine, 4-methoxyphenylalanine, biphenylalanine, and 3- chlorophenylalanine; and 2,4-diaminobutane.

[0031] In compounds of formula (I) where R2 is not part of a ring, preferred R2 side chains are: alanine, serine, and glycine.

[0032] In compounds of formula (I), preferred R3 side chains are: asparagine, aspartic acid, glutamic acid, glutamine, serine, ornithine, lysine, histidine, threonine, leucine, alanine, 2,3-diaminopropane, and 2,4-diaminobutane.

[0033] In compounds of formula (I) where R4 is not part of a ring, preferred R4 side chains are: valine, alanine, isoleucine, and glycine.

[0034] In compounds of formula (I), preferred R5 side chains are: histidine, asparagine, 2,3-diaminopropane, serine, glycine, 2,4-diaminobutane, threonine, alanine, lysine, aspartic acid, alanine, and 3-thiazolylalanine.

[0035] In compounds of formula (I), preferred R6 side chains are: leucine, aspartic acid, asparagine, glutamic acid, glutamine, serine, lysine, 3-cyclohexane, threonine, ornithine, 2,4-diaminobutane, alanine, arginine, and ornithine (COCH3).

[0036] In compounds of formula (I) where R7 is not part of a ring, preferred R7 side chains are: glycine, 2,4-diaminobutane, serine, lysine, arginine, ornithine, histidine, asparagine, glutamine, alanine, and 2,4-diaminobutane (C(O)cyclobutane).

[0037] In the compounds of formula (I) preferred R8 side chains are tryptophan and 1,2-benzisothiazolinylalanine.

[0038] In the compounds of formula (I) preferred R9 side chains are: serine, histidine, lysine, ornithine, 2,4-dibutylamine, threonine, lysine, glycine, glutamic acid, valine, 2,3-diaminopropane, arginine, aspartic acid, and tyrosine.

[0039] In the compounds of formula (I) preferred R10 side chains are: tryptophan, benzisothiazolylalanine, 1-naphthylalanine, 5-fluorotryptophan, methionine, 7-methyltryptophan, 5-chlorotryptophan, and -methyltryptophan.

[0040] In the compounds of formula (I) preferred R11 side chains are: norleucine, leucine, asparagine, phenylalanine, methionine, ethoxymethane, alanine, tryptophan, isoleucine, phenylpropane, glutamic acid, hexane, and heptane.

[0041] In compounds of formula (I) where R12 is not part of a ring, preferred R12 side chains are: norleucine, alanine, ethoxymethane, methionine, serine, phenylalanine, methoxyethane, leucine, tryptophan, isoleucine, glutamic acid, hexane, heptane, and glycine. In compounds of formula (I) preferred R13 side chains are: arginine, ornithine, alanine, 2,4-diaminobutane, 2,3-diaminopropane, leucine, aspartic acid, glutamic acid, serine, lysine, threonine, cyclopropylmethane, glycine, valine, isoleucine, histidine, and 2-aminobutane.

[0042] In the compounds of formula (II) preferred R1 side chains are: phenylalanine, 3-methoxyphenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3,4-difluorophenylalanine, 3,5-difluorophenylalanine, 3,4,5-trifluorophenylalanine, 3-fluoro,4-chlorophenylalanine, 3-chloro,4-fluorophenylalanine, 3-chlorophenylalanine, 4-chlorophenylalanine, 3.4-dichlorophenylalanine, 3,5-dichlorophenylalanine, 3.5-dichloro,4-fluorophenylalanine, 3-chloro,4,5-difluorophenylalanine, 4-bromophenylalanine, 4-nitrophenylalanine, 3-trifluoromethylphenylalanine, 4-trifluoromethylphenylalanine, and 3-pyridylalanine.

[0043] In compounds of formula (II), preferred R2 side chains are: phenylalanine, alanine, histidine, tyrosine, tryptophan, glutamic acid, 1-naphthylalanine, 2-naphthylalanine, 2-benzothiazolylalanine, 3-pyridinylalanine, and 4-pyridinylalanine.

[0044] In compounds of formula (II), preferred R3 side chains are: norleucine, alanine, tyrosine, glutamic acid, leucine, and isoleucine.

[0045] In compounds of formula (II) where R4 is not part of a ring, preferred R4 side chains are: glycine, and alanine.

[0046] In compounds of formula (II) where R5 is not part of a ring, preferred R5 side chains are: aspartic acid, glutamic acid, arginine, lysine, asparagine, serine, 2,4-diaminobutane, 2,3-diaminopropane, and 2-aminobutane.

[0047] In compounds of formula (II) preferred R6 side chains are: valine, leucine, isoleucine, N-methylthreonine, and cyclohexylmethane.

[0048] In compounds of formula (II) preferred R7 side chains are: phenylalanine and 3-fluorophenylalanine.

[0049] In compounds of formula (II) where R8 is not part of a ring, preferred R8 side chains are: tyrosine, 3-iodotyrosine, leucine, arginine, glutamic acid, glutamine, pentafluorophenylalanine, 4-aminophenylalanine, 4-aminomethylphenylalanine, 3,4-dimethoxyphenylalanine, tryptophan, 5-chlorotryptophan, 5-hydroxytryptophan, isotryptophan, lysine, ornithine, and 2,3-diaminopropane.

[0050] In the compounds of formula (II) preferred R10 side chains are: tryptophan, 5-chlorotryptophan, 7-azatryptophan, isotryptophan, 3-benzothiazolylalanine, and 1-naphthylalanine.

[0051] In compounds of formula (II) preferred R11 side chains are tyrosine, 4-fluorophenylalanine, 4-aminomethylphenylalanine, 4-aminophenylalanine, and 3,4-dihydroxyphenylalanine.

[0052] In the compounds of formula (II) preferred R12 side chains are: leucine, tyrosine, arginine, lysine, ornithine, glutamic acid, phenylalanine, 4-methylphenylalanine, 4-chlorophenylalanine, 4-aminomethylphenylalanine, norleucine, cyclohexylalanine, 2,4-diaminobutane, and 2,3-diaminopropane.

[0053] In compounds of formula (II), when R4 and R9 are part of a ring the preferred stereochemistry is that of the D-isomer and when R5 and R8 are part of a ring the preferred stereochemistry is that of the L-isomer.

[0054] One embodiment of the subject matter described in this report relates to a polypeptide comprising a sequence of formula I(a): where: A is an organic or peptide linker between Xaa1 and Xaa14, thus providing a macrocyclic peptide; Xaa1 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa2 is a naturally occurring or unnaturally occurring alkyl or N-methylated alkyl amino acid; Xaa3 is a naturally occurring or unnaturally occurring hydrophilic or alkyl or polar amino acid; Xaa4 is a naturally occurring or unnatural amino acid, an alkyl amino acid or an N-methylated alkyl amino acid; Xaa5 is a naturally occurring or unnatural heteroaromatic amino acid or a positively charged amino acid or an alkyl amino acid; Xaa6 is a naturally occurring or unnaturally occurring hydrophilic or hydrophobic or positively or negatively charged amino acid; Xaa7 is a naturally occurring or unnaturally occurring hydrophilic or hydrophobic or positively or negatively charged N-methylated or non-N-methylated amino acid; Xaa8 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl amino acid; Xaa9 is a naturally occurring or unnaturally occurring hydrophilic or hydrophobic or positively or negatively charged amino acid; Xaa10 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl or heteroalkyl amino acid; Xaa11 is a naturally occurring or unnaturally occurring N-methylated or non-N-methylated alkyl or heteroalkyl or aromatic or heteroaromatic amino acid; Xaa12 is a naturally occurring or unnaturally occurring N-methylated or non-N-methylated alkyl or heteroalkyl or aromatic or heteroaromatic amino acid; Xaa13 is a naturally occurring or non-naturally occurring hydrophilic or hydrophobic or positively or negatively charged amino acid; Xaa14 is a naturally occurring or non-naturally occurring amino acid having a functional group that can be appropriately activated to react with one end of the A-linker to give a cyclic peptide; Xaa15 is a naturally occurring or non-naturally occurring amino acid or a spacer followed by a tag or a spacer followed by a solubilizer or PK-enhancing element.

[0056] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula I(b): where: A is an electrophilic moiety such as a Michael acceptor or a chloro- or bromoacetyl group that is capable of reacting with a sulfhydryl group present on residue Xaa14 to form a covalent thioether bond, thus giving a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; and where A may optionally be present; and where, if A is present, it may be a Gly or or other spacer with a free amine, which may be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa14, thus providing an N-terminus for the cyclic lactam peptide side chain; and wherein, if A is not present, the N-terminal amino group of residue Xaa1 can be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa14, thereby providing an N-terminus for the cyclic lactam side chain peptide; and wherein, if A is present, it can be a Gly or or other spacer with a free amine, which can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaa15, thereby providing a head-to-tail cyclic peptide; and wherein, if A is not present, the N-terminal amino group of amino acid Xaa1 can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaa15, thereby providing a head-to-tail cyclic peptide; Xaa1 is a naturally or unnaturally occurring amino acid comprising L-Phe, L-Ala, L-Trp, L-Tyr, L-Phe(4-OMe), L-Phe(4-F), L-Phe(4-Cl), L-Phe(4-Br), L-Phe(4-Me), L-Phe(4-CF3), L-Phe(4-t-Bu), L- Phe(penta-F), L-1-Nal, L-2-Nal, L-Bip, L-mPhe, L-Tic, L-3-Pya, L-4- Pya, L-Tza, L-3-Tha; Xaa2 is a naturally or unnaturally occurring amino acid selected from the group consisting of L-Ala, L-mAla, mGly, L-mVal; Xaa3 is selected from the group consisting of Gly, L-Asn, and L-Ala; Xaa4 is a naturally or unnaturally occurring amino acid comprising L-Pro, L-Ala, La-Me-Pro, L-Pro(4R-OH), L-Pro(4R-OBzl), L-Pro(4R-NH2), L-Pro(3R-Ph), L-Pro(4S-Ph), L-Pro(5R-Ph), L-Azt, L-Pip, L-Oic, L-2,3-Methane-Pro, L-3,4-Methane-Pro, L-Val, L-Leu, L-Ile, L- mAla, L-mVal, L-mLeu, L-Tza; Xaa5 is a naturally or unnaturally occurring amino acid selected from the group consisting of L-His, L-Ala, L-Tza, L-Arg, L-Lys, L-Orn, L-Dab, and L-Dap; Xaa6 is a naturally occurring or unnaturally occurring amino acid comprising L-Leu, L-Ala, L-Arg, L-His, L-Glu, and L-Asp; Xaa7 is a naturally occurring or unnaturally occurring amino acid comprising mGly, Gly, L-mAla, D-mAla, L-Pro, L-Ser, L-mSer, L-Dab, L-Arg, and L-His; Xaa8 is L-Trp, L-Phe, L-Tyr, L-His, L-Phe(penta-F), L-Tza, L-Bzt, L-1-Nal, L-2-Nal, L-2-Pya, L-3-Pya, L-4-Pya; Xaa9 is a naturally occurring or unnaturally occurring amino acid comprising L-Ser, L-Ala, L-Arg, and D-Asn; Xaa10 is a naturally or unnaturally occurring amino acid selected from the group consisting of L-Trp, L-Ala, L-Met, L-Nle, L-Leu and L-Ile, L-Phe, L-Tyr, L-His, L-Phe(penta-F), L-Tza, L-Bzt, L-1-Nal, L-2-Nal, L-2-Pya, L-3-Pya, L-4-Pya; Xaa11 is a naturally or unnaturally occurring amino acid comprising L-mNle, L-Nle, L-mAla, L-Ala, L-Phe, L-mPhe and L-mLeu, L-Ser, D-Nle and L-Pro; Xaa12 is a naturally or non-naturally occurring amino acid comprising L-mNle, L-Nle, L-mAla, L-Ala, L-Phe, L-mPhe, L-mLeu, and L-Pro; Xaa13 is a naturally or non-naturally occurring amino acid comprising L-Arg, L-Ala, L-Leu, L-Lys, L-Asp, L-Glu, L-His; Xaa14 is selected from the group consisting of L-Cys, D-Cys, Asp, Glu, Gly, L-homo-Cys, D-homo-Cys, L-Pen, D-Pen, L-mCys, and D-mCys; Xaa15 is Gly or Gly followed by a PEG spacer comprised of at least two ethylene glycol units, or Gly followed by a PEG spacer comprised of at least two ethylene glycol units followed by a tag such as biotin, or Gly followed by a spacer followed by a PK enhancer element; wherein Xaa15 is optionally present and wherein the C-terminal carbonyl carbon of said amino acid is attached to a hydroxyl group to form a carboxylic acid or to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); wherein each of R1 and R2 is an alkyl or arylalkyl group; wherein, if Xaa15 is not present, the C-terminal carbonyl carbon of Xaa14 is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group.

[0057] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula I(c): where: A is an electrophilic moiety such as a Michael acceptor or a chloro- or bromoacetyl group that is capable of reacting with a sulfhydryl group present on residue Xaa14 to form a covalent thioether bond, thus giving a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; and where A may optionally be present; and where, if A is present, it may be a Gly or or other spacer with a free amine, which may be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa14, thus providing an N-terminus for the cyclic lactam peptide side chain; and where, if A is not present, the N-terminal amino group of the Xaa1 residue can be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa14, thereby providing an N-terminus for the cyclic lactam side chain peptide; and where, if A is present, it can be a Gly or other spacer with a free amine, which can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaa15, thereby providing a head-to-tail cyclic peptide; and where, if A is not present, the N-terminal amino group of the Xaa1 amino acid can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaai5, thereby providing a head-to-tail cyclic peptide; Xaa1 is a naturally or unnaturally occurring amino acid comprising L-Phe, L-Ala, L-Trp, L-Tyr, L-Phe(4-OMe), L-Phe(4-F), L-Phe(4-Cl), L-Phe(4-Br), L-Phe(4-Me), L-Phe(4-CF3), L-Phe(4-t-Bu), L- Phe(penta-F), L-1-Nal, L-2-Nal, L-Bip, L-mPhe, L-Tic, L-3-Pya, L-4- Pya, L-Tza, L-3-Tha; Xaa2 is a naturally or unnaturally occurring amino acid selected from the group consisting of L-Ala, L-mAla, mGly, L-mVal; Xaa3 is selected from the group consisting of Gly, L-Asn, and L-Ala; Xaa4 is a naturally occurring or unnaturally occurring amino acid comprising L-Pro, L-Ala, La-Me-Pro, L-Pro(4R-OH), L-Pro(4R-NH2), L-Pro(4S-Ph), L-Azt, L-Pip, and L-Oic; Xaa5 is a naturally occurring or unnaturally occurring amino acid selected from the group consisting of L-His and L-Ala; Xaa6 is a naturally occurring or unnaturally occurring amino acid comprising L-Leu, L-Ala, L-Arg, and L-Asp; Xaa7 is a naturally occurring or unnaturally occurring amino acid comprising mGly, Gly, L-mAla, D-mAla, L-Pro, L-Ser, L-mSer, L-Dab, L-Arg, and L-His; Xaa9 is a naturally occurring or unnaturally occurring amino acid comprising L-Ser, L-Ala, L-Arg, and D-Asn; Xaa10 is a naturally occurring or unnaturally occurring amino acid selected from the group consisting of L-Trp, L-Ala, L-Met, L-Leu, and L-Ile; Xaa11 is a naturally occurring or unnaturally occurring amino acid comprising L-mNle, L-Nle, L-mAla, L-Ala, L-Phe, L-mPhe, and L-mLeu, L-Ser, and D-Nle; Xaa12 is a naturally occurring or unnaturally occurring amino acid comprising L-mNle, L-Nle, L-mAla, and L-Ala; Xaa13 is a naturally occurring or unnaturally occurring amino acid comprising L-Arg, L-Ala, and L-Leu; Xaa14 is selected from the group consisting of L-Cys, D-Cys, Asp, Glu, and Gly; Xaa15 is Gly or Gly followed by a PEG spacer comprised of at least two ethylene glycol units, or Gly followed by a PEG spacer comprised of at least two ethylene glycol units followed by a tag such as biotin; where Xaa15 is optionally present and where the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group; where, if Xaa15 is not present, the C-terminal carbonyl carbon of Xaa14 is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group.

[0058] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula II(a): where: A is an organic or peptide linker between Xaa1 and Xaa13, thus providing a macrocyclic peptide; Xaa1 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa2 is a naturally occurring or unnaturally occurring N-methylated alkyl or aromatic amino acid; Xaa3 is a naturally occurring or unnaturally occurring N-methylated hydrophobic amino acid; Xaa4 is a naturally occurring or unnaturally occurring N-methylated hydrophobic amino acid; Xaa5 is a naturally occurring or unnaturally occurring alkyl amino acid or a positively or negatively charged amino acid; Xaa6 is a naturally occurring or unnaturally occurring hydrophobic amino acid; Xaa7 is a naturally occurring or unnaturally occurring N-methylated or non-N-methylated aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa8 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl amino acid; Xaa9 is a naturally occurring or unnaturally occurring N-methylated or non-N-methylated aromatic or heteroaromatic or alkyl or heteroarylalkyl amino acid: Xaa10 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl or heteroalkyl amino acid; Xaa11 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl or heteroalkyl amino acid; Xaa12 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl or heteroalkyl amino acid; Xaa13 is a naturally occurring or non-naturally occurring amino acid having a functional group that can be appropriately activated to react with one end of the A-linker to give a cyclic peptide; Xaa14 is a naturally occurring or non-naturally occurring amino acid or a spacer or a spacer followed by a tag or a spacer followed by a solubilizer or PK enhancing element.

[0059] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula II(b): where: A is an electrophilic moiety such as a Michael acceptor or a chloro- or bromoacetyl group that is capable of reacting with a sulfhydryl group present on residue Xaa13 to form a covalent thioether bond, thus giving a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; and where A may optionally be present; and where, if A is present, it may be a Gly or other spacer with a free amino terminus, which may be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa13, thus providing an N-terminus for the cyclic lactam peptide side chain; and where, if A is not present, the N-terminal amino group of residue Xaa1 can be used to cyclize the peptide via amide bond formation with a carboxyl group on the side chain of Xaa13, thereby providing an N-terminus for the side-chain cyclic lactam peptide; and where, if A is present, it can be a Gly or other spacer with a free amino terminus, which can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaa14, thereby providing a head-to-tail cyclic peptide; and where, if A is not present, the N-terminal amino group of amino acid Xaa1 can be used to cyclize the peptide via amide bond formation with the C-terminal α-carboxyl group of Xaai4, thereby providing a head-to-tail cyclic peptide; Xaa1 is a naturally occurring or unnaturally occurring amino acid comprising Phe and Ala; Xaa2 is a naturally occurring or unnaturally occurring amino acid comprising mPhe and mAla; Xaa3 is a naturally occurring or unnaturally occurring amino acid comprising mNle and mAla; Xaa4 is a naturally occurring or unnaturally occurring amino acid comprising mGly, Gly, and mAla; Xaa5 is a naturally occurring or unnaturally occurring amino acid comprising Asp and Ala; Xaa6 is a naturally occurring or unnaturally occurring amino acid comprising Val (preferred) and Ala; Xaa7 is a naturally occurring or unnaturally occurring amino acid comprising mPhe and Phe; Xaa8 is a naturally occurring or unnaturally occurring amino acid selected from the group consisting of Tyr and Ala; Xaa9 is a naturally occurring or unnaturally occurring amino acid comprising mGly mAla and Gly; Xaa11 is a naturally occurring or unnaturally occurring amino acid comprising Tyr and Ala; Xaa12 is a naturally occurring or non-naturally occurring amino acid comprising Leu and Ala; Xaa13 is a naturally occurring or non-naturally occurring amino acid comprising L-Cys, D-Cys, Asp, Glu, and Gly; Xaa14 is Gly or Gly followed by a PEG spacer comprised of at least two ethylene glycol units, or Gly followed by a PEG spacer comprised of at least two ethylene glycol units followed by a tag such as biotin, where Xaa14 is optionally present and where the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group; where, if Xaa14 is not present, the C-terminal carbonyl carbon of Xaa13 is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group.

[0060] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula III(a): where: A is an organic or peptide linker between Xaa1 and Xaa12, thus providing a macrocyclic peptide; Xaa1 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa2 is a naturally occurring or unnaturally occurring alkyl or aromatic or charged amino acid; Xaa3 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa4 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or alkyl or heteroaryl alkyl amino acid; Xaa5 is a naturally occurring or unnaturally occurring alkyl or heteroalkyl or aromatic or heteroaromatic or heteroaryl alkyl amino acid; Xaa6 is a naturally occurring or unnaturally occurring heteroaromatic or positively charged amino acid; Xaa7 is a naturally occurring or unnaturally occurring polar or charged amino acid; Xaa8 is a naturally occurring or unnaturally occurring positively charged amino acid; Xaa9 is a naturally occurring or unnaturally occurring alkyl or heteroalkyl or aromatic or heteroaromatic or heteroarylalkyl amino acid; Xaa10 is a naturally occurring or unnaturally occurring aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or alkyl or heteroalkyl amino acid; Xaa11 is an aromatic or heteroaromatic or arylalkyl or heteroarylalkyl or heteroalkyl amino acid or a naturally occurring or unnaturally occurring positively charged amino acid; Xaa12 is a naturally occurring or unnaturally occurring amino acid having a functional group that can be appropriately activated to react with one end of linker A to give a cyclic peptide; Xaa13 is a naturally occurring or non-naturally occurring amino acid or a spacer or a spacer followed by a tag or a spacer followed by a solubilizer or PK enhancing element.

[0061] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula III(b): where: A is an electrophilic moiety such as a Michael acceptor or a chloro- or bromoacetyl group that is capable of reacting with the sulfhydryl group of Cys12 to form a covalent thioether bond, thus giving a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; Xaa1 is selected from Phe and D-Phe; Xaa2 is selected from Leu, Arg, and Phe; Xaa3 is selected from He, Leu, and Phe; Xaa4 is selected from Val, Tyr, and Phe; Xaa5 is selected from He and Val; Xaa6 is selected from Arg and His; Xaa8 is selected from Arg; Xaa9 is selected from Val, Leu, Tyr, and Phe; Xaa11 is selected from Arg and Tyr; Xaa13 is Gly or Gly followed by a PEG spacer comprised of at least two ethylene glycol units, where Xaa13 is optionally present and where the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group; where, if Xaa13 is not present, the C-terminal carbonyl carbon of Cys12 is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkyl carboxamide (NR1R2); where each of R1 and R2 is an alkyl or arylalkyl group.

[0062] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula I(d): where: A is a chloroacetyl group attached to the α-amine of the N-terminal Xaai residue that is capable of reacting with a sulfhydryl group present in the Xaa14 residue to form a covalent thioether bond, thus providing a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; and where, Xaa1 is selected from the group consisting of L-Phe, L-Trp, L-Tyr, L-Phe(4-OMe), L-Phe(4-F), L-Phe(4-Cl), L-Phe(4-Br), L-Phe(4-Me), L-Phe(4-CF3), L-1-Nal, L-2-Nal, L-Bip, L-3-Pya, L-4-Pya, L-3-Tha; Xaa2 is selected from the group consisting of L-Ala, L-mAla, mGly; Xaa3 is selected from the group consisting of L-Ala and L-Asn; Xaa4 is selected from the group consisting of L-Pro, L-Ala, La-Me-Pro, L-Pro(4-OH), L-Pro(4-NH2), L-Pro(4S-Ph), L-Azt, L-Pip, and L-Oic; Xaa5 is selected from the group consisting of L-Ala, L-His, and L-Leu; Xaa6 is selected from the group consisting of L-Ala, L-Arg, L-Asp, L-His, and L-Leu; Xaa7 is selected from the group consisting of mGly, Gly, L-mAla, D- mAla, L-Pro, L-Ser, L-mSer, L-Dab, L-Arg, and L-His; Xaa9 is selected from the group consisting of L-Ala, L-Arg, and L-Ser; Xaa10 is selected from the group consisting of L-Trp, L-Met, and L-Bzt; Xaa11 is selected from the group consisting of L-Nle, L-mNle, L-mAla, L-Phe, L-mPhe, and L-mLeu and L-mSer; Xaa12 is selected from the group consisting of L-mNle and L-mAla; Xaa13 is selected from the group consisting of L-Ala, L-Arg, and L-Leu; Xaa14 is selected from the group consisting of L-Cys and D-Cys; Xaa15 is Gly or Gly followed by a PEG spacer comprised of twelve ethylene glycol units; where Xaa15 is optionally present and where the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (CONH2); where, if Xaa15 is not present, the C-terminal carbonyl carbon of Xaa14 is attached to a nitrogen to form a carboxamide (CONH2).

[0063] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula II(c): where: A is a chloroacetyl group attached to the α-amine of the N-terminal Xaai residue that is capable of reacting with a sulfhydryl group present on the Cys13 residue to form a covalent thioether bond, thus giving a macrocyclic peptide; where such thioether bond may or may not be oxidized to the corresponding diastereomeric sulfoxides; and where, Xaa2 is selected from the group consisting of L-mAla and L-mPhe; Xaa3 is selected from the group consisting of L-mAla and L-mNle; Xaa4 is selected from the group consisting of Gly, mGly, and L-mAla; Xaa5 is selected from the group consisting of L-Ala and L-Asp; Xaa6 is selected from the group consisting of L-Ala and L-Val; Xaa7 is selected from the group consisting of L-Phe and L-mPhe; Xaa8 is selected from the group consisting of L-Ala and L-Tyr; Xaa9 is selected from the group consisting of Gly, mGly, and L-mAla; Xaa12 is selected from the group consisting of L-Leu and L-Ala; Xaa14 is Gly or Gly followed by a PEG spacer comprised of twelve ethylene glycol units, where the C-terminal carbonyl carbon of Xaa14 or of Xaa14 followed by a PEG spacer is attached to a nitrogen to form a carboxamide (CONH2).

[0064] In another embodiment, the subject matter described in this invention relates to a polypeptide comprising a sequence of formula III(c): where: A is a chloroacetyl group attached to the α-amine of the N-terminal L-Phe residue that is capable of reacting with a sulfhydryl group present in the L-Cys12 residue to form a covalent thioether bond, thus giving a macrocyclic peptide; and where, Xaa2 is selected from L-Leu, L-Arg, and L-Phe; Xaa3 is selected from L-Ile and L-Phe; Xaa4 is selected from L-Phe, L-Tyr, and L-Val; Xaa5 is selected from L-Ile and L-Val; Xaa9 is selected from L-Leu, L-Phe, L-Tyr, and L-Val; where the C-terminal carbonyl carbon of Gly13 is attached to a nitrogen to form a carboxamide (CONH2).

[0065] The present invention also relates to a macrocyclic peptide comprising a sequence shown in formula I.

[0066] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula I(a).

[0067] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula I(b).

[0068] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula I(c).

[0069] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula I(d).

[0070] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula II.

[0071] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula II(a).

[0072] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula II(b).

[0073] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula II(c).

[0074] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula III.

[0075] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula III(a).

[0076] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula III(b).

[0077] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula III(c).

[0078] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula IV.

[0079] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula V.

[0080] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula VI.

[0081] The present invention also relates to macrocyclic peptides comprising a sequence shown in formula VII.

[0082] The present invention also relates to macrocyclic peptides comprising a sequence selected from the group consisting of: Compounds Nos. 1, 2, 3, 4, 71, and 99.

[0083] The present invention also relates to macrocyclic peptides comprising a sequence selected from those described in this report.

[0084] The present invention also relates to methods of using the macrocyclic peptides of the present invention to ameliorate and/or treat hyperproliferative disorders and/or viral disorders.

[0085] The present invention also relates to a method for modulating an immune response in an individual comprising administering to the individual one or more macrocyclic peptides comprising the sequence selected from the peptides described in this invention.

[0086] The present invention also relates to a method for improving, stimulating or increasing the immune response in the individual comprising administering to the individual one or more macrocyclic peptides comprising the sequence selected from those described in this invention.

[0087] The present invention also relates to a method for promoting inhibition in the immune system of tumor cell growth in an individual, comprising administering to an individual a therapeutically effective amount of one or more macrocyclic peptides comprising the sequence selected from among those peptides described in this invention.

[0088] The present invention also relates to a method for treating an infectious disease in an individual, comprising administering to an individual a therapeutically effective amount of one or more macrocyclic peptides comprising the sequence selected from those peptides described in this invention.

[0089] The present invention also relates to combinations comprising a sequence selected from the macrocyclic peptides described in this invention, with another agent, such as an antimicrobial therapy, an antiviral therapy, additional immunomodulatory therapy, a vaccine, or a cancer chemotherapeutic agent.

Brief Description of Figures

[0090] Figure 1 - Provides a schematic representation of the PD-1/PD-L1 biochemical binding assay formatted as a homogeneous time-resolved fluorescence (HTRF) format assay used to measure the ability of macrocyclic peptides to bind with PD-L1.

[0091] Figure 2 - Provides dose-response curves of control antibody to PD-1/PD-L1 for the HTRF used to measure the ability of macrocyclic peptides to bind with PD-L1.

[0092] Figure 3 - Provides PD-1/PD-L1 HTRF dose-response curves for representative macrocyclic peptides of the present invention.

[0093] Figure 4 - HTRF selectivity panel. As shown, the data demonstrate that the macrocyclic peptides bind to PD-L1 because they interfere with PD-L1 binding to PD-1 and CD80, but their binding is selective because the peptides do not block PD-1/PD-L2 or CD80/CTLA4 interactions.

[0094] Figure 5 - Cellular binding assay of selected macrocyclic peptides of the present invention. As shown, the macrocyclic peptides of the present invention block the binding of recombinant PD-L1-Ig to Jurkat-PD-1 cells, and also block the binding of recombinant PD-1-Ig to the L2987 cell line (adenocarcinoma cell line with endogenous PD-L1 expression) or LK35.2-hPD-L1 (mouse B cell line overexpressing hPD-L1. The anti-PD-L1 antibody is an in-house antibody developed by Bristol-Myers Squibb Company).

[0095] Figure 6 - Cellular binding assay of control antibodies. As shown, control antibodies (anti-PD-1 and anti-PD-L1) block the binding of recombinant PD-1-Ig (phycoerythrin, PE, labeled) to LK35.2-hPD-L1 cells.

[0096] Figure 7 - Cellular binding assay of selected macrocyclic peptides of the present invention. As shown, the macrocyclic peptides block the binding of recombinant PD-1-Ig (PE labeled) to LK35.2-hPD-L1 cells.

[0097] Figure 8 - Biotinylated Compound No. 71/PD-L1 binding assay. As shown, the macrocyclic peptides Compound No. 99, 2, and 1 are able to block the binding of the biotinylated Compound No. 71 peptide to PD-L1 using the HTRF assay. These results suggest that these peptides bind to the same binding site.

[0098] Figure 9 - Biotinylated Compound No. 71/PD-L1 Binding Assay - Anti-PD-L1 Antibody. As shown, the anti-PD-L1 monoclonal antibody is capable of blocking the binding of biotinylated Compound No. 71 to PD-L1 using the HTRF assay. These results suggest that these peptides bind to the same binding site as the anti-PD-L1 monoclonal antibody.

[0099] Figures 10A-C - Both anti-PD-L1 antibody and peptides promote IFNγ secretion by CMV-specific T cells in a dose-dependent manner. The most robust response was generated by the PD-L1-directed antibody (MDX-1105) (Anti-PD-1 Ab#l, EC50 0.6nM; Figure 10A) followed by Compound #71 (EC50 300nM; Figure 10B), Compound #1 (EC50 400nM), Compound #2 (EC50 400nM), and Compound #99 (EC50 >10,000nM). The numerical EC50 results for MDX-1105 and Compound #71, Compound #1, Compound #2, and Compound #99 are shown in Figure 10C. These results suggest that PD-L1 binding of macrocyclic peptide inhibitors may enhance IFNγ release in a memory T cell population generated from prior exposure to a persistent antigen.

[00100] Figure 11 - Both anti-PD-L1 antibody and macrocyclic peptides promote IFNγ secretion by HIV-specific T cells in a dose-dependent manner. The mean number of IFNγ spot forming cells (SFC) per well was calculated from duplicate wells and any background present in unstimulated wells (<25 SFC) was subtracted. Data are also presented as the proportional increase relative to DMSO control treatment. Both anti-PD-L1 antibody and peptide increase IFNγ secretion by HIV-specific T cells responding to at least 1 of the 6 HIV-Gag antigen clusters. These results demonstrate that ligation of PD-L1 with a peptide inhibitor can enhance IFNγ release from the T cell population responding to an existing chronic viral infection, similar to anti-PD-L1 antibody.

[00101] According to the present invention, we have discovered peptides that specifically bind to PD-L1 and are capable of inhibiting the interaction of PD-L1 with PD-1 and CD80. These macrocyclic peptides exhibit an in vitro immunomodulatory efficacy that makes them therapeutic candidates for the treatment of various diseases including cancer and infectious diseases.

[00102] The terms "specific binding" or "bind specifically" refer to the interaction between a protein and a binding molecule, such as a compound or ligand. The interaction is dependent on the presence of a particular structure (i.e., an enzyme binding site, an antigenic determinant or epitope) on the protein that is recognized by the binding molecule. For example, if a compound has specific binding to the protein binding site "A", the presence of the compound in a reaction containing a protein including the A binding site, and a labeled peptide that specifically binds to the A binding site of the protein will reduce the amount of labeled peptide bound to the protein. In contrast, nonspecific binding of a compound to protein does not result in a concentration-dependent displacement of the labeled peptide from the protein.

[00103] Other embodiments include polypeptides comprising the following structures:

[00104] Another embodiment is a pharmaceutical composition comprising a polypeptide of formula I(a), I(b), I(c), II(a), II(b), III(a), III(b), IV, V, VI, or VII, or a peptide comprising at least one of the macrocyclic peptides described in this invention.

[00105] Another embodiment relates to a pharmaceutical combination comprising a polypeptide of formula I(a), I(b), I(c), II(a), II(b), III(a), III(b), IV, V, VI, or VII or a macrocyclic peptide described in this invention, and at least one therapeutic agent selected from the group consisting of an antimicrobial agent, an antiviral agent, an anticancer agent, an anti-diabetic agent, an anti-obesity agent, an antihypertensive agent, an antiatherosclerotic agent, and a lipid-lowering agent.

[00106] Another embodiment relates to a pharmaceutical combination of a polypeptide of formula I(a), I(b), I(c), II(a), II(b), III(a), III(b), IV, V, VI, or VII, or a macrocyclic peptide described in this invention, with another agent disclosed in this invention.

[00107] Another embodiment relates to a method for treating or delaying the progression or manifestation of cancer and/or virological disorders, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a polypeptide of formula I(a), I(b), I(c), II(a), II(b), III(a), III(b), IV, V, VI, or VII, or a macrocyclic peptide described in this invention.

[00108] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C.

[00109] The isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the unlabeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously modify biological, pharmacological, or pharmacokinetic properties.

[00110] An additional aspect of the subject matter described in this report is the use of the disclosed peptides as radiolabeled ligands for the development of ligand binding assays or for monitoring in vivo adsorption, metabolism, distribution, receptor binding or occupancy, or disposition of the compound. For example, a macrocyclic peptide described in this invention can be prepared using the radioactive isotope 125I and the resulting radiolabeled peptide can be used to develop a binding assay or for metabolism studies. Alternatively, and for the same purpose, a macrocyclic peptide described in this invention can be converted to a radiolabeled form by catalytic tritiation using methods known to those skilled in the art.

[00111] The macrocyclic peptides of the present invention can also be used as PET imaging agents by addition of a radioactive tracer using methods known to those skilled in the art.

[00112] Preferred peptides include at least one of the macrocyclic peptides offered in this invention and these peptides can be included in pharmaceutical compositions and combinations.

[00113] The definitions provided in this report apply, without limitation, to the terms used throughout this descriptive report, unless otherwise limited in specific cases.

[00114] Those skilled in the art of amino acid and peptide chemistry know that an amino acid includes a compound represented by the general structure: (t.n.: L- or Sa-amino acid (if R = H); D- or R-α-amino acid (if R = H).) where R and R' are as discussed in this report.

[00115] Unless otherwise indicated, the term "amino acid" as used in this report, alone or as part of another group, includes, without limitation, an amino group and a carboxyl group attached to the same carbon, called the "a" carbon, where R and/or R' may be a natural or unnatural side chain, including hydrogen. The absolute "S" configuration on the "a" carbon is commonly called the "L" or "natural" configuration. In the case where the "R" and "R"' (line) substituents are hydrogen, the amino acid is glycine and is not chiral.

[00116] The term "naturally occurring amino acid side chain" as used in this report refers to a side chain of any of the naturally occurring amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) usually in the S- configuration (i.e., the L-amino acid).

[00117] The term “non-naturally occurring amino acid side chain” as used herein refers to a side chain of any of the naturally occurring amino acids usually in the R- configuration (i.e., the D-amino acid) or to a group other than a naturally occurring amino acid side chain in the R- or S- configuration (i.e., D- or L-amino acid, respectively) selected from: C2-C7alkenyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxycarbonylC1-C3alkyl, C1-C7alkyl, C1-C3alkylsulfanylC1-C3alkyl, amidoC1-C3alkyl, aminoC1-C3alkyl, azaindolylC1-C3alkyl, benzothiazolylC1-C3alkyl, benzothienylC1-C3alkyl, benzyloxyC1-C3alkyl, carboxyC1-C3alkyl, C3-C6cycloalkylC1-C3alkyl, diphenylmethyl, furanylC1-C3alkyl, imidazolylC1-C3alkyl, naphthylC1-C3alkyl, pyridinylC1-C3alkyl, thiazolylC1-C3alkyl, thienylC1-C3alkyl; biphenylC1-C3alkyl where the biphenyl is optionally substituted with a methyl group; indolylC1-C3alkyl where the indolyl moiety is optionally substituted with a group selected from C1-C3alkyl, carboxyC1-C3alkyl, halo, hydroxy, and phenyl, where the phenyl is further optionally substituted with one, two, or three groups independently selected from C1-C3alkoxy, C1-C3alkyl, and halo; NRaRb(C1-C7alkyl), where Ra and Rb are independently selected from hydrogen, C2-C4alkenyloxycarbonyl, C1-C3alkyl, C1-C3alkylcarbonyl, C3-C6cycloalkylcarbonyl, furanylcarbonyl, and phenylcarbonyl. When the alkyl linker contains more than one carbon an additional NRaRb group may be in the chain; NRcRdcarbonylC1-C3alkyl, where Rc and Rd are independently selected from hydrogen, C1-C3alkyl, and triphenylmethyl; phenylC1-C3alkyl wherein the phenyl moiety is optionally substituted with one, two, three, four, or five groups independently selected from C1-C4alkoxy, C1-C4alkyl, C1-C3alkylsulfonylamino, amido, amino, aminoC1-C3alkyl, aminosulfonyl, carboxy, cyano, halo, haloC1-C3alkyl, hydroxy, -NC(H2)2, nitro, and -OP(O)(OH)2; and phenoxyC1-C3alkyl wherein the phenyl is optionally substituted with a C1-C3alkyl group.

[00118] The term "C2-C4alkenyl", as used in this report, refers to a straight or branched chain group of two to four carbon atoms containing at least one carbon-carbon double bond.

[00119] The term "C2-C7alkenyl", as used in this report, refers to a straight or branched chain group of two to seven carbon atoms containing at least one carbon-carbon double bond.

[00120] The term “C2-C4alkenyloxy” as used in this report refers to a C2-C4alkenyl group attached to the parent molecular moiety through an oxygen atom.

[00121] The term “C1-C3alkoxy,” as used in this report, refers to a C1-C3alkyl group attached to the parent molecular moiety through an oxygen atom.

[00122] The term “C1-C4alkoxy,” as used in this report, refers to a C1-C4alkyl group attached to the parent molecular moiety through an oxygen atom.

[00123] The term “C1-C6alkoxy,” as used in this report, refers to a C1-C6alkyl group attached to the parent molecular moiety through an oxygen atom.

[00124] The term "C1-C3alkoxyC1-C3alkyl", as used in this report, refers to a C1-C3alkoxy group attached to the parent molecular moiety through a C1-C3alkyl group.

[00125] The term "C1-C6alkoxycarbonyl", as used in this report, refers to a C1-C6alkoxy group attached to the parent molecular moiety through a carbonyl group.

[00126] The term "C1-C6alkoxycarbonylC1-C3alkyl", as used in this report, refers to a C1-C6alkoxycarbonyl group attached to the parent molecular moiety through a C1-C3alkyl group.

[00127] The term "C1-C3alkyl", as used in this report, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to three carbon atoms.

[00128] The term "C1-C4alkyl", as used in this report, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to four carbon atoms.

[00129] The term "C1-C6alkyl", as used in this report, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.

[00130] The term "C1-C3alkylcarbonyl", as used in this report, refers to a C1-C3alkyl group attached to the parent molecular moiety through a carbonyl group.

[00131] The term "C1-C3alkylsulfanyl", as used in this report, refers to a C1-C3alkyl group attached to the parent molecular moiety through a sulfur atom.

[00132] The term "C1-C3alkylsulfanylC1-C3alkyl", as used in this report, refers to a C1-C3alkylsulfanyl group attached to the parent molecular moiety through a C1-C3alkyl group.

[00133] The term "C1-C3alkylsulfonyl" as used in this report refers to a C1-C3alkyl group attached to the parent molecular moiety through a sulfonyl group.

[00134] The term "C1-C3alkylsulfonylamino", as used in this report, refers to a C1-C3alkylsulfonyl group attached to the parent molecular moiety through an amino group.

[00135] The term "starch" as used in this report refers to -C(O)NH2.

[00136] The term "C1-C3alkyl starch", as used in this report, refers to an amido group attached to the parent molecular moiety through a C1-C3alkyl group.

[00137] The term "amino" as used in this report refers to -NH2.

[00138] The term "aminoC1-C3alkyl", as used in this report, refers to an amino group attached to the parent molecular moiety through a C1-C3alkyl group.

[00139] The term "aminosulfonyl" as used in this report refers to an amino group attached to the parent molecular moiety through a sulfonyl group.

[00140] The term "azaindolylC1-C3alkyl", as used in this report, refers to an azaindolyl group attached to the parent molecular moiety through a C1-C3alkyl group. The azaindolyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00141] The term "benzothiazolylC1-C3alkyl" as used herein refers to a benzothiazolyl group attached to the parent molecular moiety through a C1-C3alkyl group. The benzothiazolyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00142] The term "benzothienylC1-C3alkyl" as used herein refers to a benzothienyl group attached to the parent molecular moiety through a C1-C3alkyl group. The benzothienyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00143] The term “benzyloxy,” as used in this report, refers to a benzyl group attached to the parent molecular moiety through an oxygen atom.

[00144] The term "benzyloxyC1-C3alkyl" as used in this report refers to a benzyloxy group attached to the parent molecular moiety through a C1-C3alkyl group.

[00145] The term "biphenylC1-C3alkyl" as used herein refers to a biphenyl group attached to the parent molecular moiety through a C1-C3alkyl group. The biphenyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00146] The term "carbonyl" as used in this report refers to -C(O)-.

[00147] The term "carboxy" as used in this report refers to -CO2H.

[00148] The term "carboxyC1-C3alkyl" as used in this report refers to a carboxy group attached to the parent molecular moiety through a C1-C3alkyl group.

[00149] The term "cyan" as used in this report refers to -CN.

[00150] The term "C3-C6cycloalkyl", as used in this report, refers to a saturated monocyclic hydrocarbon system having three to six carbon atoms and zero heteroatoms.

[00151] The term "C3-C6cycloalkylC1-C3alkyl", as used in this report, refers to a C3-C6cycloalkyl group attached to the parent molecular moiety through a C1-C3alkyl group.

[00152] The term "C3-C6cycloalkylcarbonyl", as used in this report, refers to a C3-C6 cycloalkyl group attached to the parent molecular moiety through a carbonyl group.

[00153] The term “furanylC1-C3alkyl”, as used in this report, refers to a furanyl group attached to the parent molecular moiety through a C1-C3alkyl group. The furanyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00154] The term "furanylcarbonyl", as used in this report, refers to a furanyl group attached to the parent molecular moiety through a carbonyl group.

[00155] The terms "halo" and "halogen" as used in this report refer to F, CI, Br, or I.

[00156] The term "haloC1-C3alkyl", as used in this report, refers to a C1-C3alkyl group substituted with one, two, or three halogen atoms.

[00157] The term "halomethyl", as used in this report, refers to a methyl group substituted with one, two, or three halogen atoms.

[00158] The term “hydroxy” as used in this report refers to -OH.

[00159] The term "imidazolylC1-C3alkyl", as used in this report, refers to an imidazolyl group attached to the parent molecular moiety through a C1-C3alkyl group. The imidazolyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00160] The term "indolylC1-C3alkyl", as used in this report, refers to an indolyl group attached to the parent molecular moiety through a C1-C3alkyl group. The indolyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00161] The term “naphthylC1-C3alkyl,” as used in this report, refers to a naphthyl group attached to the parent molecular moiety through a C1-C3alkyl group. The naphthyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00162] The term "nitro" as used in this report refers to -NO2.

[00163] The term "NRaRb", as used herein, refers to two groups, Ra and Rb, which are attached to the parent molecular moiety through a nitrogen atom. Ra and Rb are independently selected from hydrogen, C2-C4alkenyloxycarbonyl, C1-C3alkylcarbonyl, C3-C6cycloalkylcarbonyl, furanylcarbonyl, and phenylcarbonyl.

[00164] The term "NRaRb(C1-C3)alkyl", as used in this report, refers to an NRaRb group attached to the parent molecular moiety through a C1-C3alkyl group.

[00165] The term "NRcRd", as used herein, refers to two groups, Rc and Rd, which are attached to the parent molecular moiety through a nitrogen atom. Rc and Rd are independently selected from hydrogen, C1-C3alkyl, and triphenylmethyl.

[00166] The term "NRcRdcarbonyl" as used in this report refers to an NRcRd group attached to the parent molecular moiety through a carbonyl group.

[00167] The term "NRcRdcarbonylC1-C3alkyl" as used in this report refers to an NRcRdcarbonyl group attached to the parent molecular moiety through a C1-C3alkyl group.

[00168] The term “phenoxy,” as used in this report, refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.

[00169] The term "phenoxyC1-C3alkyl" as used in this report refers to a phenoxy group attached to the parent molecular moiety through a C1-C3alkyl group.

[00170] The term “phenylC1-C3alkyl” as used in this report refers to a phenyl group attached to the parent molecular moiety through a C1-C3alkyl group.

[00171] The term "phenylcarbonyl" as used in this report refers to a phenyl group attached to the parent molecular moiety through a carbonyl group.

[00172] The term “pyridinylC1-C3alkyl,” as used in this report, refers to a pyridinyl group attached to the parent molecular moiety through a C1-C3alkyl group. The pyridinyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00173] The term "sulfanyl" as used in this report refers to -S-.

[00174] The term "sulfonyl" as used in this report refers to -SO2-.

[00175] The term "thiazolylC1-C3alkyl" as used herein refers to a thiazolyl group attached to the parent molecular moiety through a C1-C3alkyl group. The thiazolyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00176] The term "thienylC1-C3alkyl" as used herein refers to a thienyl group attached to the parent molecular moiety through a C1-C3alkyl group. The thienyl group may be attached to the alkyl moiety through any substitutable atom in the group.

[00177] The term “treat” refers to: (i) preventing the occurrence of a disease, disorder, or condition in a patient who may be predisposed to the disease, disorder, and/or condition but who has not yet been diagnosed with it; (ii) inhibiting the disease, disorder, or condition, i.e., stopping its development; and (iii) alleviating the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition and/or symptoms associated with the disease, disorder, and/or condition.

[00178] Unless otherwise indicated, the term "alkyl" as used herein alone or as part of another group includes, but is not limited to, straight chain and branched chain hydrocarbons containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, among others.

[00179] In addition, alkyl groups as defined herein may be optionally substituted on any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to, alkyl, aryl, alkenyl, alkynyl, hydroxy, arylalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, arylalkyloxy, heteroaryloxy, heteroarylalkyloxy, alkanoyl, halo, hydroxyl, thio, nitro, cyano, carboxyl, carbonyl, carboxamido, amino, alkylamino, dialkylamino, amido, alkylamino, arylamido, heteroarylamido, azido, guanidino, amidino, phosphonic, phosphinic, sulfonic, sulfonamido, haloaryl, CF3, OCF2, OCF3, aryloxy, heteroaryl, cycloalkylalkoxyalkyl, cycloheteroalkyl among others to form alkyl groups such as trifluoromethyl 3-hydro, -xyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl, among others.

[00180] Unless otherwise indicated, the term "cycloalkyl" as used herein alone or as part of another group includes, but is not limited to, saturated or partially unsaturated cyclic hydrocarbon groups (containing 1 or 2 double bonds) containing 1 to 3 rings, attached or fused, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 7 carbons forming each ring; which may be fused to 1 aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, any of these groups may be optionally substituted on any available carbon atoms with 1 or more groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, oxo, cyano, carboxyl, carbonyl, carboxamido, amino, substituted amino where the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), amido, azido, guanidino, amidino, phosphonic, phosphinic, sulfonic, sulfonamido, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or any of the above-mentioned alkyl substituents.

[00181] The term "aryl" as used herein alone or as part of another group refers to, but is not limited to, monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl) and may optionally include one to three additional rings fused to the "aryl" (such as aryl, cycloalkyl, heteroaryl or heterocycloalkyl rings) and may be optionally substituted through any available carbon atoms with 1 or more groups selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, fluorenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, heteroarylalkyloxy, heteroarylalkyloxyalkyl, hydroxy, nitro, oxo, cyano, amino, substituted amino where the amino includes 1 or 2 substituents (which are alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyrylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heteroarylaminocarbonyl alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl, or any of the other alkyl substituents mentioned above.

[00182] The term "arylalkyl" as used herein alone or as part of another group refers, without limitation, to alkyl groups as defined above having an aryl substituent, such as benzyl, phenethyl or naphthylpropyl, where said aryl and/or alkyl groups may be optionally substituted as already defined above.

[00183] The term "alkoxy", "aryloxy", "heteroaryloxy", "arylalkyloxy", or "heteroarylalkyloxy" as used herein alone or as part of another group includes, but is not limited to, an alkyl or aryl group already defined above attached through an oxygen atom.

[00184] The term "heterocycle", "heterocycle", "heterocyclyl" or "heterocyclic", as used herein, represents, without limitation, a stable, unsubstituted or substituted, 4-, 5-, 6-, or 7-membered monocyclic ring system that may be saturated or unsaturated, and that consists of carbon atoms and one to four heteroatoms selected from nitrogen, sulfur, oxygen and/or an SO or SO2 group, where the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic ring may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, tetrahydrofuranoyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, piperazinyl, oxopyrrolidinyl, oxopiperazinyl, oxopiperidinyl, and oxadiazolyl. Optionally a heterocyclic group may be substituted with one or more functional groups, such as those described for "alkyl" or "aryl".

[00185] The term "heterocycloalkyl" as used herein alone or as part of another group refers, without limitation, to alkyl groups already defined above having a heterocycloalkyl substituent, where said "heterocycle" and/or alkyl groups may be optionally substituted as already defined above.

[00186] The term "heteroaryl" as used herein refers, without limitation, to a 5-, 6- or 7-membered aromatic heterocyclic ring containing one or more heteroatoms selected from nitrogen, sulfur, oxygen and/or a SO or SO2 group. Such rings may be fused to another aryl or heteroaryl ring and include possible N-oxides; examples of such heteroaryl groups include, but are not limited to, furan, pyrrole, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, isoxazole, oxazole, imidazole among others. Optionally a heteroaryl group may be substituted with one or more functional groups commonly attached to such chains, such as those described for "alkyl" or "aryl".

[00187] The term "heteroarylalkyl" as used in this report alone or as part of another group refers, without limitation, to alkyl groups already defined above having a heteroaryl substituent, where said heteroaryl and/or alkyl groups may be optionally substituted as already defined above.

[00188] The “inhibitory concentration” of PD-1/PD-L1 inhibitor means the concentration at which a compound screened in an assay of the invention inhibits a measurable percentage of the interaction of PD-1 with PD-L1. Exemplary “inhibitory concentration” values range from IC50 to IC90, and are preferably IC50, IC60, IC70, IC80, or IC90, which represent a 50%, 60%, 70%, 80%, or 90% reduction in PD-1/PD-L1 binding activity, respectively. More preferably, the “inhibitory concentration” is measured as the IC50 value. It is understood that another designation for IC50 is the half-maximal inhibitory concentration.

[00189] The binding of macrocyclic peptides to PD-L1 can be measured, for example, by methods such as homogeneous time-resolved fluorescence (HTRF), surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) spectroscopy, among others. In addition, the binding of macrocyclic peptides to PD-L1 expressed on the surface of cells can be measured as described in this report in cell binding assays.

[00190] Administration of a therapeutic agent described herein includes, but is not limited to, administration of a therapeutically effective amount of the therapeutic agent. The term "therapeutically effective amount" as used herein refers, without limitation, to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the PD-1/PD-L1 binding inhibitors described herein. Such an amount is an amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example and without limitation, treatment or prevention of the conditions listed herein. The exact effective amount for an individual will depend on the size and health of the individual, the nature and extent of the condition being treated, the recommendations of the treating physician, and the therapeutics and combinations of therapeutics selected for administration. Therefore, it is not convenient to specify in advance an exact effective amount.

[00191] The macrocyclic peptides of the present invention show potent PD-L1 binding activity in both HTRF and cellular binding assays. In addition, the macrocyclic peptides also demonstrate biological activity in CMV recall and HIV Elispot assays demonstrating their utility in the amelioration and/or treatment of hyperproliferative disorders such as cancer and virology indications including HIV.

[00192] In another aspect, the invention relates to methods for inhibiting tumor cell growth in a subject using the macrocyclic peptides of the present invention. As demonstrated in this report, the macrocyclic peptides of the present invention are capable of binding to PD-L1, disrupting the interaction between PD-L1 and PD-1, competing with PD-L1 binding with anti-PD-1 monoclonal antibodies that are known to block the interaction with PD-1, increasing IFNy secretion from CMV-specific T cells, and increasing IFNg secretion from HIV-specific T cells. As a result, the macrocyclic peptides of the present invention are useful for modifying an immune response, treating diseases such as cancer or infectious diseases, stimulating a protective autoimmune response, or stimulating antigen-specific immune responses (e.g., by co-administration of PD-L1 blocking peptides with an antigen of interest).

[00193] In order that the present invention may be more easily understood, certain terms are defined first. Additional definitions are set forth throughout the detailed description.

[00194] The terms "Programmed Death Ligand 1", "Programmed Cell Death Ligand 1", "PD-L1 Protein", "PD-L1", "PDL1", "PDCDL1", "hPD-L1", "hPD-L1", "CD274" and "B7-H1" are used interchangeably, and include variants, isoforms, species homologs of human PD-L1, and analogs having at least one epitope in common with PD-L1. The complete sequence of PD-L1 can be found in GENBANK® Accession No. NP_054862.

[00195] The terms "Programmed Death 1", "Programmed Cell Death 1", "PD-1 Protein", "PD-1", "PD1", "PDCD1", "hPD-1" and "hPD-I" are used interchangeably, and include variants, isoforms, species homologs of human PD-1, and analogs having at least one epitope in common with PD-1. The complete sequence of PD-1 can be found in GENBANK® Accession No. U64863.

[00196] The terms "cytotoxic T-lymphocyte-associated antigen-4", "CTLA-4", "CTLA4", "CTLA-4 antigen", and "CD 152" (see, e.g., Murata, Am. J. Pathol, 155:453-460 (1999)) are used interchangeably, and include variants, isoforms, species homologs of human CTLA-4, and analogs having at least one epitope in common with CTLA-4 (see, e.g., Balzano, Int. J. Cancer Suppl, 7:28-32 (1992)). The complete nucleic acid sequence of CTLA-4 can be found in GENBANK® Accession No. LI 5006.

[00197] The term "immune response" refers to the action of, for example, lymphocytes, antigen-presenting cells, phagocytic cells, granulocytes, soluble macromolecules produced by the above cells or by the liver (including macrocyclic peptides, cytokines, and complement) that results in selective damage, destruction, or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancerous cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.

[00198] A “signal transduction pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in transmitting a signal from one portion of a cell to another portion of a cell. As used herein, the term “cell surface receptor” includes, for example, molecules and complexes of molecules capable of receiving a signal and transmitting such a signal across the plasma membrane of a cell. An example of a “cell surface receptor” of the present invention is the PD-1 receptor.

[00199] The term "macrocyclic peptide derivatives" refers to any modified form of the macrocyclic peptides disclosed in this invention, e.g., mutations, isoforms, peptides with altered linker backbones, conjugates with an antibody and/or another agent, etc.

[00200] As used herein, a macrocyclic peptide of the present invention that “specifically binds to human PD-L1” refers to a macrocyclic peptide that binds to human PD-L1 with an IC50 of less than about 200 nM, less than about 150 nM, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 40 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, or less. In this context, the term “about” should be interpreted as any value between ± 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nM greater or less than the cited amount.

[00201] The term "treatment" or "therapy" refers to the administration of an active agent for the purpose of curing, healing, alleviating, ameliorating, altering, remedying, ameliorating, benefiting, or affecting the condition (e.g., a disease), the symptoms of the condition, or preventing or delaying the manifestation of the symptoms, complications, biochemical signs of a disease, or even stopping or inhibiting the development of the disease, condition, or disorder in a statistically significant manner.

[00202] An "adverse event" (AE) as used herein is any generally unexpected, even undesirable, unfavorable sign, symptom, or condition (including an abnormal laboratory finding) associated with the use of a medical treatment. For example, an adverse event may be associated with the activation of the immune system or expansion of immune system cells (e.g., T cells) in response to a treatment. A medical treatment may have one or more associated AEs, and each AE may have the same level of severity or different levels of severity. Reference to methods capable of "altering adverse events" means a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

[00203] As used herein, "hyperproliferative disease" refers to conditions in which cell growth is increased relative to normal levels. For example, hyperproliferative diseases or disorders include malignant diseases (e.g., esophageal cancer, colon cancer, biliary cancer) and nonmalignant diseases (e.g., atherosclerosis, benign hyperplasia, and benign prostatic hypertrophy).

[00204] As used in this report, "about" or "comprising essentially" means within an acceptable range of error for the particular value as determined by one skilled in the art, which will depend in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" or "comprising essentially" may mean within one or more standard deviations by practice in the art. Alternatively, "about" or "comprising essentially" may mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the terms may mean up to an order of magnitude or up to 5 times a value. When particular values are given in the application and claims, unless otherwise indicated, the meaning of "about" or "comprising essentially" should be interpreted as ranging within an acceptable range of error for that particular value.

[00205] As described in this report, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the stated range, and where appropriate, fractions thereof (such as one tenth or one hundredth of an integer), unless otherwise indicated.

Competition Trials

[00206] The present invention also relates to macrocyclic peptides that are capable of competing with the binding of a reference anti-PD-L1 antibody (MDX-1105) by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100%. Such macrocyclic peptides may share structural homology with one or more macrocyclic peptides disclosed in this invention, including mutant, conservative substitution, functional substitution, and deletion forms, as long as they specifically bind to PD-L1. For example, if a macrocyclic peptide binds to substantially the same region of PD-L1 as a reference anti-PD-L1 antibody, the macrocyclic peptide should bind to an epitope of PD-L1 that at least overlaps with the PD-L1 epitope to which the anti-PD-L1 monoclonal antibody binds. The region of overlap can range from one amino acid residue to several hundred amino acid residues. The macrocyclic peptide should then compete with and/or block the binding of the anti-PD-L1 monoclonal antibody to PD-L1 and thereby decrease the binding of the anti-PD-L1 monoclonal antibody to PD-L1, preferably by at least about 50% in a competition assay (see Figure 9).

[00207] Anti-PD-L1 antibodies that can be used as reference antibodies for competition assay purposes are known in the literature. For example, the following representative anti-PD-L1 antibodies can be used: MDX-1105 (BMS); L01X-C (Serono), L1X3 (Serono), MSB-0010718C (Serono), and PD-L1 Probody (CytomX), and the PD-L1 antibodies disclosed in WO 2007/005874 under the same co-ownership.

[00208] Anti-PD-1 antibodies that can be used as reference antibodies for competition assay purposes are known in the literature. For example, the following representative anti-PD-1 antibodies can be used: nivolumab (BMS); 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4 all of which are disclosed in co-owned U.S. Patent No. 8,008,449 (BMS); MK-3475 (Merck, disclosed in U.S. Patent No. 8,168,757); and the antibodies disclosed in U.S. Patent No. 7,488,802.

Variant Macrocyclic Peptides

[00209] In yet another embodiment, a macrocyclic peptide of the invention comprises amino acid sequences that are homologous to the amino acid sequences of the macrocyclic peptides described in this invention, and where the macrocyclic peptides retain the desired functional and/or biological properties of the macrocyclic peptide of the invention.

[00210] For example, the invention provides a macrocyclic peptide, or a binding accessory portion thereof, comprising: an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the compounds described herein; and the macrocyclic peptide exhibits one or more of the following properties: (a) the macrocyclic peptide binds to human PD-L1 with an IC50 of 200 nM or less; (b) the macrocyclic peptide does not substantially bind to human CD28, CTLA-4, or ICOS; (c) the macrocyclic peptide increases IFNγ secretion from CMV-specific T cells; (d) the macrocyclic peptide increases IFNγ secretion from HIV-specific T cells; (e) the macrocyclic peptide binds to human PD-1 and one or more of the following: cynomolgus monkey PD-1; woodchuck PD-1, and/or mouse PD-1; (f) the macrocyclic peptide inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (g) the macrocyclic peptide is capable of competing with the binding of anti-PD-1 monoclonal antibodies, including nivolumab (BMS-936558, MDX-1106); (h) the macrocyclic peptide inhibits tumor cell growth in a cellular assay and/or in an in vivo assay; and/or (i) the macrocyclic peptide inhibits HIV in a cellular assay and/or in an in vivo assay.

[00211] In other embodiments, the amino acid sequences of the macrocyclic peptide can be about 80%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the sequences set forth above. In this context, the term "about" should be interpreted as any value between plus or minus 1, 2, 3, 4, or 5 percent of the recited amount. A macrocyclic peptide of the present invention having sequences with high identity (i.e., 80% or more) to the sequences presented above can be obtained by mutating the sequences during chemical synthesis, for example, followed by testing the altered macrocyclic peptide for conserved function (i.e., the functions presented in items (a) to (i) above) using the functional assays described herein. The biological and/or functional activity of the amino acid sequences of the variant macrocyclic peptide can be at least about 1x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, or 10x greater than that of the reference macrocyclic peptide on which the variant is based. In this context, the term “about” should be interpreted as any value between plus or minus 0.1x, 0.2x, 0.3x, 0.4x, 0.5x, 0.6x, 0.7x, 0.8x, or 0.9x the quantity cited.

[00212] As used in this report, the percentage homology between two amino acid sequences is equivalent to the percentage identity between the two sequences. The percentage identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions / # total positions. times. 100), taking into account the number of gaps, and the length of each gap, which needs to be introduced for optical alignment of the two sequences. The comparison of sequences and the determination of the percentage identity between the two sequences can be done using a mathematical algorithm, as described in the non-limiting examples below.

[00213] The percent identity between two amino acid sequences can be determined using the algorithm of Meyers E. et al., (Comput. Appl. BioscL, 4: 11-17 (1988)) which was incorporated into the ALIGN program (version 2.0), using a “PAM120 weight residue table”, a “gap length penalty” of 12 and a “gap penalty” of 4. Furthermore, the percent identity between the two amino acid sequences can be determined using the algorithm of Needleman et al. (J. Mol. Biol., 48:444-453 (1970)) that was incorporated into the GAP program in the GCG® software package (available at www.gcg.com), using a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[00214] Macrocyclic Peptides with Conservative Modifications

[00215] In yet another embodiment, a macrocyclic peptide of the invention comprises amino acid sequences that are homologous to the amino acid sequences of the macrocyclic peptides described in this invention, and where the macrocyclic peptides retain the desired functional and/or biological properties of the macrocyclic peptide of the invention.

[00216] For example, the invention provides a macrocyclic peptide, or antigen-binding portion thereof, comprising: an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the macrocyclic peptides described herein, wherein one or more amino acids have been replaced with a conservative amino acid; and the macrocyclic peptide exhibits one or more of the following properties: (a) the macrocyclic peptide binds to human PD-L1 with an IC50 of 200 nM or less; (b) the macrocyclic peptide does not substantially bind to human CD28, CTLA-4, or ICOS; (c) the macrocyclic peptide increases IFNγ secretion from CMV-specific T cells; (d) the macrocyclic peptide increases IFNγ secretion from HIV-specific T cells; (e) the macrocyclic peptide binds to human PD-L1 and one or more of the following: cynomolgus monkey PD-L1; woodchuck PD-L1, and/or mouse PD-L1; (f) the macrocyclic peptide inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (g) the macrocyclic peptide is capable of competing with the binding of anti-PD-1 monoclonal antibodies, including nivolumab (BMS-936558, MDX-1106); (h) the macrocyclic peptide inhibits tumor cell growth in a cellular assay and/or in an in vivo assay; and/or (i) the macrocyclic peptide inhibits HIV in a cellular assay and/or in an in vivo assay.

[00217] As used in this report, the term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the macrocyclic peptide containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody of the invention by traditional techniques known in the literature, such as peptide amidite substitution during chemical synthesis, site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which the amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have already been defined in the literature. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Accordingly, one or more amino acid residues within the antigen-binding regions of the macrocyclic peptides of the invention may be replaced with other amino acid residues from the same side chain family, and the altered antibody may be tested for conserved function (i.e., the functions set forth in items (a) through (i) above) using the functional assays described herein. Conservative amino acid substitutions may also be selected from one or more non-naturally occurring amino acids described in this report. Pharmaceutical compositions

[00218] The invention also relates to the polypeptides described in this report where the sequence comprises one or more amino acid deletions either from the C-terminus or the N-terminus.

[00219] In preferred embodiments, the following N-terminal Compound No. 99 deletion polypeptides are encompassed by the present invention: X1-X13, X2-X13, X3-X13, X4-X13, X5-X13, X6-X13, X7X13, X8-X13, X9-X13, X10-X13, X11-X13, and/or X12-X13 of Compound No. 99, where each X is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00220] In preferred embodiments, the following C-terminal Compound No. 99 deletion polypeptides are encompassed by the present invention: X1-X13, X1-X12, X1-X11, X1-X10, X1-X9, X1-X8, X1-X7, X1-X6, X1-X5, X1-X4 and/or X1-X3 of Compound No. 99, where each X is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00221] In preferred embodiments, the following N-terminal Compound No. 1 deletion polypeptides are encompassed by the present invention: X1-X15, X2-X15, X3-X15, X4-X15, X5-X15, X6-X15, X7-X15, X8-X15, X9-X15, X10-X15, X11-X15, and/or X12-X15 of Compound No. 1, where each L is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00222] In preferred embodiments, the following C-terminal Compound No. 1 deletion polypeptides are encompassed by the present invention: X1-X15, X1-X14, X1-X13, X1-X12, X1-X11, X1-X10, X1-X9, X1-X8, X1-X7, X1-X6, X1-X5, X1-X4 and/or X1-X3 of Compound No. 1, where each X is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00223] In preferred embodiments, the following N-terminal Compound No. 71 deletion polypeptides are encompassed by the present invention: X1-X14, X2-X14, X3-X14, X4-X14, X5-X14, X6-X14, X7X14, X8-X14, X9-X14, X10-X14, X1-X14, and/or X12-X14 of Compound No. 71, where each X is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00224] In preferred embodiments, the following C-terminal Compound No. 71 deletion polypeptides are encompassed by the present invention: X1-X14, X1-X13, X1-X12, X1-X11, X1-X10, X1-X9, X1-X8, X1-X7, X1-X6, X1-X5, X1-X4 and/or X1-X3 of Compound No. 71, where each X is representative of an amino acid at the indicated position for each peptide disclosed herein. The present invention also encompasses cyclic forms of these deletion mutants using the ligation chemistries described elsewhere herein.

[00225] In another aspect, the present invention provides a composition, e.g., a pharmaceutical composition, containing a macrocyclic peptide or a combination of macrocyclic peptides, or antigen-binding portions thereof, of the present invention, formulated together with a pharmaceutically acceptable carrier. Such compositions may include a macrocyclic peptide or a combination of (e.g., two or more) different macrocyclic peptides, or immunoconjugates or bispecific molecules of the invention. For example, a pharmaceutical composition of the invention may comprise a combination of macrocyclic peptides (or immunoconjugates or bispecific molecules) that bind to different epitopes on the target antigen or that have complementary activities.

[00226] The pharmaceutical compositions of the invention may also be administered in combination therapy, i.e., combined with other agents. For example, combination therapy may include a macrocyclic peptide combined with at least one anti-inflammatory or immunosuppressive agent. Examples of therapeutic agents that may be used in combination therapy are described in more detail below in the section on uses of the macrocyclic peptides of the invention.

[00227] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, among others, that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound, i.e., a macrocyclic peptide, immunoconjugate, or bispecific molecule, may be coated with a material to protect the compound against the action of acids and other natural conditions that may inactivate the compound.

[00228] The pharmaceutical compounds of the invention may include one or more pharmaceutically acceptable salts. A “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesirable toxicological effects (see, e.g., Berge, S.M. et al., J. Pharm. Sep., 66: 1-19 (1977)). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, among others, as well as from non-toxic organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, alkanoic hydroxy acids, aromatic acids, and aliphatic and aromatic sulfonic acids, among others. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, and calcium, among others, as well as from non-toxic organic amines such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, among others.

[00229] A pharmaceutical composition of the invention may also include a pharmaceutically acceptable antioxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, among others; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, among others; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, among others.

[00230] Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, among others), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00231] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the presence of microorganisms may be ensured both by sterilization procedures, above, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, among others. It may be desirable to include isotonic agents, such as sugars, sodium chloride, among others in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be caused by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[00232] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the literature. Except to the extent that any conventional media or agent is incompatible with the active compound, its use in the pharmaceutical compositions of the invention is contemplated. Supplemental active compounds may also be incorporated into the compositions.

[00233] Therapeutic compositions should typically be sterile and stable under the conditions of production and storage. The composition may be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high concentration of the drug. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, among others), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of injectable compositions may be caused by the inclusion of an agent that delays absorption, for example, monostearate salts and gelatin.

[00234] Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in an appropriate solvent with a principal or combination of principals enumerated above, as required, followed by sterilization by microfiltration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying (lyophilization) which produce a powder of the active principal plus any additional principal desired from a previously sterile filtered solution thereof.

[00235] The amount of active ingredient that can be combined with a carrier material to produce an individual dosage form will vary depending on the individual being treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce an individual dosage form will generally be that amount of the composition that produces a therapeutic effect. Generally, at one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent active ingredient, preferably from about 0.1 percent to about 70 percent, more preferably from about 1 percent to about 30 percent active ingredient in combination with a pharmaceutically acceptable carrier.

[00236] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as dictated by the demands of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the dosage unit forms of the invention are dictated by and directly dependent upon (a) the unique characteristics of the active compound and the particular therapeutic effect to be obtained, and (b) the inherent limitations in the art of compounding such active compound for the treatment of sensitivity in subjects.

[00237] For administration of the macrocyclic peptide, the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of host body weight. For example, dosages may be 0.3 mg/kg of body weight, 1 mg/kg of body weight, 3 mg/kg of body weight, 5 mg/kg of body weight, or 10 mg/kg of body weight, or range from 1 to 10 mg/kg. An exemplary treatment regimen entails administration once daily, twice weekly, three times weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, once every 3 months, or once every three to 6 months. Preferred dosage regimens for a macrocyclic peptide of the invention include 1 mg/kg of body weight or 3 mg/kg of body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six doses, then every three months; (ii) every three weeks; (iii) 3 mg/kg of body weight once followed by 1 mg/kg of body weight every three weeks.

[00238] In some methods, two or more macrocyclic peptides with different binding specificities are administered simultaneously, in which case the dosage of each compound administered is within the ranges indicated. The compounds are usually administered on multiple occasions. The intervals between individual dosages may be, for example, weekly, monthly, quarterly or yearly. The intervals may also be irregular as indicated by measurement of blood levels of macrocyclic peptide for the target antigen in the patient. In some methods, the dosage is adjusted to achieve a plasma antibody concentration of about 1-1000 μg/ml and in some methods about 25300 μg/ml.

[00239] Alternatively, the macrocyclic peptide may be administered as a systematic release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the macrocyclic peptide in the patient. Dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively sporadic intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until disease progression is slowed or halted, and preferably until the patient shows partial or complete improvement in disease symptoms. Thereafter, the patient may be placed on a prophylactic regimen.

[00240] The effective dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied in order to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The dosage level selected will depend on a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compositions, the age, sex, weight, condition, general health and past medical history of the patient being treated, and similar factors well known in the medical arts.

[00241] A “therapeutically effective dosage” of a macrocyclic peptide of the invention preferably results in a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or a prevention of disability or incapacity due to the disease. For example, for the treatment of tumors, a “therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth and/or HIV can be assessed in an animal model system predictive of efficacy in human tumors or viral efficacy. Alternatively, this property of a composition can be assessed by examining the compound's ability to inhibit such inhibition in vitro by assays known to one of skill in the art. A therapeutically effective amount of a therapeutic compound may decrease tumor size, decrease viral load, or otherwise improve symptoms in an individual. One of skill in the art will be able to determine such amounts based on factors such as the size of the individual, the severity of the individual's symptoms, and the particular composition or route of administration selected.

[00242] In another aspect, the present invention provides a pharmaceutical kit of parts comprising a macrocyclic peptide and an anti-CTLA-4 antibody as described herein. The kit may also comprise instructions for use in the treatment of a hyperproliferative disease (such as cancer as described herein) and/or antiviral disease.

[00243] A composition of the present invention may be administered by one or more routes of administration using one or more of a variety of methods known in the literature. As will be appreciated by one skilled in the art, the route and/or mode of administration will vary depending on the desired results. Preferred routes of administration for the macrocyclic peptides of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The term "parenteral administration" as used in this report means modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[00244] Alternatively, a macrocyclic peptide of the invention may be administered by a non-parenteral route, such as a topical, epidermal or mucosal route of administration, e.g., intranasal, oral, vaginal, rectal, sublingual or topical.

[00245] The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are proprietary or generally known to those skilled in the art. See, for example, Robinson, J.R., ed., Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, Inc., New York (1978).

[00246] The therapeutic compositions can be administered with medical devices known in the literature. For example, in a preferred embodiment, a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of well-known implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable microinfusion pump for dispensing drug at a controlled rate; U.S. Patent No. 4,486,194, which discloses a therapeutic device for administering drug through the skin; U.S. Patent No. 4,447,233, which discloses a drug infusion pump for delivering drug at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable-flow implantable infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Patent No. 4,475,196, which discloses an osmotic drug delivery system. These patents are incorporated herein by reference. Many other such implants, delivery systems, and modules are known to those skilled in the art.

[00247] In certain embodiments, the macrocyclic peptides of the invention can be formulated to ensure proper delivery in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB (if desired), they can be formulated, for example, into liposomes. For methods of producing liposomes, see, for example, U.S. Patent Nos. 4,522,811, 5,374,548, and 5,399,331. The liposomes can comprise one or more moieties that are selectively transported to specific cells or organs, thereby enhancing the delivery of specific drugs (see, for example, Ranade, V.V., J. Clin. Pharmacol, 29:685 (1989)). Exemplary vectoring moieties include folate or biotin (see, e.g., U.S. Pat. No. 5,416,016 to Low et al.); mannosides (Umezawa et al., Biochem. Biophys. Res. Commun., 153 : 1038 (1988)); macrocyclic peptides (Bloeman, P. G. et al., FEBS Lett., 357 : 140 (1995); Owais, M. et al., Antimicrob. Agents Chemother., 39 : 180 (1995)); surfactant protein A receptor (Briscoe et al., Am. J. Physiol, 1233 : 134 (1995)); p120 (Schreier et al., J. Biol Chem., 269 : 9090 (1994)); see also Keinanen, K. et al., FEBS Lett., 346: 123 (1994); Killion, J. J. et al., Immunomethods 4:273 (1994).

Uses and Methods of the Invention

[00248] The macrocyclic peptides, compositions, and methods of the present invention have numerous in vitro and in vivo utilities involving, for example, detection of PD-L1 or enhancement of the immune response by blocking PD-L1. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, for example, in vivo, to enhance immunity in a variety of situations. Accordingly, in one aspect, the invention provides a method of modifying an immune response in a subject comprising administering to the subject the antibody, or antigen-binding portion thereof, of the invention so that the immune response in the subject is modified. Preferably, the response is enhanced, stimulated, or upregulated. In other aspects, the macrocyclic peptide has anti-cynomolgus, anti-mouse, and/or anti-woodchuck binding activity.

[00249] As used herein, the term "subject" is intended to include both human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, marmots, amphibians, and reptiles, although mammals, such as non-human primates, sheep, dogs, cats, cows, and horses, are preferred. Preferred subjects include human patients in need of enhancing an immune response. The methods are particularly suited to treating human patients having a disorder that can be treated by enhancing the T-cell-mediated immune response. In a particular modality, the methods are particularly suited to treating cancer cells in vivo. To achieve an enhancement of antigen-specific immunity, the macrocyclic peptides can be administered together with an antigen of interest. When macrocyclic peptides for PD-L1 are administered together with another agent, the two can be administered in any order or simultaneously.

[00250] The invention further provides methods for detecting the presence of human, woodchuck, cynomolgus, and/or mouse PD-L1 antigen in a sample, or measuring the amount of human, woodchuck, cynomolgus, and/or mouse PD-L1 antigen, comprising contacting the sample, and a control sample, with a reference monoclonal antibody, or an antigen-binding portion thereof, that specifically binds to human, woodchuck, cynomolgus, and/or mouse PD-L1, under conditions that allow for the formation of a complex between the antibody or portion thereof and human, woodchuck, cynomolgus, and/or mouse PD-L1. The formation of a complex is then detected, where a different complex formation between the sample compared to the control sample is indicative of the presence of human, woodchuck, cynomolgus, and/or mouse PD-L1 antigen in the sample.

[00251] Given the specific binding of the macrocyclic peptides of the invention to PD-L1, compared to CD28, ICOS and CTLA-4, the macrocyclic peptides of the invention can be used to specifically detect the expression of PD-L1 on the surface of cells and, further, they can be used to purify PD-L1 via immunoaffinity purification.

Cancer

[00252] Blockade of PD-1 by macrocyclic peptides may enhance the immune response to cancer cells in the patient. The ligand for PD-1, PD-L1, is not expressed on normal human cells but is abundant on a variety of human cancers (Dong et al., Nat. Med., 8:787-789 (2002)). The interaction between PD-1 and PD-L1 results in a decrease in tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune evasion by cancer cells (Dong et al., J. Mol. Med., 81:281-287 (2003); Blank et al., Cancer Immunol. Immunother., 54:307-314 (2005); Konishi et al., Clin. Cancer Res., 10:5094-5100 (2004)). Immune suppression can be reversed by inhibiting the interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked (Iwai et al., Proc. Natl. Acad. Sep, 99: 12293-12297 (2002); Brown et al., J. Immunol, 170: 1257-1266 (2003)). Although previous studies have shown that T cell proliferation can be restored by inhibiting the interaction of PD-1 with PD-L1, there are no reports of a direct effect on the growth of cancerous tumors in vivo by blocking the PD-1/PD-L1 interaction. In one aspect, the present invention relates to treating a subject in vivo using a macrocyclic peptide so that the growth of cancerous tumors is inhibited. A macrocyclic peptide can be used alone to inhibit the growth of cancerous tumors. Alternatively, a macrocyclic peptide may be used in conjunction with other immunogenic agents, traditional cancer treatments, or other macrocyclic peptides, as described below.

[00253] Accordingly, in one embodiment, the invention provides a method for inhibiting the growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of a macrocyclic peptide, or antigen-binding portion thereof.

[00254] Preferred cancers whose growth can be inhibited using the macrocyclic peptides of the invention include cancers typically responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cell carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma and castration-resistant prostate cancer), breast cancer, colorectal cancer, and lung cancer (e.g., squamous and non-squamous non-small cell lung cancer). Additionally, the invention includes refractory and recurrent malignancies whose growth can be inhibited using the macrocyclic peptides of the invention.

[00255] Examples of other cancers that may be treated using the methods of the invention include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer/gastric cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemias include acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic, solid tumors of childhood, lymphocytic lymphoma, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The present invention is also useful for treating metastatic cancers, especially metastatic cancers expressing PD-L1 (Iwai et al., Int. Immunol, 17: 133-144 (2005)).

[00256] Optionally, the macrocyclic peptides for PD-L1 can be combined with an immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines (He et al., J. Immunol, 173:4919-4928 (2004)). Non-limiting examples of tumor vaccines that can be used include peptides from melanoma antigens, such as gp100 peptides, MAGE, Trp-2, MARTI, and/or tyrosinase antigens, or tumor cells transfected to express the cytokine GM-CSF (discussed later).

[00257] In humans, some tumors have been shown to be immunogenic such as melanomas. It has been predicted that by increasing the threshold for T cell activation by blocking PD-L1, we might expect to activate tumor responses in the host.

[00258] It is possible that PD-L1 blockade may be more effective when combined with a vaccination protocol. Many experimental strategies for tumor vaccination have been devised (see Rosenberg, S., Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62 (2000); Logothetis, C, ASCO Educational Book Spring: 300-302 (2000); Khayat, D., ASCO Educational Book Spring: 414-428 (2000); Foon, K., ASCO Educational Book Spring: 730-738 (2000); see also Restifo, N. et al., Cancer Vaccines, Chapter 61, pp. 3023-3043, in DeVita, V. et al., eds., Cancer. Principles and Practice of Oncology, Fifth Edition (1997)). In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent antigen presentation activator for tumor vaccination (Dranoff et al., Proc. Natl. Acad. Sci. USA, 90: 3539-3543 (1993)).

[00259] The study of gene expression and gene expression patterns on a large scale in various tumors has led to the definition of so-called tumor-specific antigens (Rosenberg, S.A., Immunity, 10:281-287 (1999)). In many cases, these tumor-specific antigens are differentiation antigens expressed on the tumors and on the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. Most importantly, it is possible to show that these antigens are targets of tumor-specific T cells found in the host. Blockade of PD-L1 can be used in conjunction with a collection of recombinant proteins and/or peptides expressed on a tumor to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self-antigens and are therefore tolerant to them. Tumor antigen may also include the protein telomerase, which is required for the synthesis of chromosome telomeres and is expressed in over 85% of human cancers and in only a limited number of somatic tissues (Kim, N. et al., Science, 266:2011-2013 (1994)). (These somatic tissues can be protected from immune attack by a variety of means.) Tumor antigen may also be "neoantigens" expressed on cancer cells because of somatic mutations that alter the protein sequence or create fusion proteins between two unrelated sequences (i.e., bcr-abl on the Philadelphia chromosome), or idiotypes from B-cell tumors.

[00260] Other tumor vaccines may include proteins from viruses involved in human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Another form of tumor-specific antigen that may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSPs) isolated from tumor tissue itself. These heat shock proteins contain protein fragments from tumor cells, and these HSPs are highly efficient at delivering to antigen-presenting cells to elicit tumor immunity (Suot, R. et al., Science, 269: 1585-1588 (1995); Tamura, Y. et al., Science, 278: 117-120 (1997)).

[00261] Dendritic cells (DCs) are potent antigen-presenting cells that can be used to elicit antigen-specific responses. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al., Nat. Med., 4:328-332 (1998)). DCs can also be genetically transduced to express these tumor antigens. DCs have also been fused directly to tumor cells for immunization purposes (Kugler, A. et al., Nat. Med., 6:332-336 (2000)). As a method of vaccination, immunization with DCs can be effectively combined with PD-L1 blockade to elicit more potent antitumor responses.

[00262] PD-L1 blockade can also be combined with traditional cancer treatments. PD-L1 blockade can be effectively combined with chemotherapeutic regimens. In these cases, it may be possible to reduce the dose of the chemotherapeutic reagent administered (Mokyr, M. et al., Cancer Res., 58:5301-5304 (1998)). An example of such a combination is a macrocyclic peptide in combination with decarbazine for the treatment of melanoma. Another example of such a combination is a macrocyclic peptide in combination with interleukin-2 (IL-2) for the treatment of melanoma. The scientific basis behind the combined use of PD-L1 blockade and chemotherapy is that cell death, which is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may synergize with PD-L1 blockade through cell death include radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors can also be combined with PD-L1 blockade. Inhibition of angiogenesis leads to the death of tumor cells that can feed tumor antigen into the host antigen presentation pathways.

[00263] PD-L1 blocking macrocyclic peptides can also be used in combination with bispecific macrocyclic peptides that target effector cells expressing the Fc alpha or Fc gamma receptor to tumor cells (see, e.g., U.S. Patent Nos. 5,922,845 and 5,837,243).

[00264] Bispecific macrocyclic peptides can be used to target two separate antigens. For example, bispecific macrocyclic peptides for anti-Fc receptor/anti-tumor antigen (e.g., Her-2/neu) have been used to target macrophages to tumor sites. Such targeting may more effectively activate tumor-specific responses. The T cell arm of these responses would be enhanced by the use of PD-L1 blockade. Alternatively, antigen can be delivered directly to DCs by the use of bispecific macrocyclic peptides that bind to both the tumor antigen and a cell surface marker specific for dendritic cells.

[00265] Tumors escape host immune surveillance by a wide variety of mechanisms. Many of these mechanisms can be overcome by inactivation of proteins that are expressed by tumors and that are immunosuppressive. These include, among others, TGF-beta (Kehrl, J. et al., J. Exp. Med., 163: 1037-1050 (1986)), IL-10 (Howard, M. et al., Immunology Today, 13: 198-200 (1992)), and Fas ligand (Hahne, M. et al., Science, 274: 1363-1365 (1996)). Macrocyclic peptides for each of these entities can be used in combination with anti-PD-L1 to neutralize the effects of the immunosuppressive agent and favor immune responses against the tumor by the host.

[00266] Other macrocyclic peptides that can be used to activate host immune responsiveness can be used in combination with anti-PD-L1. These include molecules on the surface of dendritic cells that activate DC function and antigen presentation. Anti-CD40 macrocyclic peptides are able to effectively substitute for T cell helper activity (Ridge, J. et al., Nature, 393:474-478 (1998)) and can be used in conjunction with antibodies to PD-1 (Ito, N. et al., Immunobiology, 201(5):527-540 (2000)). Activating macrocyclic peptides for T cell costimulatory molecules such as CTLA-4 (e.g., U.S. Patent No. 5,811,097), OX-40 (Weinberg, A. et al., Immunol, 164:2160-2169 (2000)), 4-IBB (Melero, I. et al., Nat. Med., 3:682-685 (1997), and ICOS (Hutloff, A. et al., Nature, 397:262-266 (1999)) can also be used to provide increased levels of T cell activation.

[00267] Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. Although graft-versus-host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft-versus-tumor responses. Blockade of PD-L1 may be used to enhance the efficacy of engrafted donor tumor-specific T cells.

[00268] There are also several experimental treatment protocols that involve activation and expansion of antigen-specific T cells ex vivo and adoptive transfer of these cells into tumor antigen-specific T cell recipients (Greenberg, R. et al., Science, 285:546-551 (1999)). These methods can also be used to activate T cell responses to infectious agents such as CMV. Ex vivo activation in the presence of macrocyclic peptides might be expected to increase the frequency and activity of adoptively transferred T cells.

Infectious Diseases

[00269] Other methods of the invention are used to treat patients who have been exposed to particular toxins or pathogens. Accordingly, another aspect of the invention provides a method for treating an infectious disease in a subject comprising administering to the subject a macrocyclic peptide of the present invention, or antigen-binding portion thereof, so that the subject is treated for the infectious disease. Preferably, the antibody is a human anti-human PD-L1 macrocyclic peptide (such as any of the macrocyclic peptides described herein). Additionally or alternatively, the antibody may be a chimeric or humanized antibody.

[00270] Similar to its applications to tumors as discussed above, antibody-mediated PD-L1 blockade can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are not completely effective. ve. These include, but are not limited to, HIV, Hepatitis (A, B, and C), Influenza, Herpes, Giardia, Malaria (Butler, N.S. et al., Nature Immunology, 13: 188-195 (2012); Hafalla, J.C.R., et al., PLOS Pathogens (February 2, 2012)), Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa. PD-L1 blockade is particularly useful against established infections with agents such as HIV that present antigens that change during the course of the infection. These new epitopes are recognized as foreign upon administration of human anti-PD-L1, thus eliciting a strong T cell response that is not inhibited by negative signals through PD-L1.

[00271] Some examples of pathogenic viruses that cause infections treatable by the methods of the invention include HIV, hepatitis (A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenoviruses, influenza viruses, flaviviruses, echoviruses, rhinoviruses, coxsackieviruses, cornoviruses, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillary virus, molluscum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[00272] Some examples of bacteria that cause infections treatable by the methods of the invention include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria.

[00273] Some examples of pathogenic fungi that cause infections treatable by the methods of the invention include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[00274] Some examples of pathogenic parasites that cause infections treatable by the methods of the invention include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[00275] In all of the above methods, PD-L1 blockade may be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, agents vectoring VEGF activity or VEGF receptors, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provide increased presentation of tumor antigens (see, e.g., Holliger, Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993); Poljak, Structure, 2: 11211123 (1994)).

[00276] Autoimmune Reactions

[00277] Macrocyclic peptides can elicit and amplify autoimmune responses.

[00278] Indeed, induction of antitumor responses using tumor cell and peptide vaccines reveals that many antitumor responses involve anti-self reactivities (depigmentation observed in anti-CTLA-4+GM-CSF-modified B16 melanoma in van Elsas et al., supra; depigmentation in Trp-2-vaccinated mice (Overwijk, W. et al., Proc. Natl. Acad. Sci. USA, 96:2982-2987 (1999)); autoimmune prostatitis caused by TRAMP tumor cell vaccines (Hurwitz, A., supra (2000)); vaccination against melanoma peptide antigen and vitiligo observed in human clinical trials (Rosenberg, S. A. et al., J. Immunother. Emphasis Tumor Immunol, 19(l):81-84 (1996)).

[00279] Therefore, it is also possible to consider using anti-PD-L1 blockade in conjunction with various self-proteins to design vaccination protocols to efficiently generate immune responses against these self-proteins for the treatment of diseases. For example, Alzheimer's disease involves the inappropriate accumulation of the A.beta peptide in amyloid deposits in the brain; antibody responses against amyloid are capable of clearing these amyloid deposits (Schenk et al., Nature, 400: 173-177 (1999)).

[00280] Other self proteins may also be targeted such as IgE for the treatment of allergy and asthma, and TNF. Alpha for rheumatoid arthritis. Finally, antibody responses to various hormones may be induced by the use of the macrocycles disclosed in this invention.

[00281] Neutralizing antibody responses to reproductive hormones can also be used for contraception.

[00282] Neutralizing antibody responses to hormones and other soluble factors that are necessary for the growth of particular tumors may also be considered possible vaccination targets.

[00283] Analogous methods described above for use of the anti-PD-L1 macrocycles may be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self antigens, such as amyloid deposits, including A.beta in Alzheimer's disease, cytokines such as TNF.alpha, and IgE.

Vaccines

[00284] Macrocyclic peptides can be used to stimulate antigen-specific immune responses by co-administration of an anti-PD-1 macrocycle with an antigen of interest (e.g., a vaccine). Accordingly, in another aspect the invention provides a method for enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) an anti-PD-1 macrocycle, or antigen-binding portion thereof, so that an immune response to the antigen in the subject is enhanced. The antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen, or an antigen from a pathogen. Non-limiting examples of such antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria, or other pathogens described above.

[00285] Suitable routes for administering the compositions (e.g., macrocyclic peptides, multispecific and bispecific molecules, and immunoconjugates) of the invention in vivo and in vitro are well known in the literature and can be selected by those skilled in the art. For example, the compositions can be administered by injection (e.g., intravenously or subcutaneously). Suitable dosages of the molecules used will depend on the age and weight of the individual and the concentration and/or formulation of the composition.

[00286] As previously described, the macrocyclic peptides of the invention may be co-administered with one or more other therapeutic agents, for example, a cytotoxic agent, a radiotoxic agent, or an immunosuppressive agent. The peptide may be linked to the agent (as an immune complex) or may be administered separately from the agent. In the latter case (separate administration), the peptide may be administered before, after, or concomitantly with the agent, or may be co-administered with other known therapies, for example, an anticancer therapy, e.g., radiation. Such therapeutic agents include, but are not limited to, antineoplastic agents such as doxorubicin (Adriamycin), cisplatin, bleomycin sulfate, carmustine, chlorambucil, decarbazine, and cyclophosphamide hydroxyurea, which, alone, are effective only at levels that are toxic or subtoxic to a patient. Cisplatin is administered intravenously as 100 mg/ml dose once every four weeks and adriamycin is administered intravenously as a 60-75 mg/ml dose once every 21 days. Coadministration of the macrocyclic peptides, or antigen-binding fragments thereof, of the present invention with chemotherapeutic agents provides two anticancer agents that operate via different mechanisms that produce a cytotoxic effect to human tumor cells. Such coadministration may solve problems due to the development of drug resistance or a change in the antigenicity of the tumor cells that would render them unreactive with the peptides.

[00287] Also within the scope of the present invention are kits comprising compositions of the invention (e.g., macrocyclic peptides, bispecific or multispecific molecules, or immunoconjugates) and instructions for use. The kit may further contain at least one additional reagent, or one or more additional macrocyclic peptides of the invention (e.g., a human antibody having a complementarity activity that binds to an epitope on the PD-L1 antigen distinct from the macrocycle). The kits include a label indicating the intended use of the kit contents. The term label includes any written or engraved material provided on or with the kit, or otherwise accompanying the kit.

Combination therapy

[00288] The combination of the macrocyclic peptides of the present invention with another PD-L1 antagonist and/or CTLA-4 antagonist is useful for enhancing an immune response against a hyperproliferative disease by blocking PD-L1 and CTLA-4. For example, these molecules can be administered to cells in culture, in vitro or ex vivo, or to human subjects, e.g., in vivo, to enhance immunity in various situations. Accordingly, in one aspect, the invention provides a method for modifying an immune response in a subject comprising administering to the subject a combination of antibodies, or a combination of antigen-binding portions thereof, of the invention so that the immune response in the subject is modified. Preferably, the response is enhanced, stimulated, or upregulated. In another embodiment, the present invention provides a method for altering adverse events associated with the treatment of a hyperproliferative disease with an immunostimulatory therapeutic agent, comprising administering a macrocyclic peptide of the present invention and a subtherapeutic dose of anti-CTLA-4 antibody to a subject.

[00289] Blockade of PD-L1 and CTLA-4 by macrocyclic peptides may enhance the immune response to cancer cells in the patient. Cancers whose growth may be inhibited using the macrocyclic peptides of the present invention include cancers typically responsive to immunotherapy. Representative examples of cancers for treatment with the combination therapy of the present invention include melanoma (e.g., metastatic malignant melanoma), kidney cancer, prostate cancer, breast cancer, colon cancer, and lung cancer. Examples of other cancers that may be treated using the methods of the present invention include bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid gland cancer, parathyroid gland cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphoma lymphocytic, bladder cancer, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The present invention is also useful for treating metastatic cancers.

[00290] In certain embodiments, the combination of therapeutic agents containing at least one macrocyclic peptide discussed herein can be administered concomitantly as a single composition in a pharmaceutically acceptable carrier, or concomitantly as separate compositions where each agent can be administered sequentially. For example, an anti-CTLA-4 antibody and a macrocyclic peptide of the present invention can be administered sequentially, such as the anti-CTLA-4 being administered first and the macrocyclic peptide second, or the macrocyclic peptide being administered first and anti-CTLA-4 second. Furthermore, if more than one dose of the combination therapy is administered sequentially, the order of sequential administration can be reversed or maintained in the same order on each administration occasion, sequential administrations can be combined with concomitant administrations, or any combination thereof. For example, the first administration of a combination of anti-CTLA-4 antibody and macrocyclic peptide may be concomitant, the second administration may be sequential with anti-CTLA-4 first and macrocyclic peptide second, and the third administration may be sequential with macrocyclic peptide first and anti-CTLA-4 second, etc. Another representative dosing schedule may involve a first administration that is sequential with macrocyclic peptide first and anti-CTLA-4 second, and subsequent administrations may be concomitant.

[00291] Optionally, the combination of the macrocyclic peptide and the anti-CTLA-4 agent can be further combined with an immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulatory cytoximes (He et al., J. Immunol, 173:4919-4928 (2004)). Non-limiting examples of tumor vaccines that can be used include peptides from melanoma antigens, such as gp100 peptides, MAGE, Trp-2, MARTI, and/or tyrosinase antigens, or tumor cells transfected to express the cytokine GM-CSF (discussed later).

[00292] A combination of PD-L1 macrocyclic peptide and CTLA-4 blockade can be further combined via a vaccination protocol. Many experimental strategies for tumor vaccination have already been devised (see Rosenberg, S., Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62 (2000); Logothetis, C, ASCO Educational Book Spring: 300-302 (2000); Khayat, D., ASCO Educational Book Spring: 414-428 (2000); Foon, K., ASCO Educational Book Spring: 730-738 (2000); see also Restifo et al., Cancer Vaccines, Chapter 61, pp. 3023-3043 in DeVita et al., eds., Cancer. Principles and Practice of Oncology, Fifth Edition (1997)). In one of these strategies, a vaccine is prepared using autologous or allogeneic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent antigen presentation activator for tumor vaccination (Dranoff et al., Proc. Natl. Acad. Sci. USA, 90:3539-3543 (1993)).

[00293] The study of gene expression and gene expression patterns on a large scale in various tumors has led to the definition of so-called tumor-specific antigens (Rosenberg, Immunity, 10:281287 (1999)). In many cases, these tumor-specific antigens are differentiation antigens expressed on tumors and the cell from which the tumor arose, for example melanocyte antigens gp100, MAGE antigens, and Trp-2. Most importantly, it is possible to show that these antigens are targets of tumor-specific T cells found in the host. In certain embodiments, a combination of PD-L1 macrocyclic peptide and CTLA-4 blockade using the antibody compositions described herein can be used in conjunction with a collection of recombinant proteins and/or peptides expressed on a tumor to generate an immune response to these proteins. These proteins are normally viewed by the immune system as self-antigens and are therefore tolerant to them. Tumor antigen may also include the protein telomerase, which is required for the synthesis of chromosome telomeres and is expressed in over 85% of human cancers and in only a limited number of somatic tissues (Kim, N. et al., Science, 266:2011-2013 (1994)). (These somatic tissues can be protected from immune attack by a variety of means.) Tumor antigen may also be "neoantigens" expressed on cancer cells because of somatic mutations that alter the protein sequence or create fusion proteins between two unrelated sequences (i.e., bcr-abl on the Philadelphia chromosome), or idiotypes from B-cell tumors.

[00294] Other tumor vaccines may include proteins from viruses involved in human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Another form of tumor-specific antigen that may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSPs) isolated from tumor tissue itself. These heat shock proteins contain protein fragments from tumor cells, and these HSPs are highly efficient at delivery to antigen-presenting cells to elicit tumor immunity (Suot, R. et al., Science, 269: 1585-1588 (1995); Tamura, Y. et al., Science, 278: 117-120 (1997)).

[00295] Other tumor vaccines may include proteins from viruses involved in human cancers such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Another form of tumor-specific antigen that may be used in conjunction with PD-L1 macrocyclic peptide blockade is purified heat shock proteins (HSPs) isolated from the tumor tissue itself. These heat shock proteins contain protein fragments from tumor cells, and these HSPs are highly efficient at delivery to antigen-presenting cells to elicit tumor immunity (Suot, R. et al., Science, 269: 1585-1588 (1995); Tamura, Y. et al., Science, 278: 117-120 (1997)).

[00296] Dendritic cells (DC) are potent antigen-presenting cells that can be used to elicit antigen-specific responses. DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al., Nat. Med., 4:328-332 (1998)).

[00297] DCs can also be genetically transduced to express these tumor antigens. DCs have also been fused directly to tumor cells for immunization purposes (Kugler et al., Nat. Med., 6:332-336 (2000)). As a vaccination method, DC immunization can be effectively combined with a combination of PD-L1 macrocyclic peptide and CTLA-4 blockade to activate more potent antitumor responses.

[00298] A combination of anti-PD-L1 macrocyclic peptide and CTLA-4 blockade may also be further combined with traditional cancer treatments. For example, a combination of macrocyclic peptide and CTLA-4 blockade may be effectively combined with chemotherapeutic regimens. In such cases, as is seen with the combination of a macrocyclic peptide and an anti-CTLA-4 agent, it may be possible to reduce the dose of the chemotherapeutic reagent administered with the combination of the present invention (Mokyr et al., Cancer Res., 58:5301-5304 (1998)). An example of such a combination is a combination of a macrocyclic peptide and an anti-CTLA-4 agent in further combination with decarbazine for the treatment of melanoma. Another example is a combination of a macrocyclic peptide and an anti-CTLA-4 agent in combination with interleukin-2 (IL-2) for the treatment of melanoma. The scientific basis behind the combined use of a macrocyclic peptide PD-L1 and CTLA-4 blockade with chemotherapy is that cell death, which is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway. Other combination therapies that may synergize with a combination of a macrocyclic peptide anti-PD-L1 and CTLA-4 blockade through cell death include radiation, surgery, or hormone deprivation. Each of these protocols creates a source of tumor antigen in the host. Angiogenesis inhibitors can also be combined with PD-L1 and CTLA-4 blockade. Inhibition of angiogenesis leads to tumor cell death, which may also be a source of tumor antigen to be introduced into the host antigen presentation pathway.

[00299] A combination of PD-L1 and CTLA-4 blocking agents may also be used in combination with bispecific macrocyclic peptides that target effector cells expressing the Fc.alpha or Fc.gamma receptor to tumor cells (see, e.g., U.S. Patent Nos. 5,922,845 and 5,837,243). Bispecific macrocyclic peptides may be used to target two separate antigens. For example, bispecific macrocyclic peptides for anti-Fc receptor/anti-tumor antigen (e.g., Her-2/neu) have previously been used to target macrophages to tumor sites. Such targeting may more effectively activate tumor-specific responses. The T cell arm of these responses would be enhanced by the use of combined PD-L1 and CTLA-4 blockade. Alternatively, antigen can be delivered directly to DCs by the use of bispecific macrocyclic peptides that bind to tumor antigen and a cell surface marker specific for dendritic cells.

[00300] In another example, a combination of a macrocyclic peptide and an anti-CTLA-4 agent can be used in combination with macrocyclic antineoplastic agents, such as RITUXAN® (ri-tuximab), HERCEPTIN® (trastuzumab), BEXXAR® (tositumomab), ZEVALIN® (ibritumomab), CAMPATH® (alemtuzumab), Lymphocide (eprtuzumab), AVASTIN® (bevacizumab), and TARCEVA® (erlotinib), among others. By way of example and without wishing to be bound by theory, treatment with an anticancer agent or with an anticancer antibody conjugated to a toxin can lead to the death of cancer cells (e.g., tumor cells) that would potentiate an immune response mediated by CTLA-4 or PD-L1. In an exemplary embodiment, treatment of a hyperproliferative disease (e.g., a cancerous tumor) may include an anti-cancer antibody in combination with a macrocyclic peptide and anti-CTLA-4 agents, concomitantly or sequentially, or any combination thereof, which may potentiate an immune response against the tumor by the host.

[00301] Tumors escape host immune surveillance by a wide variety of mechanisms. Many of these mechanisms can be overcome by inactivation of proteins that are expressed by tumors and that are immunosuppressive. These include, among others, TGF-beta (Kehrl, J. et al., J. Exp. Med., 163: 1037-1050 (1986)), IL-10 (Howard, M. et al., Immunology Today, 13: 198-200 (1992)), and Fas ligand (Hahne, M. et al., Science, 274: 1363-1365 (1996)). In another example, antibodies to each of these entities can be further combined with a combination of macrocyclic peptide and anti-CTLA-4 to neutralize the effects of immunosuppressive agents and favor immune responses against the tumor by the host.

[00302] Other agents that can be used to activate host immune responsiveness can further be used in combination with a macrocyclic peptide of the present invention. These include molecules on the surface of dendritic cells that activate DC function and antigen presentation. Anti-CD40 macrocyclic peptides are capable of effectively overriding T cell helper activity (Ridge, J. et al., Nature, 393:474-478 (1998)) and can be used in conjunction with the macrocyclic peptides of the present invention, either alone or in combination with an anti-CTLA-4 combination (Ito, N. et al., Immunobiology, 201(5):527-540 (2000)). Macrocyclic peptides activating T cell costimulatory molecules such as OX-40 (Weinberg, A. et al., Immunol, 164:2160-2169 (2000)), 4-IBB (Melero, I. et al., Nat. Med., 3:682-685 (1997), and ICOS (Hutloff, A. et al., Nature, 397:262-266 (1999)) can also be used to provide increased levels of T cell activation.

[00303] Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. Although graft-versus-host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft-versus-tumor responses. A macrocyclic peptide of the present invention, either alone or in combination with CTLA-4 blockade, may be used to enhance the efficacy of engrafted donor tumor-specific T cells.

[00304] There are also several experimental treatment protocols that involve activation and expansion of antigen-specific T cells ex vivo and adoptive transfer of these cells into tumor antigen-specific T cell recipients (Greenberg, R. et al., Science, 285:546-551 (1999)). These methods can also be used to activate T cell responses to infectious agents such as CMV. Ex vivo activation in the presence of a macrocyclic peptide of the present invention, either alone or in combination with an anti-CTLA-4 antagonist, can be expected to increase the frequency and activity of the adoptively transferred T cells.

[00305] In certain embodiments, the present invention provides a method of altering an adverse event associated with the treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a macrocyclic peptide of the present invention in combination with a subtherapeutic dose of an anti-CTLA-4 antibody to a subject. For example, the methods of the present invention provide a method of reducing the incidence of immunostimulatory therapeutic antibody-induced colitis or diarrhea by administering a non-absorbable steroid to the patient. Because any patient who is to receive an immunostimulatory therapeutic antibody is at risk of developing colitis or diarrhea induced by such treatment, this entire patient population is suitable for therapy according to the methods of the present invention. Although steroids are administered to treat inflammatory bowel disease (IBD) and prevent exacerbations of IBD, they have not yet been used to prevent (reduce the incidence of) IBD in patients who have not been diagnosed with IBD. The significant side effects associated with steroids, even nonabsorbable steroids, have discouraged their prophylactic use.

[00306] In other embodiments, a macrocyclic peptide of the present invention, either alone or in combination with CTLA-4 blockade, may be further combined with the use of any non-absorbable steroid. As used herein, a “non-absorbable steroid” is a glucocorticoid that exhibits extensive first-pass metabolism such that, subsequent to metabolism in the liver, the bioavailability of the steroid is low, i.e., less than about 20%. In one embodiment of the invention, the non-absorbable steroid is budesonide. Budesonide is a locally acting glucocorticosteroid that is extensively metabolized, primarily in the liver, subsequent to oral administration. ENTOCORT® EC (Astra-Zeneca) is a pH- and time-dependent oral formulation of budesonide designed to optimize drug delivery to the ileum and throughout the colon. ENTOCORT® EC has been approved in the United States for the treatment of mild to moderate Crohn's disease involving the ileum and/or ascending colon. The usual oral dosage of ENTOCORT® EC for the treatment of Crohn's disease is 6 to 9 mg/day. ENTOCORT® EC is released in the intestine before being absorbed and retained in the intestinal mucosa. After it crosses the target intestinal mucosal tissue, ENTOCORT® EC is extensively metabolized by the P450 chromosome system in the liver to metabolites with negligible glucocorticoid activity. Consequently, bioavailability is low (approximately 10%). The low bioavailability of budesonide results in an improved therapeutic ratio compared with other glucocorticoids with less extensive first-pass metabolism. Budesonide results in fewer adverse effects, including less hypothalamic-pituitary suppression, than systemically acting corticosteroids. However, chronic administration of ENTOCORT® EC may result in systemic glucocorticoid effects such as hypercorticism and adrenal suppression. See Physicians' Desk Reference Supplement, 58th Edition, 608-610 (2004).

[00307] In still other embodiments, a combination of PD-L1 and CTLA-4 blockade (i.e., anti-PD-L1 and anti-CTLA-4 immunostimulatory therapeutic macrocyclic peptides) in conjunction with a non-absorbable steroid can be further combined with a salicylate. Salicylates include 5-ASA agents such as, for example: sulfasalazine (AZULFIDI E®, Pharmacia &Upjohn); olsalazine (DIPENTUM®, Pharmacia &UpJohn); balsalazide (COLAZAL®, Salix Pharmaceuticals, Inc.); and mesalamine (ASACOL®, Procter & Gamble Pharmaceuticals; PENTASA®, Shire US; CANASA®, Axcan Scandipharm, Inc.; ROWASA®, Solvay).

Dosage and Formulation

[00308] A suitable peptide of formula I, or more specifically a macrocyclic peptide described in this invention, can be administered to patients to treat diabetes and other related diseases as the compound alone and/or mixed with an acceptable carrier in the form of pharmaceutical formulations. Those skilled in the art of treating diabetes can readily determine the dosage and route of administration of the compound for mammals, including humans, in need of such treatment. The route of administration can include, but is not limited to, oral, intraoral, rectal, transdermal, buccal, intranasal, pulmonary, subcutaneous, intramuscular, intradermal, sublingual, intracolonic, intraocular, intravenous, or intestinal administration. The compound is formulated according to the route of administration based on acceptable pharmacy practice (Fingl et al., in The Pharmacological Basis of Therapeutics, Chapter 1, p. 1 (1975); Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA (1990)).

[00309] The pharmaceutically acceptable peptide compositions described herein may be administered in multiple dosage forms such as tablets, capsules (each including systemic release formulations or timed release formulations), pills, powders, granules, elixirs, in situ gels, microspheres, crystalline complexes, liposomes, microemulsions, tinctures, suspensions, syrups, aerosol sprays, and emulsions. The compositions described herein may also be administered in an oral, intravenous (bolus or infusion), intraperitoneal, subcutaneous, transdermal, or intramuscular form, all using dosage forms well known to those skilled in the pharmaceutical arts. The compositions may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and traditional pharmaceutical practice.

[00310] The dosage regimen for the compositions described in this invention will naturally vary depending on known factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the type of concomitant treatment; the frequency of treatment; the route of administration; the renal and hepatic function of the patient; and the desired effect. The physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counteract, or arrest the progression of the pathological condition.

[00311] As a general guide, the daily oral dosage of the active ingredient when used for the indicated purposes will range from about 0.001 to 1000 mg/kg body weight, preferably from about 0.01 to 100 mg/kg body weight per day, and most preferably from about 0.6 to 20 mg/kg/day. Intravenously, the daily dosage of the active ingredient when used for the indicated purposes will range from 0.001 ng to 100.0 ng per min/per kg body weight by constant rate infusion. Such constant intravenous infusion may preferably be administered at a rate of 0.01 ng to 50 ng per min per kg body weight and more preferably at a rate of 0.01 ng to 10.0 mg per min per kg body weight. The compositions described in this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily. The compositions described in this invention may also be administered by a depot formulation that will allow for the systematic release of the drug over a period of days/weeks/months, as desired.

[00312] The compositions described herein may be administered in an intranasal form via the topical use of suitable intranasal vehicles, or by transdermal routes using transdermal patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous and not intermittent during the dosage regimen.

[00313] The compositions are administered in a mixture with diluents, excipients, or pharmaceutical carriers (collectively referred to in this report as pharmaceutical carriers) appropriately selected for the intended form of administration, i.e., oral tablets, capsules, elixirs, aerosol sprays generated with or without propellant, and syrups, and consistent with conventional pharmaceutical practices.

[00314] For example, for oral administration in the form of a tablet or capsule, the active drug component may be combined with a pharmaceutically acceptable, non-toxic, oral inert carrier such as, but not limited to, lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, and sorbitol; for oral administration in liquid form, the oral drug components may be combined with any pharmaceutically acceptable, non-toxic, oral inert carrier such as, but not limited to, ethanol, glycerol, and water. Additionally, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may also be incorporated into the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as, but not limited to, glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, and waxes. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride.

[00315] Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, and xanthan gum.

[00316] The compositions described in this invention may also be administered in the form of mixed micellar or liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. Permeation enhancers may be added to improve drug absorption.

[00317] Since prodrugs are known to improve numerous desirable qualities of drugs (i.e., solubility, bioavailability, production, etc.), the compounds described herein may be delivered in prodrug form. Accordingly, the subject matter described herein is intended to cover prodrugs of the compounds claimed herein, methods of delivery thereof, and compositions containing the same.

[00318] The compositions described in this invention can also be coupled with soluble polymers as vectorizable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compositions described in this invention can be combined with a class of biodegradable polymers useful for obtaining controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and cross-linked or amphipathic block copolymers of hydrogels.

[00319] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 0.01 milligram to about 500 milligrams of active ingredient per dosage unit. In such pharmaceutical compositions the active ingredient will normally be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[00320] Gelatin capsules may contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, and stearic acid. Similar diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as time-release products to provide continuous release of the drug over a period of hours. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[00321] Liquid dosage forms for oral administration may contain coloring and flavoring agents to enhance patient acceptance.

[00322] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. A solution for parenteral administration preferably contains a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium deta are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[00323] Suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company (1995), a standard reference text in this field.

[00324] Representative pharmaceutical dosage forms useful for administering the compounds described in this invention can be illustrated as follows:

Capsules

[00325] A large number of unit capsules can be prepared by filling two-part hard gelatin capsules with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

Soft Gelatin Capsules

[00326] A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected into gelatin by means of a positive displacement pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

[00327] Tablets may be prepared by conventional procedures so that the dosage unit has, for example, 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectables

[00328] An injectable formulation of a peptide composition described in this invention may or may not require the use of excipients such as those that have already been approved by regulatory agencies. Such excipients include, but are not limited to, solvents and co-solvents, solubilizing agents, emulsifiers or thickeners, chelating agents, antioxidants and reducing agents, antimicrobial preservatives, buffers and pH adjusting agents, bulking agents, protectants and tonicity adjusting agents, and special additives. An injectable formulation must be sterile, pyrogen-free, and, in the case of solutions, free of particulate matter.

[00329] A parenteral composition suitable for administration by injection may be prepared by stirring, for example, 1.5% by weight of active ingredient in a pharmaceutically acceptable buffer which may or may not contain a co-solvent or other excipient. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

[00330] An aqueous suspension may be prepared for oral and/or parenteral administration so that, for example, each 5 mL contains 100 mg of finely divided active ingredient, 20 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin or other palatable flavoring.

Biodegradable Microparticles

[00331] A systemically released parenteral composition suitable for administration by injection can be prepared, for example, by dissolving a suitable biodegradable polymer in a solvent, adding to the polymer solution the active agent to be incorporated, and removing the solvent from the matrix thereby forming the polymer matrix with the active agent distributed throughout the matrix.

Peptide Synthesis

[00332] The macrocyclic peptides of the present invention can be produced by methods known in the literature, such as they can be synthesized chemically, recombinantly in a cell-free system, recombinantly in a cell, or they can be isolated from a biological source. Chemical synthesis of a macrocyclic peptide of the present invention can be done using a variety of art-recognized methods, including stepwise solid phase synthesis, semisynthesis via conformationally assisted religation of peptide fragments, enzyme ligation of cloned or synthetic peptide segments, and chemical ligation. A preferred method for synthesizing the macrocyclic peptides and analogs thereof described in this invention is chemical synthesis using various solid phase techniques such as those described in Chan, W.C. et al., eds., Fmoc Solid Phase Synthesis, Oxford University Press, Oxford (2000); Barany, G. et al., The Peptides: Analysis, Synthesis, Biology, Vol. 2: "Special Methods in Peptide Synthesis, Part A", pp. 3-284, Gross, E. et al., eds., Academic Press, New York (1980); and in Stewart, J.M. et al., Solid-Phase Peptide Synthesis, 2nd Edition, Pierce Chemical Co., Rockford, IL (1984). The preferred strategy relies on the Fmoc (9-Fluorenylmethyl methyloxycarbonyl) group for temporary protection of the α-amino group, in combination with the tert-butyl group for temporary protection of the amino acid side chains (see for example Atherton, E. et al., "The Fluorenylmethoxycarbonyl Amino Protecting Group", in The Peptides: Analysis, Synthesis, Biology, Vol. 9: "Special Methods in Peptide Synthesis, Part C", pp. 138, Undenfriend, S. et al., eds., Academic Press, San Diego (1987).

[00333] Peptides can be synthesized stepwise on an insoluble polymer support (also called a "resin") starting from the C-terminus of the peptide. A synthesis is initiated by attaching the C-terminal amino acid of the peptide to the resin through the formation of an amide or ester bond. This allows for the eventual release of the resulting peptide as a C-terminal amide or carboxylic acid, respectively.

[00334] It is necessary that the C-terminal amino acid and all other amino acids used in the synthesis have their α-amino and side chain functional groups (if present) protected in different ways so that the α-amino protecting group can be selectively removed during synthesis. Coupling of an amino acid is done by activating its carboxyl group as an active ester and reacting it with the unblocked α-amino group of the N-terminal amino acid attached to the resin. The sequence of deprotection and coupling of the α-amino groups is repeated until the entire peptide sequence is assembled. The peptide is then released from the resin with concomitant deprotection of the side chain functionalities, usually in the presence of appropriate scavengers to limit side reactions. The resulting peptide is finally purified by reversed-phase HPLC.

[00335] The synthesis of the peptidyl resins required as precursors to the final peptides utilizes commercially available cross-linked polystyrene polymer resins (Novabiochem, San Diego, CA; Applied Biosystems, Foster City, CA). Preferred solid supports are: 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetyl-p-methyl benzhydrylamine resin (Rink's MBHA amide resin); 9-Fmoc-amino-xanthen-3-yloxy-Merrifield resin (Sieber's amide resin); 4-(9-Fmoc)aminomethyl-3,5-dimethoxyphenoxy)valeryl-aminomethyl-Merrifield resin (PAL resin), for C-terminal carboxamides. Coupling of the first amino acid and subsequent amino acids can be done using HOBt, 6-Cl-HOBt or HOAt active esters produced from DIC/HOBt, HBTU/HOBt, BOP, PyBOP, or from DIC/6-Cl-HOBt, HCTU, DIC/HOAt or HATU, respectively. Preferred solid supports are 2-Chlorotrityl chloride resin and 9-Fmoc-amino-xanthen-3-yloxy-Merrifield resin (Sieber amide resin) for protected peptide fragments. Loading of the first amino acid onto the 2-chlorotrityl chloride resin is best achieved by reacting the Fmoc-protected amino acid with the resin in dichloromethane and DIEA. If necessary, a small amount of DMF can be added to facilitate dissolution of the amino acid.

[00336] The syntheses of the peptide analogs described in this invention can be done using a single-channel or multi-channel peptide synthesizer, such as a CEM Liberty Microwave synthesizer, or a Prelude (6-channel) or Symphony (12-channel) Protein Technologies, Inc. synthesizer. Fmoc-derived amino acids are shown below. Examples of orthogonally protected amino acids used in solid phase synthesis

[00337] The peptidyl resin precursors to their respective peptides can be cleaved and deprotected using any traditional procedure (see, e.g., King, D.S. et al., Int. J. Peptide Protein Res., 36:255-266 (1990)). One desired method is the use of TFA in the presence of water and TIS as scavengers. Typically, the peptidyl resin is shaken in TFA/water/TIS (94:3:3, v:v:v; 1 mL/100 mg peptidyl resin) for 2-6 hours at room temperature. The spent resin is then removed by filtration and the TFA solution is concentrated or dried under reduced pressure. The resulting crude peptide is either precipitated and washed with Et2O or directly redissolved in DMSO or 50% aqueous acetic acid for preparative HPLC purification.

[00338] Peptides of the desired purity can be obtained by purification using preparatory HPLC, for example, on a Waters Model 4000 or a Shimadzu Model LC-8A liquid chromatograph. The crude peptide solution is injected onto a YMC S5 ODS column (20 x 100 mm) and eluted with a linear gradient of MeCN in water, both buffered with 0.1% TFA, using a flow rate of 14-20 mL/min with monitoring of the effluent by UV absorbance at 220 nm. The structures of the purified peptides can be confirmed by electrospray MS analysis.

[00339] A list of the non-naturally occurring amino acids mentioned in this report is given below.

[00339] The following abbreviations are used in the examples and elsewhere in this report: Ph = phenyl Bn = benzyl i-Bu = iso-butyl i-Pr = iso-propyl Me = methyl Et = ethyl Pr = n-propyl Bu = n-butyl t-Bu = tert-butyl Trt = trityl TMS = trimethylsilyl TIS = triisopropylsilane Et20 = diethyl ether HOAc or AcOH = acetic acid MeCN or AcCN = acetonitrile DMF = N,N-dimethylformamide EtOAc = ethyl acetate THF = tetrahydrofuran TFA = trifluoroacetic acid TFE = α,α,α-trifluoroethanol Et2NH = diethylamine NMM = N-methylmorpholine NMP = N-methylpyrrolidone DCM = dichloromethane TEA = triethylamine min. = minute(s) h or hr = hour(s) L = liter mL or ml = milliliter μL = microliter g = gram(s) mg = milligram(s) mol = mole(s) mmol = millimole(s) meq = milliequivalent rt or RT = room temperature sat or sat'd = saturated aq. = aqueous mp = melting point reagent BOP = benzotriazol-1-yloxy-tris-dimethylamino-phosphonium hexafluorophosphate (Castro's reagent) reagent PyBOP = benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate HBTU = 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HATU = O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate T3P = 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide DMAP = 4-(dimethylamino)pyridine DIEA = diisopropylethylamine Fmoc or FMOC = fluorenylmethyloxycarbonyl Boc or BOC = tert-butyloxycarbonyl HOBT or HOBT.H2O = 1-hydroxybenzotriazole hydrate Cl-HOBt = 6-Chloro-benzotriazole HOAT = 1-hydroxy-7-azabenzotriazole HPLC = high performance liquid chromatography LC/MS = high performance liquid chromatography/mass spectrometry MS or Mass Spec = mass spectrometry NMR = nuclear magnetic resonance Sc or SC = subcutaneous IP or ip = intraperitoneal

EXAMPLES EXAMPLE 1 - SOLID PHASE PEPTIDE SYNTHESIS AND PEPTIDE CYCLIZATION

[00340] The procedures described in this example, either in whole or in part where noted, were used to synthesize the macrocyclic peptides shown in Tables 1, 2, 3, 4, and 5. TABLE 1 - SERIES OF PEPTIDES OF FORMULA I± ±Compounds Nos. 1 to 70 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine. SCHEME I - COMMON SYNTHESIS METHOD USED FOR THIOETHER-CYCLIZED PEPTIDES (EXAMPLES 2 TO 88)

[00341] General protocol for solid-phase peptide synthesis and macrocyclization. On a Symphony peptide synthesizer (Protein Technology Inc. Tucson, AZ), a Prelude peptide synthesizer (Protein Technology Inc. Tucson, AZ), or Liberty (CEM Matthews, NC), Sieber amide resin (0.71 mmol/g, 0.100 mmol, 141 mg) was swelled with DMF (7 mL x 4 min) and mixed with a gentle stream of N2 every 30 seconds. The solvent was drained and the following method was used to couple the first amino acid: the Fmoc group was removed from the resin-supported building block by washing the resin twice with a 20% piperidine solution in DMF (5 mL and 2.5 min per wash) and mixing with a gentle stream of N2 every 30 seconds. The resin was washed three times with DMF (58 mL and 1.5 min per wash). 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)acetic acid (0.2 M solution in DMF, 0.5 mmol) was then added, followed by coupling activator (i.e., HATU (Chem-Impex Int'l, 0.4 M solution without DMF, 1.25 mL, 0.5 mmol)) and base (i.e., N-methyl morpholine (Aldrich, 0.8 M in DMF, 1.25 mL, 1 mmol)). The reaction mixture was stirred by a gentle stream of nitrogen for 1 h. The reactants were drained from the reaction vessel, and the resin was washed three times with DMF (5 mL × 1.5 min). It should be noted that typical reagents for Liberty CEM were as follows: HCTU (0.45 M in DMF) as the coupling activator, DIEA (2 M in NMP) as the base, and 5% piperazine in DMF with 0.1 M HOBt as the deprotection solution.

[00342] The resulting resin-supported Fmoc-protected dipeptide was then sequentially deprotected and coupled with the third amino acid and so on in an iterative manner to give the desired resin-supported product.

[00343] LCMS analysis was performed on an aliquot of the peptide, which was cleaved from the resin (an analytical amount was treated with a TFA/TIS (96:4) solution (0.2 mL) at room temperature. Subsequent to confirmation of the desired linear sequence, the Fmoc group was removed from the N-terminus by washing the resin twice with a 20% piperidine solution in DMF (5 mL and 2.5 min per wash) and vortexing the suspension. The resin was washed with DMF (2 × 5 mL). To the peptide resin was successively added 2-chloroacetic acid (0.6 mmol, 57 mg), DMF (5.26 mL), and DIC (0.6 mmol, 93 μL). The new suspension was vortexed for 1-2 days when the peptide resin was washed with DMF (1 × 5 mL × 1 min) and DCM (3 × DCM × 1 min).

[00344] The peptide was deprotected and cleaved from the resin by treatment with a TFA/TIS (96:4) solution (10 mL) for 1 h. The resin was removed by filtration, washed with a cleavage cocktail (2 x 1 mL), the combined filtrates were added to Et2O (10-15 mL), and the solution was cooled to 0 °C to cause the peptide to precipitate from solution. The suspension was centrifuged to pellet the solids, and the supernatant was decanted. Fresh Et2O (25 mL) was added, and the process was repeated three times to wash the solids. To the wet solids was added a solution of 0.1 M NH4HCO3/acetonitrile (1/1 to 3/1 (v/v), pH = 8.6) or 6 M guanidine HCl in 100 mM NaH2PO4 (pH = 8.4). The solution was stirred for 1-2 days and monitored by LCMS. The reaction solution was purified by preparative HPLC to obtain the desired product. GENERAL ANALYTICAL PROTOCOLS AND SYNTHESIS METHODS± ±The following analytical protocols and synthesis methods were used in Examples 1 to 4000.

Analytical Data:

[00345] Mass spectrometry: "ESI-MS(+)" means electrospray ionization mass spectrometry performed in positive ion mode; "ESI-MS(-)" means electrospray ionization mass spectrometry performed in negative ion mode; "ESI-HRMS(+)" means electrospray ionization high-resolution mass spectrometry performed in positive ion mode; "ESI-HRMS(-)" means electrospray ionization high-resolution mass spectrometry performed in negative ion mode. Detected masses are reported using the “m/z” unit designation. Compounds with exact masses greater than 1000 were frequently detected as doubly or triply charged ions.

[00346] LCMS Analysis Condition A: Column: BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Temperature: 50 °C; Gradient: 2% B to 98% B over 2 min, then a 0.5 min hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm.

[00347] LCMS Analysis Condition B: Column: BEH C 18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow rate: 1.11 mL/min.

[00348] LCMS Analysis Condition C: Column: BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: water with 0.2% formic acid and 0.01% TFA; Mobile phase B: Acetonitrile with 0.2% formic acid and 0.01% TFA; Temperature: 50 °C; Gradient: 2% B to 80% B over 2 min, 80% B to 98% B over 0.1 min, then a 0.5 min hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm.

[00349] LCMS Analysis Condition D: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm.

[00350] LCMS Analysis Condition E: Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm.

[00351] LCMS Analysis Condition F: Column: Waters XBridge C18, 2.1 x 50 mm; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 35 °C; Gradient: 0-100% B over 4 minutes, then a 1 minute hold at 100% B; Flow rate: 4 mL/min; Detection: UV at 220 nm.

[00352] LCMS Analysis Condition G: Finnigan LTQ mass spectrometer; column: FENOMENEX® Jupiter C4, 1 x 50 mm; Mobile phase A: 1% formic acid in water; Mobile phase B: 0.1% formic acid in acetonitrile; Temperature: 30 °C; Gradient: 1% B, 1 minute hold; 1-95% B over 3 minutes, then a 3 minute hold at 95% B; Flow rate: 0.15 mL/min.

[00353] HPLC Analysis Condition A: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 35% B to 80% B over 25 min.; Flow rate: 1 mL/min; Detection: UV at 217 nm.

[00354] HPLC Analysis Condition B: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 25% B to 75% B over 25 min.; Flow rate: 1 mL/min; Detection: UV at 217 nm.

[00355] HPLC Analysis Condition C: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 20% B to 70% B over 25 min.; Flow rate: 1 mL/min; Detection: UV at 217 nm.

[00356] HPLC Analysis Condition D: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 15% B to 65% B over 25 min.; Flow rate: 1 mL/min; Detection: UV at 217 nm.

[00357] HPLC Analysis Condition E: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 25% B to 60% B over 20 min.; Flow rate: 1.25 mL/min; Detection: UV at 217 nm.

[00358] HPLC Analysis Condition F: Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 60 °C; Gradient: from 25% B to 65% B over 20 min.; Flow rate: 1.25 mL/min; Detection: UV at 217 nm.

[00359] HPLC Analysis Condition G: Column: SunFire C18 3.5μm, 3.0x150mm; Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; temperature: 50 °C; Gradient: 10-100% B over 12 minutes, then a 3 minute hold at 100% B; Flow rate: 1 mL/min; Detection: UV at 220 nm.

[00360] HPLC Analysis Condition H. Column: XBridge Phenyl 3.5x150μm, Mobile phase A: 5:95 acetonitrile:water with 0.05% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.05% trifluoroacetic acid; temperature: 50 °C; Gradient: 10-100% B over 12 minutes, then a 3-minute hold at 100% B; Flow rate: 1 mL/min; Detection: UV at 220 nm.

[00361] HPLC Analysis Condition I: Column: FENOMENEX® Luna 5μ C18(2) 150 x 4.6 mm; mobile phase A: water with 0.1% trifluoroacetic acid, mobile phase B: acetonitrile with 0.1% trifluoroacetic acid, Gradient 5-100% B over 20min, then a 5-minute hold at 100% B; Flow rate 1 mL/min, Detection: UV at 220.

[00362] HPLC Analysis Condition J: Column: FENOMENEX® Luna 5μ C18(2) 150 x 4.6 mm; mobile phase A: water with 0.1% trifluoroacetic acid, mobile phase B: acetonitrile with 0.1% trifluoroacetic acid, Gradient 10-100% B over 20min, then a 5-min hold at 100% B; Flow rate 1 mL/min, Detection: UV at 220. General Procedures: Prelude Method A:

[00363] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 or 45 mL polypropylene tube equipped with a bottom frit. The tube is connected to the Prelude peptide synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly waters the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube.

[00364] "Periodic agitation" describes a brief pulse of N2 gas through the lower frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. DMF = dimethylformamide; DIC = N,N'-diisopropylcarbodiimide; HOAt = 1-hydroxy 7-azabenzotriazole; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00365] The “Prelude Method A” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as “Resin Swelling Procedure.” Coupling of amino acids to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Coupling of Fmoc-N-methyl amino acids and coupling to a secondary amine N-terminus used the “Secondary Amine Coupling Procedure” described below. Coupling of the chloroacetyl group to the N-terminus of the peptide is described by the “Chloroacetyl Coupling Procedure” "Chloroacetic Acid Coupling Procedure" or "Chloroacetic Acid Coupling Procedure" detailed below. Resin Swelling Procedure:

[00366] To a 40 mL polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (140 mg, 0.100 mmol). The resin was washed three times as follows: to the reaction vessel were added DMF (5.0 mL) and DCM (5.0 mL), and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained. Simple coupling procedure:

[00367] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 s before the solution was drained through the frit. To the reaction vessel was added a solution of the amino acid and HOAt (0.2M in DMF, 5.0 mL, 10 eq.), and then DIC (0.2M in DMF, 5.0 mL, 10 eq.). The mixture was stirred periodically for 60 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00368] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 s before the solution was drained through the frit. To the reaction vessel was added a solution of the amino acid and HOAt (0.2M in DMF, 5.0 mL, 5 eq.), and then DIC (0.2M in DMF, 5.0 mL, 5 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetyl chloride coupling procedure:

[00369] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added 3.0 mL of a solution of DIPEA (4.0 mmol, 0.699 mL, 40 eq.), and chloroacetyl chloride (2.0 mmol, 0.160 mL, 20 eq.) in DMF. The mixture was stirred periodically for 12 to 18 h, and then the solution was drained. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained. The resin was washed successively four times as follows: for each wash, DCM (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained. Prelude B Method:

[00370] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures were performed in a 10 or 45 mL polypropylene tube equipped with a bottom frit. DMF and DCM can be added through the top of the tube, which evenly coats the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube. "Periodic agitation" describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00371] The “Prelude Method B” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Amino acid coupling to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Amino acid coupling to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. Chloroacetyl group coupling to the N-terminus of the peptide is described as the “Chloroacetyl Chloride Coupling Procedure” or “Chloroacetyl Chloride Coupling Procedure.” chloroacetic acid" detailed below. Resin swelling procedure:

[00372] To a 40 mL polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (140 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel were added DMF (5.0 mL) and DCM (5.0 mL), and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[00373] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 5.0 mL, 10 eq.), followed by HCTU (0.2 M in DMF, 5.0 mL, 10 eq.), and finally DIPEA (0.8 M in DMF, 2.5 mL, 20 eq.). The mixture was stirred periodically for 30 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. A solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Double coupling procedure:

[00374] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 5.0 mL, 10 eq.), followed by HCTU (0.2 M in DMF, 5.0 mL, 10 eq.), and finally DIPEA (0.8 M in DMF, 2.5 mL, 20 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed successively 3 times with DMF (4.0 mL) through the top of the vessel, and the resulting mixture was stirred periodically for 60 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 5.0 mL, 10 eq.), followed by HCTU (0.2 M in DMF, 5.0 mL, 10 eq.), and finally DIPEA (0.8 M in DMF, 2.5 mL, 20 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00375] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 2.5 mL, 10 eq.), followed by HCTU (0.2 M in DMF, 2.5 mL, 10 eq.), and finally NMM (0.8 M in DMF, 1.5 mL, 12 eq.). The mixture was stirred periodically for 12 h, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetyl chloride coupling procedure A:

[00376] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added 3.0 mL of a solution of DIPEA (4.0 mmol, 0.699 mL, 40 eq.), and chloroacetyl chloride (2.0 mmol, 0.160 mL, 20 eq.) in DMF. The mixture was stirred periodically for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. Chloroacetic acid coupling procedure B :

[00377] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel were added DMF (2.0 mL), chloroacetic acid (1.2 mmol, 113 mg, 12 eq.), and N,N'-Diisopropylcarbodiimide (1.2 mmol, 0.187 mL, 12 eq.). The mixture was stirred periodically for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the upper part of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the upper part of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. Prelude C Method:

[00378] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 or 45 mL polypropylene tube equipped with a bottom frit. The tube is connected to the Prelude peptide synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly waters the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube.

[00379] "Periodic agitation" describes a brief pulse of N2 gas through the lower frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)- OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00380] The “Prelude Method C” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the described volumes by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Amino acid coupling to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Amino acid coupling to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. The final resin wash used the “Final Wash Procedure” described below. Resin Swelling Procedure:

[00381] To a 40 mL polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (140 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel were added DMF (5.0 mL) and DCM (5.0 mL), and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[00382] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 5.0 mL, 10 eq.), followed by HATU (0.2 M in DMF, 5.0 mL, 10 eq.), and finally DIPEA (0.8 M in DMF, 2.5 mL, 20 eq.). The mixture was stirred periodically for 60 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00383] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), followed by HATU (0.2 M in DMF, 2.5 mL, 5 eq.), and finally DIPEA (0.8 M in DMF, 1.5 mL, 12 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), followed by HATU (0.2 M in DMF, 2.5 mL, 5 eq.), and finally DIPEA (0.8 M in DMF, 1.5 mL, 12 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[00384] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 0.5 to 2.5 mL, 1 to 5 eq.), followed by HATU (0.2 M in DMF, 0.5 to 2.5 mL, 1 to 5 eq.), and finally DIPEA (0.8 M in DMF, 0.5 to 1.5 mL, 4 to 12 eq.). The mixture was stirred periodically for 60 min to 600 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Final wash procedure:

[00385] The resin was washed successively two times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DCM (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetic Acid Coupling Procedure:

[00386] Note the manual step. To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred at room temperature for 5 min, and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred before the solution was drained through the frit. To the reaction vessel were added DMF (2.0 mL), chloroacetic acid (1.2 mmol, 113 mg, 12 eq.), and N,N'-Diisopropylcarbodiimide (1.2 mmol, 0.187 mL, 12 eq.). The mixture was stirred at room temperature for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. Prelude D Method:

[00387] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 or 45 mL polypropylene tube equipped with a bottom frit. The tube is connected to the Prelude peptide synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly waters the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube.

[00388] "Periodic agitation" describes a brief pulse of N2 gas through the lower frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)- OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00389] The “Prelude D Method” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Amino acid coupling to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Amino acid coupling to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. The final resin wash used the “Final Wash Procedure” described below. Resin Swelling Procedure:

[00390] To a 40 mL polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (140 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel were added DMF (5.0 mL) and DCM (5.0 mL), and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[00391] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 2.5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 2.5 eq.), and finally DIPEA (0.8 M in DMF, 0.75 mL, 5 eq.). The mixture was stirred periodically for 30 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 15 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00392] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 2.5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 2.5 eq.), and finally DIPEA (0.8 M in DMF, 0.75 mL, 5 eq.). The mixture was stirred periodically for 30 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino (0.2 M in DMF, 1.25 mL, 2.5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 2.5 eq.), and finally DIPEA (0.8 M in DMF, 0.75 mL, 5 eq.). The mixture was stirred periodically for 30 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. A solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 15 min, and then the solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 15 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Final wash procedure:

[00393] The resin was washed successively twice as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DCM (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetic Acid Coupling Procedure:

[00394] Note the manual step. To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred at room temperature for 5 min, and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred before the solution was drained through the frit. To the reaction vessel were added DMF (2.0 mL), chloroacetic acid (1.2 mmol, 113 mg, 12 eq.), and N,N'-Diisopropylcarbodiimide (1.2 mmol, 0.187 mL, 12 eq.). The mixture was stirred at room temperature for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. CEM Method A:

[00395] All manipulations were performed with automation on a CEM Liberty microwave peptide synthesizer (CEM Corporation). All procedures, unless noted, were performed in a 30 or 125 mL polypropylene tube equipped with a bottom frit for a CEM Liberty microwave unit. The tube is connected to the CEM Liberty synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top and bottom of the tube, which evenly waters the sides of the tube. All solutions are removed through the bottom of the tube except when resin is being transferred from the top.

[00396] "Periodic bubbling" describes a brief bubbling of N2 gas through the lower frit. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected in nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Other common resins such as Rink, ChloroTrityl, or other acid-sensitive linkers may be employed in the synthesis, Seiber amide resin is used unless otherwise indicated in specific examples.

[00397] Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Orn(Boc)-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00398] The “CEM Method A” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Coupling of amino acids to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Coupling of amino acids to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. Coupling of the chloroacetyl group to the N-terminus of the peptide is described by the “Chloroacetyl Chloride Coupling Procedure” or "Chloroacetic acid coupling procedure" detailed above. Resin swelling procedure:

[00399] To a 50 mL polypropylene conical tube was added Merrifield:Sieber resin (140 mg, 0.100 mmol). Then DMF (7 mL) was added to the tube followed by DCM (7 mL). The resin was then transferred to the reaction vessel from the top of the vessel. The procedure was repeated two more times. DMF (7 mL) was added followed by DCM (7 mL). The resin was allowed to swell with N2 bubbling from the bottom of the reaction vessel for 15 min before the solvent was drained through the frit. Standard coupling procedure:

[00400] To the reaction vessel containing the resin from the previous step was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. Double-pair coupling procedure:

[00401] To the reaction vessel containing the resin from the previous step was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00402] To the reaction vessel containing the resin from the previous step was added a solution of 5% piperazine and 0.1 M HOBt in DMF (7 mL). The mixture was stirred periodically for 3 min at 75 °C and then the solution was drained. This procedure was repeated one more time. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HCTU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids (50 °C for Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH), followed by 6 h without heating. After drainage, the resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained. The resin was washed successively three times as follows: DMF washing (7 mL) from the top, followed by DMF washing (7 mL) from the bottom, and finally DMF washing (7 mL) from the top. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[00403] To the reaction vessel containing the resin from the previous step was added a solution of piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a solution of piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel was added the amino acid solution (1.25 mL to 5 mL, 2.5 eq. to 10 eq.) containing HATU (2.5 eq. to 10 eq.), and finally DIPEA (2 M in NMP, 0.5 mL to 1 mL, 20 eq.). The mixture was mixed by bubbling N2 for 5 min to 2 h at a temperature of 25 °C to 75 °C, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the upper part, followed by washing with DMF (7 mL) from the lower part, and finally washing with DMF (7 mL) from the upper part. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. Simphony A method:

[00404] All manipulations were performed with automation on a Symphony peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in Symphony polypropylene tubing equipped with a bottom frit. The tubing is connected to the Symphony peptide synthesizer through the bottom and top of the tubing. All solvents, DMF, DCM, amino acids, and reagents are added through the bottom of the tubing and passed up the frit to contact the resin. All solutions are removed through the bottom of the tubing. "Periodic agitation" describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 15 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; NMM= n-Methyl morpholine; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected in nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Other common acid-sensitive resins can also be used in the synthesis such as Rink resin or trityl-functionalized chloro resin. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00405] The “Simphony Method A” procedures describe an experiment performed on a 0.050 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. This scale corresponds to approximately 70 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.050 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Swelling Procedure.” Amino acid coupling to the N-terminus of a primary amine used the “Standard Coupling Procedure” described below. Amino acid coupling to the N-terminus of a secondary amine used the “Double Coupling,” custom amino acids are coupled via a manual addition of the amino acid “blank” blank described below. Swelling Procedure:

[00406] To a Symphony polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (70 mg, 0.050 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel was added DMF (2.5 mL) and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.5 mL). The mixture was stirred periodically for 2.5 min and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel, and then the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 s before the solvent was drained through the frit. The resulting resin was used directly in the next step. Standard coupling procedure:

[00407] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) and added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00408] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) and added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[00409] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. The synthesis was interrupted by the Symphony software to manually add the custom amino acid (0.2M in DMF, 1.25 mL, 5 eq.) to the reaction vessel, and then restart the automation: adding HATU (0.2M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed six times as follows with DMF (2.5 mL) added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. AC2O/DIPEA/DMF (v/v/v 1 : 1 : 3 2.5 mL) was added to the reaction vessel, the mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resulting resin was used directly in the next step. Simphony B method:

[00410] All manipulations were performed with automation on a Symphony peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a Symphony polypropylene tube equipped with a bottom frit. The tube is connected to the Symphony peptide synthesizer through the bottom and top of the tube. All solvents, DMF, DCM, amino acids, and reagent are added through the bottom of the tube and passed up the frit to contact the resin. All solutions are removed through the bottom of the tube. "Periodic agitation" describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 15 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; NMM= n-Methyl morpholine; DIEA or DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (nitrogen-protected Fmoc-); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Other common acid-sensitive resins can also be used in the synthesis such as Rink resin or chlorotrityl-functionalized resin. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[00411] The “Simphony Method B” procedures describe an experiment performed on a 0.050 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. This scale corresponds to approximately 70 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.050 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Swelling Procedure.” Amino acid coupling to the N-terminus of a primary amine used the “Standard Coupling Procedure” described below. Amino acid coupling to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure B,” custom amino acids are coupled via a manual addition of amino acid blank “Custom Amino Acid Coupling Procedure” described below, and chloroacetyl anhydride is added to the resin. final position of the sequence using the "Final Capping Procedure" described below. Swelling Procedure:

[00412] To a Symphony soli polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (70 mg, 0.050 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel was added DMF (2.5 mL) and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.5 mL). The mixture was stirred periodically for 2.5 min and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel, and then the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 s before the solvent was drained through the frit. The resulting resin was used directly in the next step. Standard coupling procedure:

[00413] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed 6 times as follows: DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added AC2O/DIPEA/DMF (v/v/v 1 : 1 : 3 2.5 mL), the mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[00414] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) and added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.25 mL, 5 eq.), followed by HATU (0.2 M in DMF, 1.25 mL, 5 eq.), and finally NMM (0.8 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. Ac20/DIPEA/DMF (v/v/v 1 : 1 : 3 2.5 mL) was added to the reaction vessel, and the mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[00415] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. The system was stopped by the system to manually add the custom amino acid (0.2M in DMF, 1.25 mL, 5 eq.) to the reaction vessel, and then the automation was restarted to add HATU (0.2M in DMF, 1.25 mL, 5 eq.) and finally NMM (0.8M in DMF, 1.25 mL, 10 eq.) to the reaction vessel. The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed 6 times as follows: DMF (2.5 mL) was added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. AC2O/DIPEA/DMF (v/v/v 1 : 1 : 3 2.5 mL) was added to the reaction vessel, the mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Final capping procedure:

[00416] The resin was washed three times as follows: DMF (2.5 mL) was added to the reaction vessel and the mixture was then stirred periodically with N2 bubbling from the bottom of the reaction vessel for 30 seconds before the solvent was drained through the frit. Piperidine:DMF (20:80 v/v, 2.5 mL) was added to the reaction vessel. The mixture was stirred periodically for 2.5 minutes and the solution was then drained through the frit. The resin was washed 6 times as follows: for each wash, DMF (2.5 mL) was added from the bottom of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added NMM (0.8 M in DMF, 1.25 mL, 10 eq.) followed by the addition of chloroacetic anhydride (0.4 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed with DMF (6.25 mL) and added through the bottom of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added NMM (0.8 M in DMF, 1.25 mL, 10 eq.) followed by the addition of chloroacetic anhydride (0.4 M in DMF, 1.25 mL, 10 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed 6 times as follows: DMF (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added AC2O/DIPEA/DMF (v/v/v 1 : 1 : 3 2.5 mL) and the mixture was stirred periodically for 10 min, and then the reaction solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DCM (2.5 mL) was added through the bottom of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. The resulting resin was then dried with a stream of nitrogen for 10 min. Global deprotection method A:

[00417] All manipulations were done manually unless otherwise stated. The "Global Deprotection Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the described volumes by the scale multiple. A "deprotection solution" was prepared using trifluoroacetic acid:water:triisopropylsilane:dithiothreitol (92.5:2.5:2.5:2.5 v:v:v:w). The resin was removed from the reaction vessel and transferred to a 25 mL syringe equipped with a frit. The “deprotection solution” (5.0 mL) was added to the syringe. The mixture was mixed on a shaker for 85 min. The solution was filtered, concentrated, and diluted in diethyl ether (30 mL). The precipitated solid was centrifuged for 3 min. The supernatant solution was decanted, and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 min. The supernatant was decanted, and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 min. The supernatant was decanted, and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Global deprotection method B:

[00418] All manipulations were done manually unless otherwise stated. The “Global Deprotection Method B” procedure describes an experiment performed on a 0.04 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. The procedure can be scaled up above the 0.04 mmol scale by adjusting the volumes described by the scale multiple. A “deprotection solution” was prepared using trifluoroacetic acid:triisopropylsilane (96:4; v:v). The resin was removed from the reaction vessel and transferred to a 10 mL syringe equipped with a frit. To the syringe was added the “deprotection solution” (2.0-3.0 mL). The mixture was mixed on a shaker for 1 hour or 1.5 hours. The solution was filtered, washed with deprotection solution (0.5 mL), concentrated and diluted in diethyl ether (30 mL). The precipitated solid was centrifuged for 3 minutes. The supernatant solution was decanted and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Global deprotection method C:

[00419] All manipulations were done manually unless otherwise noted. The “Global Deprotection Method C” procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the described volumes by the multiple of the scale. A “deprotection solution” was prepared using trifluoroacetic acid:triisopropylsilane:dithiothreitol (95:2.5:2.5 v:v:w). The resin was removed from the reaction vessel and transferred to a BioRad tube. To the Bio-Rad tube was added the “deprotection solution” (4.0 mL). The mixture was mixed on a shaker for 60 minutes. The solution was filtered and diluted in diethyl ether (30 mL). The precipitated solid was centrifuged for 3 minutes. The supernatant solution was decanted and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Global deprotection method D:

[00420] All manipulations were done manually unless otherwise stated. The procedure "Global Deprotection Method B" describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the described volumes by the scale multiple. A "deprotection solution" was prepared using trifluoroacetic acid:triisopropylsilane:dithiothreitol (94:3:3 v:v:w). The resin was removed from the reaction vessel and transferred to a 25 mL syringe equipped with a frit. The “deprotection solution” (5.0 mL) was added to the syringe. The mixture was mixed on a shaker for 5 minutes. The solution was filtered and diluted in diethyl ether (30 mL). The precipitated solid was centrifuged for 3 minutes. The supernatant solution was decanted and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Overall deprotection method E:

[00421] All manipulations were done manually unless indicated. The "Global Deprotection Method E" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Fmoc Gly-ClTrt linker bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the described volumes by the multiple of the scale. A "deprotection solution" was prepared using trifluoroacetic acid:triisopropylsilane:dithiothreitol (95:2.5:2.5 v:v:w). The resin was removed from the reaction vessel and transferred to a Bio-Rad tube. To the Bio-Rad tube was added the “deprotection solution” (2.0 mL). The mixture was mixed on a shaker for 3 minutes. The solution was filtered and collected in a centrifuge tube. To the Bio-Rad tube was added the “deprotection solution” (2.0 mL). The mixture was mixed on a shaker for 3 minutes. The solution was filtered and collected in a centrifuge tube. To the Bio-Rad tube was added the “deprotection solution” (2.0 mL). The mixture was mixed on a shaker for 3 minutes. The solution was filtered, and collected in a centrifuge tube. The solution in the centrifuge tube was allowed to stand for 60 minutes. The collected solution was then diluted with diethyl ether (30 mL), and a precipitate formed. The precipitated solid was centrifuged for 3 minutes. The supernatant solution was decanted, and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted, and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 minutes. The supernatant was decanted, and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Overall deprotection method F:

[00422] All manipulations were done manually unless otherwise noted. The "Global Deprotection Method F" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the volumes described by the multiple of the scale. A "deprotection solution" was prepared using trifluoroacetic acid:triisopropylsilane:dithiothreitol (95:2.5:2.5 v:v:w). The resin was removed from the reaction vessel and transferred to a 6 mL Bio-Rad tube. To the Bio-Rad was added the “deprotection solution” (4.0 mL). The mixture was mixed on a shaker for 90 min. The solution was filtered and diluted in diethyl ether (30 mL). The precipitated solid was centrifuged for 3 min. The supernatant solution was decanted and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 min. The supernatant was decanted and the remaining solid was suspended in diethyl ether (25 mL). The suspension was centrifuged for 3 min. The supernatant was decanted and the remaining solid was dried under high vacuum. The crude peptide was obtained as a white to off-white solid. Cyclization method A

[00423] All manipulations were done manually unless otherwise noted. The "Cyclization Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. The crude peptide solids were dissolved in a solution of 8 M aqueous acetonitrile:guanidine/50 mM TRIS (1:3) (pH 8.6) (7 mL:18 mL or similar ratio), and the solution was then adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M), if necessary. The solution was then mixed using a shaker for 12 to 18 hours. The reaction solution was concentrated and the residue was then dissolved in acetonitrile:water. This solution was subjected to reverse-phase HPLC purification to give the desired cyclic peptide. Cyclization method C:

[00424] All manipulations were done manually unless indicated. The "Cyclization Method C" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the multiple of the scale. The crude peptide solids were dissolved in a solution of acetonitrile:0.1 M aqueous ammonium bicarbonate buffer (11 mL:24 mL or similar ratio), and the solution was then cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then mixed using a shaker for 12 to 18 hours. The reaction solution was concentrated and the residue was then dissolved in acetonitrile:water. This solution was subjected to reverse-phase HPLC purification to give the desired cyclic peptide. Cyclization method D:

[00425] All manipulations were done manually unless otherwise noted. The "Cyclization Method D" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. The crude peptide solids were dissolved in a solution of acetonitrile:0.1 M aqueous ammonium bicarbonate buffer (11 mL:24 mL), and the solution was then cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then mixed with stirring for 12 to 18 h. The reaction solution was concentrated, and the residue was then dissolved in acetonitrile:water. This solution was subjected to reverse-phase HPLC purification to give the desired cyclic peptide. Cyclization method E:

[00426] All manipulations were done manually unless otherwise indicated. The procedure "Cyclization Method E" describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the multiple of the scale. The crude peptide solids were dissolved in a solution of 6 M aqueous guanidine HCl buffer (15 mL), the solution was then mixed with stirring for 12 to 18 hours. The reaction solution was concentrated and 15 mL of DMSO was added to the residue giving a suspension that was filtered. This filtered solution was subjected to purification by reversed-phase HPLC to give the desired cyclic peptide. Manual coupling procedure A:

[00427] To the Bio-Rad reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 5 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred for 60 sec before the solution was drained through the frit. To the reaction vessel was added the amino acid (1.2-10 equivalents) typical (0.2M in DMF, 2.5 mL, 5 eq.), then HATU (1.2-10 equivalents) typical (0.2M in DMF, 2.5 mL, 5 eq.), and finally DIPEA (2.4-20 equivalents) typical (0.8M in DMF, 1.25 mL, 10 eq.). The mixture was stirred for 60 min to 18 h, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred for 60 s before the solution was drained through the frit. N-methylation methylation on resin Method A. (Turner, R.A. et al., Org. Lett., 15(19):5012–5015 (2013)):

[00428] All manipulations were done manually unless otherwise indicated. The "N-methylation methylation on resin Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of resin-bound Sieber ligand that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple.

[00429] The resin was transferred to a 25 mL fritted syringe. To the resin was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred for 3 min and then the solution was drained through the frit. The resin was washed 3 times with DMF (4.0 mL). To the reaction vessel was added piperidine:DMF (20:80 v/v, 4.0 mL). The mixture was stirred for 3 min and then the solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). The resin was suspended in DMF (2.0 mL) and ethyl trifluoroacetate (0.119 mL, 1.00 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.181 mL, 1.20 mmol). The mixture was placed on a shaker for 60 min. The solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL).

[00430] The resin was washed three times with dry THF (2.0 mL) to remove any residual water. To an oven-dried 4.0 mL vial was added THF (1.0 mL) and triphenylphosphine (131 mg, 0.500 mmol) over 4 Å molecular sieves (20 mg). The solution was transferred to the resin and diisopropyl azodicarboxylate (0.097 mL, 0.5 mmol) was added slowly. The resin was stirred for 15 min. The solution was drained through the frit and the resin was washed three times with dry THF (2.0 mL) to remove any residual water. To an oven-dried 4.0 mL vial was added THF (1.0 mL), triphenylphosphine (131 mg, 0.500 mmol) over 4 Å molecular sieves (20 mg). The solution was transferred to the resin, and diisopropyl azodicarboxylate (0.097 mL, 0.5 mmol) was added slowly. The resin was stirred for 15 min. The solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). The resin was suspended in ethanol (1.0 mL) and THF (1.0 mL), and sodium borohydride (37.8 mg, 1.000 mmol) was added. The mixture was stirred for 30 min and drained. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). Microcleavage A:

[00431] To a small sample < 10 mg of resin add 2 drops of TIS and 1 mL of trifluoroacetic acid, and shake at room temperature. After 1 hour, remove a small aliquot and dilute with 0.5 mL of acetonitrile, filter, and obtain analysis by LC-MS.

[00432] Synthesis protocols for specific peptides disclosed in this invention are given in the examples that follow.

[00433] Examples 2 to 71 provide synthetic schemes for the macrocyclic peptides of formula 1(a) to 1(d).

[00434] Examples 72 to 88 provide synthetic schemes for the macrocyclic peptides of formula 11(a) to 11(c).

[00435] Examples 100 to 116 provide synthetic schemes for the macrocyclic peptides of formula 111(a) to III(c).

[00436] Examples 116 to 119 provide synthetic schemes for the C-terminally PEGylated macrocyclic peptides of formulae I and II. EXAMPLE 2 - SYNTHESIS OF COMPOUND NO. 1 Molecular weight: 1852.17

[00437] To a 40 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin Swelling Procedure” was followed; “CEM Method A: Single Coupling Procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Single Coupling Procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Double Coupling Procedure” was followed with Fmoc-Arg(Pbf)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Trp(Boc)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Ser(tBu)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Trp(Boc)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-[N-Me]Gly-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Leu-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-His(Trt)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Pro-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Asn(Trt)-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-[N-Me]Ala-OH; “CEM Method A: Simple coupling procedure” was followed with Fmoc-Phe-OH; “Chloroacetyl chloride coupling procedure A” was followed; “Global deprotection method A” was followed; “Cyclization method A” was followed.

[00438] The crude material was purified via preparatory HPLC using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 20-70% B over 50 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The product yield was 16 mg, and its purity estimated by HPLC analysis was 97%. LCMS analysis Condition A: retention time = 1.30 min.; ESI-MS(+) m/z 926.7 (M+2H). HPLC analysis Condition A: retention time = 11.16 min. EXAMPLE 3 - SYNTHESIS OF COMPOUND NO. 2 Molecular weight: 1918.23

[00439] Example 3 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00440] The crude material was purified via preparatory HPLC using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 20-75% B over 55 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 18 mg, and its purity estimated by HPLC analysis was 93%.

[00441] LCMS analysis Condition A: retention time = 1.19 min.; ESI-MS(+) m/z 959.8 (M+2H).

[00442] HPLC analysis Condition B: retention time 14.49 min. EXAMPLE 4 - SYNTHESIS OF COMPOUND NO. 3 Molecular weight: 1937.28

[00443] Example 4 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00444] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 8.1 mg, and its purity estimated by HPLC analysis was 98%.

[00445] LCMS analysis Condition A: retention time = 1.21 min.; ESI-MS(+) m/z 970.0 (M+2H).

[00446] HPLC analysis Condition B: retention time = 19.91 min. EXAMPLE 5 - SYNTHESIS OF COMPOUND NO. 4 Example 5

[00447] Example 5 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00448] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 2.1 mg, and its purity estimated by HPLC analysis was 99%.

[00449] LCMS analysis Condition A: retention time = 1.28 min.; ESI-MS(+) m/z 948.3 (M+2H).

[00450] HPLC analysis Condition C: retention time = 19.03 min. EXAMPLE 6 - SYNTHESIS OF COMPOUND NO. 5 Molecular weight: 1776.07

[00451] To a 40 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: "Prelude Method A: Resin Swelling Procedure" was followed; "Prelude Method A: Simple Coupling Procedure" was followed; "Prelude Method A: Secondary Amine Coupling Procedure" was followed for couplings to the Fmoc-N-Methyl amino acids and for couplings to an N-terminus of the secondary amine; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A" was followed; "Global Deprotection Method C" was followed; "Cyclization Method C" was followed.

[00452] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.8 mg, and its purity estimated by LCMS analysis was 98% by “LCMS analysis conditions B and D".

[00453] LCMS Analysis Condition B: Retention time = 1.412 min; ESI-MS(+) m/z 888.75 (M+2H).

[00454] LCMS Analysis Condition D: Retention time = 1.539 min; ESI-MS(+) m/z 888.50 (M+2H). EXAMPLE 7 - SYNTHESIS OF COMPOUND NO. 6 Molecular weight: 1838.14

[00455] Example 7 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00456] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 24 mg, and its purity estimated by HPLC analysis was 99%.

[00457] LCMS analysis Condition A: retention time = 1.20 min.; ESI-MS(+) m/z 920.3 (M+2H).

[00458] HPLC analysis Condition C: retention time 15.66 min Example 8 - SYNTHESIS OF COMPOUND NO. 7 Molecular weight: 1838.14

[00459] Example 8 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00460] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10 70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 11.5 mg, and its purity estimated by HPLC analysis was 97%.

[00461] LCMS analysis Condition A: retention time = 1.24 min.; ESI-MS(+) m/z 920.2 (M+2H).

[00462] HPLC analysis Condition C: retention time = 16.39 min. EXAMPLE 9 - SYNTHESIS OF COMPOUND NO. 8 Molecular weight: 1809.14

[00463] Example 9 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00464] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 12 mg, and its purity estimated by HPLC analysis was 92%.

[00465] LCMS analysis Condition A: retention time = 1.27 min.; ESI-MS(+) m/z 905.8 (M+2H).

[00466] HPLC analysis Condition C: retention time = 17.18 min. EXAMPLE 10 - SYNTHESIS OF COMPOUND NO. 9 Molecular weight: 1826.13

[00467] Example 10 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00468] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 16 mg, and its purity estimated by HPLC analysis was 93%.

[00469] LCMS analysis Condition A: retention time = 1.26 min.; ESI-MS(+) m/z 914.3 (M+2H).

[00470] HPLC analysis Condition C: retention time = 16.98 min. EXAMPLE 11 - SYNTHESIS OF COMPOUND NO. 10 Molecular weight: 1786.11

[00471] Example 11 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00472] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC AQ-ODS, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 10-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 3.9 mg, and its purity estimated by HPLC analysis was 99%.

[00473] LCMS analysis Condition A: retention time = 1.45 min.; ESI-MS(+) m/z 894.2 (M+2H).

[00474] HPLC analysis Condition D: retention time = 23.00 min. EXAMPLE 12 - SYNTHESIS OF COMPOUND NO. 11 Molecular weight: 1810.09

[00475] Example 12 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00476] The crude material was purified via preparatory HPLC using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-75% B over 45 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 3.6 mg, and its purity estimated by HPLC analysis was 99%.

[00477] LCMS Analysis Condition G: ESI-MS(+) m/z 905.8 (M+2H).

[00478] HPLC analysis Condition E: retention time = 14.68 min. EXAMPLE 13 - SYNTHESIS OF COMPOUND NO. 12 Molecular weight: 1838.14

[00479] Example 13 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00480] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-70% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 3.0 mg, and its purity estimated by HPLC analysis was 92%.

[00481] LCMS analysis Condition G: retention time = 4.06 min.; ESI-MS(+) m/z 919.8 (M+2H).

[00482] HPLC analysis Condition E: retention time = 13.71 min. EXAMPLE 14 - SYNTHESIS OF COMPOUND NO. 13 Molecular weight: 1866.19

[00483] Example 14 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: “Chloroacetyl Chloride Coupling Procedure A”, "Global Deprotection Method C", and "Cyclization Method C".

[00484] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 25-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.1 mg, and its purity estimated by LCMS analysis was 95% by “LCMS analysis conditions B and D".

[00485] LCMS Analysis Condition B: Retention time = 1.683 min; ESI-MS(+) m/z 933.70 (M+2H).

[00486] LCMS Analysis Condition D: Retention time = 1.750min; ESI-MS(+) m/z 933.95 (M+2H). EXAMPLE 15 - SYNTHESIS OF COMPOUND NO. 14 Molecular weight: 1866.19

[00487] Example 15 was prepared by following the general synthesis sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A:

[00488] Chloroacetyl chloride coupling procedure A", "Global deprotection method C" and "Cyclization method C".

[00489] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.3 mg, and its estimated purity by LCMS analysis was 98% by “LCMS analysis conditions B and D".

[00490] LCMS Analysis Condition B: Retention time = 1.566 min; ESI-MS(+) m/z 933.95 (M+2H).

[00491] LCMS Analysis Condition D: Retention time = 1.630 min; ESI-MS(+) m/z 934.00 (M+2H). EXAMPLE 16 - SYNTHESIS OF COMPOUND NO. 15 Molecular weight: 1737.04

[00492] Example 16 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “CEM Method A: N-Methyl Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[00493] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-60% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 7.0 mg, and its purity estimated by HPLC analysis was 93%.

[00494] LCMS analysis Condition A: retention time = 1.15 min.; ESI-MS(+) m/z 869.6 (M+2H).

[00495] HPLC analysis Condition E: retention time 10.49 min. EXAMPLE 17 - SYNTHESIS OF COMPOUND NO. 16 Molecular weight: 1836.17

[00496] Example 17 was prepared by following the general synthetic sequence described for the preparation of Example 2, consisting of the following general procedures: "CEM Method A: Resin Swelling Procedure", "CEM Method A: Single Coupling Procedure", "CEM Method A: Double Coupling Procedure", "CEM Method A: N-Methyl Amino Acid Coupling Procedure", "Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[00497] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-60% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 8.4 mg, and its purity estimated by HPLC analysis was 99%.

[00498] LCMS analysis Condition G: retention time = 3.76 min.; ESI-MS(+) m/z 919.8 (M+2H).

[00499] HPLC analysis Condition E: retention time = 14.69 min. EXAMPLE 18 - SYNTHESIS OF COMPOUND NO. 17 Molecular weight: 1737.04

[00500] Example 18 was prepared by following the general synthetic sequence described for the preparation of Example 2, consisting of the following general procedures: "CEM Method A: Resin Swelling Procedure", "CEM Method A: Single Coupling Procedure", "CEM Method A: Double Coupling Procedure", "CEM Method A: N-Methyl Amino Acid Coupling Procedure", "Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[00501] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-65% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 10.5 mg, and its purity estimated by HPLC analysis was 93%.

[00502] LCMS analysis Condition G: retention time = 3.60 min.; ESI-MS(+) m/z 869.3 (M+2H).

[00503] HPLC analysis Condition F: retention time = 11.75 min. EXAMPLE 19 - SYNTHESIS OF COMPOUND NO. 18 Molecular weight: 1838.14

[00504] To a 40 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: "Prelude Method B: Resin Swelling Procedure" was followed; "Prelude Method B: Double Coupling Procedure" was followed for couplings to the primary amine N-terminus; "Prelude Method B: Secondary Amine Coupling Procedure" was followed for couplings to the secondary amine N-terminus; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A" was followed; "Global Deprotection Method B" was followed; "Cyclization Method C" was followed.

[00505] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-75% B over 45 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 15 mg, and its purity estimated by HPLC analysis was 95%.

[00506] LCMS analysis Condition G: retention time = 3.53 min.; ESI-MS(+) m/z 919.8 (M+2H).

[00507] HPLC analysis Condition F: retention time 15.29 min. EXAMPLE 20 - SYNTHESIS OF COMPOUND NO. 19 Molecular weight: 1810.09

[00508] Example 20 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00509] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-55% B over 25 min, then a 5 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.6 mg, and its purity estimated by LCMS analysis was 97% by “LCMS analysis conditions B and D".

[00510] LCMS Analysis Condition B: Retention time = 1.434 min; ESI-MS(+) m/z 906.30 (M+2H).

[00511] LCMS Analysis Condition D: Retention time = 1.483min; ESI-MS(+) m/z 905.70 (M+2H). EXAMPLE 21 - SYNTHESIS OF COMPOUND NO. 20 Molecular weight: 1838.14

[00512] Example 21 was prepared by following the general synthetic sequence described for the preparation of Example 19, consisting of the following general procedures: "Prelude Method B: Resin Swelling Procedure", "Prelude Method B: Double Coupling Procedure" for couplings to the N-terminus of the primary amine; "Prelude Method B: Secondary Amine Coupling Procedure" for couplings to the N-terminus of the secondary amine; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[00513] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-65% B over 45 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 21.3 mg, and its purity estimated by HPLC analysis was 91%.

[00514] LCMS analysis Condition G: retention time = 3.84 min.; ESI-MS(+) m/z 919.8 (M+2H).

[00515] HPLC analysis Condition E: retention time 16.82 min. EXAMPLE 22 - SYNTHESIS OF COMPOUND NO. 21 Molecular weight: 1810.09

[00516] Example 22 was prepared by following the general synthetic sequence described for the preparation of Example 19, consisting of the following general procedures: "Prelude Method B: Resin Swelling Procedure", "Prelude Method B: Double Coupling Procedure" for couplings to the N-terminus of the primary amine; "Prelude Method B: Secondary Amine Coupling Procedure" for couplings to the N-terminus of the secondary amine; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[00517] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-50% B over 45 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 7.5 mg, and its purity estimated by HPLC analysis was 99%.

[00518] LCMS analysis Condition G: retention time = 3.89 min.; ESI-MS(+) m/z 905.8 (M+2H).

[00519] HPLC analysis Condition E: retention time = 13.23 min. EXAMPLE 23 - SYNTHESIS OF COMPOUND NO. 22 Molecular weight: 1767.06

[00520] Example 23 was prepared by following the general synthetic sequence described for the preparation of Example 19, consisting of the following general procedures: "Prelude Method B: Resin Swelling Procedure", "Prelude Method B: Double Coupling Procedure" for primary amine N-terminal couplings; "Prelude Method B: Secondary Amine Coupling Procedure" for secondary amine N-terminal couplings; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[00521] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 25-70% B over 45 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 25 mg, and its purity estimated by HPLC analysis was 99%.

[00522] LCMS analysis Condition G: retention time = 3.91 min.; ESI-MS(+) m/z 884.5 (M+2H).

[00523] HPLC analysis Condition E: retention time = 13.23 min. EXAMPLE 24 - SYNTHESIS OF COMPOUND NO. 23 Molecular weight: 1852.17

[00524] Example 24 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00525] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 15-55% B over 25 min, then a 5 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.8 mg, and its purity estimated by LCMS analysis was 98% by “LCMS analysis conditions B and D".

[00526] LCMS Analysis Condition B: Retention time = 1.505 min; ESI-MS(+) m/z 926.70 (M+2H).

[00527] LCMS Analysis Condition D: Retention time = 1.537 min; ESI-MS(+) m/z 926.80 (M+2H). EXAMPLE 25 - SYNTHESIS OF COMPOUND NO. 24 Molecular weight: 1795.12

[00528] Example 25 was prepared by following the general synthesis sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00529] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-60% B over 25 min, then a 5 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.9 mg, and its purity estimated by LCMS analysis was 100% by “LCMS analysis conditions B and D".

[00530] LCMS Analysis Condition B: Retention time = 1.676 min; ESI-MS(+) m/z 898.20 (M+2H).

[00531] LCMS Analysis Condition D: Retention time = 1.749 min; ESI-MS(+) m/z 898.45 (M+2H). EXAMPLE 26 - SYNTHESIS OF COMPOUND NO. 25 Molecular weight: 1891.20

[00532] Example 26 was prepared starting from intermediate resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual coupling procedure A", "Chloroacetic acid coupling procedure B", "Global deprotection method C", and "Cyclization method D". Fmoc-Trp(Boc)-OH was used in the first amino acid coupling step.

[00533] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5A particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.7 mg, and its purity estimated by LCMS analysis was 100%.

[00534] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 946.4 (M+2H).

[00535] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 946.4 (M+2H). EXAMPLE 27 - SYNTHESIS OF COMPOUND NO. 26 Molecular weight: 1902.23

[00536] Example 27 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-2-Nal-OH was used in the first amino acid coupling step.

[00537] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.4 mg, and its purity estimated by LCMS analysis was 100%.

[00538] LCMS Analysis Condition D: Retention time = 1.84 min; ESI-MS(+) m/z 951.9 (M+2H).

[00539] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 951.7 (M+2H).EXAMPLE 28 - SYNTHESIS OF COMPOUND NO. 27 Molecular weight: 1902.

[00540] Example 28 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-1-Nal-OH was used in the first amino acid coupling step.

[00541] The crude material was purified via preparatory LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.2 mg, and its purity estimated by LCMS analysis was 99.8%.

[00542] LCMS Analysis Condition A: Retention time = 0.83 min; ESI-MS(+) m/z 1903.7 (M+H), 952.3 (M+2H).

[00543] HPLC Analysis Condition J: Retention time = 13.9 min. EXAMPLE 29 - SYNTHESIS OF COMPOUND NO. 28 Molecular weight: 1928.:

[00544] Example 29 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-Bip-OH was used in the first amino acid coupling step.

[00545] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 100%.

[00546] LCMS Analysis Condition D: Retention time = 1.91 min; ESI-MS(+) m/z 964.9 (M+2H).

[00547] LCMS Analysis Condition E: Retention time = 1.84 min; ESI-MS(+) m/z 964.9 (M+2H). EXAMPLE 30 - SYNTHESIS OF COMPOUND NO. 29 Molecular weight: 1864.1

[00548] Example 30 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-1-Tiq-OH was used in the first amino acid coupling step.

[00549] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.2 mg, and its purity estimated by LCMS analysis was 100%.

[00550] LCMS Analysis Condition A: Retention time 0.81 min; ESI-MS(+) m/z 933.2 (M+2H).

[00551] HPLC Analysis Condition J: Retention time 13.85 min. EXAMPLE 31 - SYNTHESIS OF COMPOUND NO. 30 Molecular weight: 1868.17

[00552] Example 31 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-Tyr(tBu)-OH was used in the first amino acid coupling step.

[00553] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.8 mg, and its purity estimated by LCMS analysis was 100%.

[00554] LCMS Analysis Condition D: Retention time = 1.48 min; ESI-MS(+) m/z 934.8 (M+2H).

[00555] LCMS Analysis Condition E: Retention time = 1.45 min; ESI-MS(+) m/z 934.8 (M+2H). EXAMPLE 32 - SYNTHESIS OF COMPOUND NO. 31 Molecular weight: 1882.1

[00556] Example 32 was prepared starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-methoxy-Phe-OH was used in the first amino acid coupling step.

[00557] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 99.6%.

[00558] LCMS Analysis Condition A: Retention time 0.78 min; ESI-MS(+) m/z 942.0 (M+2H).

[00559] HPLC Analysis Condition J: Retention time 13.27 min. EXAMPLE 33 - SYNTHESIS OF COMPOUND NO. 32 Molecular weight: 1870.1

[00560] Example 33 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-Flouro-Phe-OH was used in the first amino acid coupling step.

[00561] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.85 mg, and its purity estimated by LCMS analysis was 99.8%.

[00562] LCMS Analysis Condition A: Retention time = 0.78 min; ESI-MS(+) m/z 936.6 (M+2H).

[00563] HPLC Analysis Condition J: Retention time = 13.58 min. EXAMPLE 34 - SYNTHESIS OF COMPOUND NO. 33 Molecular weight: 1886.61

[00564] Example 34 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-Chloro-Phe-OH was used in the first amino acid coupling step.

[00565] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.7 mg, and its purity estimated by LCMS analysis was 100%.

[00566] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 944.1 (M+2H).

[00567] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 943.6 (M+2H).EXAMPLE 35 - SYNTHESIS OF COMPOUND NO. 34 Molecular weight: 1931.06

[00568] Example 35 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-Bromo-Phe-OH was used in the first amino acid coupling step.

[00569] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 99.7%.

[00570] LCMS Analysis Condition A: Retention time 0.83 min; ESI-MS(+) m/z 966.3 (M+2H).

[00571] HPLC Analysis Condition J: Retention time 13.99 min. EXAMPLE 36 - SYNTHESIS OF COMPOUND NO. 35 Molecular weight: 1920.1

[00572] Example 36 was prepared starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-triflouromethyl-Phe-OH was used in the first amino acid coupling step.

[00573] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.5 mg, and its purity estimated by LCMS analysis was 91%.

[00574] LCMS Analysis Condition D: Retention time = 1.824 min; ESI-MS(+) m/z 960.90 (M+2H).

[00575] LCMS Analysis Condition E: Retention time = 1.59 min; ESI-MS(+) m/z 960.4 (M+2H). EXAMPLE 37 - SYNTHESIS OF COMPOUND NO. 36 Molecular weight: 1866.1

[00576] Example 37 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-methyl-Phe-OH was used in the first amino acid coupling step.

[00577] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 100%.

[00578] LCMS Analysis Condition D: Retention time = 1.847 min; ESI-MS(+) m/z 933.9 (M+2H).

[00579] LCMS Analysis Condition E: Retention time = 1.742 min; ESI-MS(+) m/z 933.9 (M+2H). EXAMPLE 38 - SYNTHESIS OF COMPOUND NO. 37 Molecular weight: 1908.:

[00580] Example 38 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-t-Butyl-Phe-OH was used in the first amino acid coupling step.

[00581] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 35-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 95%.

[00582] LCMS Analysis Condition D: Retention time = 2.003 min; ESI-MS(+) m/z 954.6 (M+2H).

[00583] LCMS Analysis Condition E: Retention time = 1.786 min; ESI-MS(+) m/z 954.6 (M+2H).EXAMPLE 39 - SYNTHESIS OF COMPOUND NO. 38 Molecular weight: 1853.16

[00584] Example 39 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-3-Pyr-OH was used in the first amino acid coupling step.

[00585] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.2 mg, and its purity estimated by LCMS analysis was 96%.

[00586] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 921 A (M+2H).

[00587] LCMS Analysis Condition E: Retention time = 1.13 min; ESI-MS(+) m/z 927.4 (M+2H).EXAMPLE 40 - SYNTHESIS OF COMPOUND NO. 39 Molecular weight: 1853.16

[00588] Example 40 was prepared, starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-4-Pyr-OH was used in the first amino acid coupling step.

[00589] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 94%.

[00590] LCMS Analysis Condition D: Retention time = 1.448 min; ESI-MS(+) m/z 921.55 (M+2H).

[00591] LCMS Analysis Condition E: Retention time = 1.121 min; ESI-MS(+) m/z 927.65 (M+2H).EXAMPLE 41 - SYNTHESIS OF COMPOUND NO. 40 Molecular weight: 1858.20

[00592] Example 41 was prepared starting from Intermediate Resin I, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-3-thienyl Alanine-OH was used in the first amino acid coupling step.

[00593] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.6 mg, and its purity estimated by LCMS analysis was 100%.

[00594] LCMS Analysis Condition D: Retention time = 1.649 min; ESI-MS(+) m/z 1858.8 (M+1), 929.9 (M+2H).

[00595] LCMS Analysis Condition E: Retention time = 1.589 min; ESI-MS(+) m/z 929.9 (M+2H).EXAMPLE 42 - SYNTHESIS OF COMPOUND NO. 41 Molecular weight: 1880.:

[00596] Example 42 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00597] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.5 mg, and its purity estimated by LCMS analysis was 100%.

[00598] LCMS Analysis Condition A: Retention time = 0.79 min; ESI-MS(+) m/z 941.2 (M+2H).

[00599] HPLC Analysis Condition J: Retention time = 13.45 min. EXAMPLE 43 - SYNTHESIS OF COMPOUND NO. 42 Molecular weight: 1852.17

[00600] Example 43 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00601] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.8 mg, and its purity estimated by LCMS analysis was 90%.

[00602] LCMS Analysis Condition D: Retention time = 1.553 min; ESI-MS(+) m/z 926.9 (M+2H).

[00603] LCMS Analysis Condition E: Retention time = 1.356 min; ESI-MS(+) m/z 926.7 (M+2H). EXAMPLE 44 - SYNTHESIS OF COMPOUND NO. 43 Molecular weight: 1795.1

[00604] Example 44 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00605] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.8 mg, and its purity estimated by LCMS analysis was 99.2%.

[00606] LCMS Analysis Condition A: Retention time = 0.76 min; ESI-MS(+) m/z 898.6 (M+2H).

[00607] HPLC Analysis Condition J: Retention time = 12.91 min. EXAMPLE 45 - SYNTHESIS OF COMPOUND NO. 44 Molecular weight: 1866.19

[00608] Example 45 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00609] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 20-60% B over 25 minutes; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.9 mg, and its purity estimated by LCMS analysis was 98% by "LCMS analysis conditions B and D".

[00610] LCMS Analysis Condition B: Retention time = 1.547 min; ESI-MS(+) m/z 934.65 (M+2H).

[00611] LCMS Analysis Condition D: Retention time = 1.732 min; ESI-MS(+) m/z 933.95 (M+2H). Example 46 - SYNTHESIS OF COMPOUND NO. 45 Molecular weight: 1906.26

[00612] Example 46 was prepared by following the general synthesis sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00613] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 30-70% B over 25 min; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.5 mg, and its purity estimated by LCMS analysis was 95% by “LCMS analysis conditions B and D".

[00614] LCMS Analysis Condition B: Retention time = 1.710 min; ESI-MS(+) m/z 954.20 (M+2H).

[00615] LCMS Analysis Condition D: Retention time = 1.966 min; ESI-MS(+) m/z 954.20 (M+2H). EXAMPLE 47 - SYNTHESIS OF COMPOUND NO. 46 Molecular weight: 1928.26

[00616] Example 47 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00617] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 25-70% B over 25 min; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.4 mg, and its purity estimated by LCMS analysis was 96% by “LCMS analysis conditions B and D".

[00618] LCMS Analysis Condition B: Retention time = 1.851 min; ESI-MS(+) m/z 964.95 (M+2H).

[00619] LCMS Analysis Condition D: Retention time = 1.957 min; ESI-MS(+) m/z 964.75 (M+2H). EXAMPLE 48 - SYNTHESIS OF COMPOUND NO. 47 Molecular weight: 1868.17

[00620] Example 48 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00621] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15-60% B over 25 min; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.5 mg, and its purity estimated by LCMS analysis was 98% by “LCMS analysis conditions B and D".

[00622] LCMS Analysis Condition B: Retention time = 1.486 min; ESI-MS(+) m/z 934.95 (M+2H).

[00623] LCMS Analysis Condition D: Retention time = 1.636 min; ESI-MS(+) m/z 935.00 (M+2H). EXAMPLE 49 - SYNTHESIS OF COMPOUND NO. 48 Molecular weight: 1867.18

[00624] Example 49 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00625] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 20-65% B over 25 min, then a 5 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.7 mg, and its purity estimated by LCMS analysis was 99% by “LCMS analysis conditions B and D".

[00626] LCMS Analysis Condition B: Retention time = 1.290 min; ESI-MS(+) m/z 934.45 (M+2H).

[00627] LCMS Analysis Condition D: Retention time = 1.567 min; ESI-MS(+) m/z 934.55 (M+2H).EXAMPLE 50 - SYNTHESIS OF COMPOUND NO. 49 Molecular weight: 1866.19

[00628] Example 50 was prepared by following the general synthesis sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00629] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15-60% B over 25 min, then a 5 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.7 mg, and its purity estimated by LCMS analysis was 99% by “LCMS analysis conditions B and D".

[00630] LCMS Analysis Condition B: Retention time = 1.623 min; ESI-MS(+) m/z 933.95 (M+2H).

[00631] LCMS Analysis Condition D: Retention time = 1.841 min; ESI-MS(+) m/z 933.95 (M+2H).EXAMPLE 51 - SYNTHESIS OF COMPOUND NO. 50 Molecular weight: 1838.14

[00632] Example 51 was prepared by following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method C", and "Cyclization Method C".

[00633] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.8 mg, and its purity estimated by LCMS analysis was 97% by “LCMS analysis conditions B and D".

[00634] LCMS Analysis Condition B: Retention time = 1.476 min; ESI-MS(+) m/z 920.00 (M+2H).

[00635] LCMS Analysis Condition D: Retention time = 1.670 min; ESI-MS(+) m/z 919.95 (M+2H).EXAMPLE 52 - SYNTHESIS OF COMPOUND NO. 51 Molecular weight: 1854.10

[00636] Example 52 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00637] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 3 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.3 mg, and its purity estimated by LCMS analysis was 97.5%.

[00638] LCMS Analysis Condition A: Retention time = 0.80 min; ESI-MS(+) m/z 928.0 (M+2H).

[00639] HPLC Analysis Condition J: Retention time = 13.38 min.EXAMPLE 53 - SYNTHESIS OF COMPOUND NO. 52 Molecular weight: 1881.21

[00640] Example 53 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00641] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.6 mg, and its purity estimated by LCMS analysis was 100%.

[00642] LCMS Analysis Condition D: Retention time = 1.390 min; ESI-MS(+) m/z 941.35 (M+2H), 1881.85 (M+H).

[00643] LCMS Analysis Condition E: Retention time = 1.355 min; ESI-MS(+) m/z 941.50 (M+2H).EXAMPLE 54 - SYNTHESIS OF COMPOUND NO. 53 Molecular weight: 1918.23

[00644] Example 54 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00645] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.7 mg, and its purity estimated by LCMS analysis was 100%.

[00646] LCMS Analysis Condition D: Retention time = 1.682 min; ESI-MS(+) m/z 959.85 (M+2H).

[00647] LCMS Analysis Condition E: Retention time = 1.607 min; ESI-MS(+) m/z 959.85 (M+2H).EXAMPLE 55 - SYNTHESIS OF COMPOUND NO. 54 Molecular weight: 1937.28

[00648] Example 55 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00649] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 0 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.5 mg, and its purity estimated by LCMS analysis was 100%.

[00650] LCMS Analysis Condition D: Retention time = 1.398 min; ESI-MS(+) m/z 969.45 (M+2H).

[00651] LCMS Analysis Condition E: Retention time = 1,360 min; ESI-MS(+) m/z 969.75 (M+2H).EXAMPLE 56 - SYNTHESIS OF COMPOUND NO. 55 Exact mass: 1876.96

[00652] Example 56 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00653] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.0 mg, and its purity estimated by LCMS analysis was 100%.

[00654] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 940.2 (M+2H).

[00655] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 940.2 (M+2H).EXAMPLE 57 - SYNTHESIS OF COMPOUND NO. 56 Molecular weight: 1882.19

[00656] Example 57 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00657] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.0 mg, and its purity estimated by LCMS analysis was 98%.

[00658] LCMS Analysis Condition D: Retention time = 1.714 min; ESI-MS(+) m/z 1882.85 (M+1), 941.90 (M+2).

[00659] LCMS Analysis Condition E: Retention time = 1.532 min; ESI-MS(+) m/z 941.90 (M+2).EXAMPLE 58 - SYNTHESIS OF COMPOUND NO. 57 Molecular weight: 1868.17

[00660] Example 58 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00661] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.68 mg, and its purity estimated by LCMS analysis was 97.4%.

[00662] LCMS Analysis Condition D: Retention time = 1.714 min; ESI-MS(+) m/z 1868.85 (M+1), 934.85 (M+2).

[00663] LCMS Analysis Condition E: Retention time = 1.526 min; ESI-MS(+) m/z 934.65 (M+2).EXAMPLE 59 - SYNTHESIS OF COMPOUND NO. 58 Molecular weight: 1879.19

[00664] Example 59 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00665] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.45 mg, and its purity estimated by LCMS analysis was 99%.

[00666] LCMS Analysis Condition D: Retention time = 1.454 min; ESI-MS(+) m/z 1879.90 (M+1), 940.55 (M+2).EXAMPLE 60 - SYNTHESIS OF COMPOUND NO. 59 Molecular weight: 1894.20

[00667] Example 60 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00668] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.7 mg, and its purity estimated by LCMS analysis was 94.4%.

[00669] LCMS Analysis Condition D: Retention time = 1.452 min; ESI-MS(+) m/z 947.60 (M+2).

[00670] LCMS Analysis Condition E: Retention time = 1.257 min; ESI-MS(+) m/z 947.65 (M+2).EXAMPLE 61 - SYNTHESIS OF COMPOUND NO. 60 Molecular weight: 1751.06

[00671] Example 61 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00672] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.1 mg, and its purity estimated by LCMS analysis was 92.5%.

[00673] LCMS Analysis Condition D: Retention time = 1,800 min; ESI-MS(+) m/z 1751.85 (M+1), 876.35 (M+2).

[00674] LCMS Analysis Condition E: Retention time = 1.620 min; ESI-MS(+) m/z 876.35 (M+2).EXAMPLE 62 - SYNTHESIS OF COMPOUND NO. 61 Molecular weight: 1797.15

[00675] Example 62 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00676] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.1 mg, and its purity estimated by LCMS analysis was 100%.

[00677] LCMS Analysis Condition D: Retention time = 1.616 min; ESI-MS(+) m/z 899.40 (M+2H).

[00678] LCMS Analysis Condition E: Retention time = 1.558 min; ESI-MS(+) m/z 899.35 (M+2H).EXAMPLE 63 - SYNTHESIS OF COMPOUND NO. 62 Molecular weight: 1779.12

[00679] Example 63 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00680] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.2 mg, and its purity estimated by LCMS analysis was 99%.

[00681] LCMS Analysis Condition D: Retention time = 1.575 min; ESI-MS(+) m/z 1779.90 (M+1), 890.30 (M+2).

[00682] LCMS Analysis Condition E: Retention time = 1.37 min; ESI-MS(+) m/z 889.9 (M+2H).

[00683] EXAMPLE 64 - SYNTHESIS OF COMPOUND NO. 63 Molecular weight: 1779.12

[00684] Example 64 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00685] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.5 mg, and its purity estimated by LCMS analysis was 100%.

[00686] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 890.4 (M+2H).

[00687] LCMS Analysis Condition E: Retention time = 1.54 min; ESI-MS(+) m/z 890.3 (M+2H).EXAMPLE 65 - SYNTHESIS OF COMPOUND NO. 64 Molecular weight: 1869.22

[00688] Example 65 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00689] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.1 mg, and its purity estimated by LCMS analysis was 96.4%.

[00690] LCMS Analysis Condition D: Retention time = 1.847 min; ESI-MS(+) m/z 935.70 (M+2).

[00691] LCMS Analysis Condition E: Retention time = 1.658 min; ESI-MS(+) m/z 935.60 (M+2).EXAMPLE 66 - SYNTHESIS OF COMPOUND NO. 65 Molecular weight: 1852.17

[00692] Example 66 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00693] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.44 mg, and its purity estimated by LCMS analysis was 100%.

[00694] LCMS Analysis Condition D: Retention time = 1.605 min; ESI-MS(+) m/z 926.95 (M+2).EXAMPLE 67 - SYNTHESIS OF COMPOUND NO. 66 Molecular weight: 1826.09

[00695] Example 67 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00696] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.41 mg, and its purity estimated by LCMS analysis was 97.3%.

[00697] LCMS Analysis Condition D: Retention time = 1.388 min; ESI-MS(+) m/z 914.35 (M+2).

[00698] LCMS Analysis Condition E: Retention time = 1.228 min; ESI-MS(+) m/z 914.30 (M+2).EXAMPLE 68 - SYNTHESIS OF COMPOUND NO. 67 Molecular weight: 1886.1

[00699] Example 68 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00700] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.9 mg, and its purity estimated by LCMS analysis was 98%.

[00701] LCMS Analysis Condition D: Retention time=1.659 min; ESI-MS(+) m/z 1886.80 (M+1), 943.90 (M+2).

[00702] LCMS Analysis Condition E: Retention time=1.449 min; ESI-MS(+) m/z 943.90 +2).EXAMPLE 69 - SYNTHESIS OF COMPOUND NO. 68 Molecular weight: 1812.

[00703] Example 69 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00704] The material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.3 mg, and its purity estimated by LCMS analysis was 95%.

[00705] LCMS Analysis Condition D: Retention time = 1.402 min; ESI-MS(+) m/z 1812.80 (M+1), 906.80 (M+2).

[00706] LCMS Analysis Condition E: Retention time=1.216 min; ESI-MS(+) m/z 906.80 (M+2).EXAMPLE 70 - SYNTHESIS OF COMPOUND NO. 69 Molecular weight: 1872.1

[00707] Example 70 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00708] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity estimated by LCMS analysis was 98%.

[00709] LCMS Analysis Condition D: Retention time=1.590 min; ESI-MS(+) m/z 1872.85 (M+1), 936.90 (M+2).

[00710] LCMS Analysis Condition E: Retention time=1.377 min; ESI-MS(+) m/z 936.65 (M+2).EXAMPLE 71 - SYNTHESIS OF COMPOUND NO. 70 Molecular weight: 1838.1

[00711] Example 71 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00712] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 minutes, then a 3-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 97.9%.

[00713] LCMS Analysis Condition A: Retention time = 0.80 min; ESI-MS(+) m/z 920.1 (M+2H).

[00714] HPLC analysis Condition J: Retention time = 13.01 min.TABLE 2 - SERIES OF PEPTIDES OF FORMULA II * *Compounds Nos. 71 through 87 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine. EXAMPLE 72 - SYNTHESIS OF COMPOUND NO. 71 Molecular weight: 1796.09

[00715] To a 40 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: "Prelude Method A: Resin Swelling Procedure" was followed; "Prelude Method A: Simple Coupling Procedure" was followed with Fmoc-Gly-OH; "Prelude Method A: Simple Coupling Procedure" was followed with Fmoc-Cys(Trt)-OH; "Prelude Method A: Simple Coupling Procedure" was followed with Fmoc-Leu-OH; "Prelude Method A: Simple Coupling Procedure" was followed with Fmoc-Tyr(tBu)-OH; "Prelude Method A: Simple coupling procedure" was followed with Fmoc-Trp(Boc)-OH; "Prelude Method A: Simple coupling procedure" was followed with Fmoc-Sar-OH; "Prelude Method A: Custom amino acid coupling procedure" was followed with Fmoc-Tyr(tBu)-OH using 10 eq for 10 h; "Prelude Method A: Simple coupling procedure" was followed with Fmoc-[N-Me]Phe-OH; "Prelude Method A: Secondary amine coupling procedure" was followed with Fmoc-Val-OH; "Prelude Method A: Simple coupling procedure" was followed with Fmoc-Asp(OtBu)-OH; "Prelude Method A: Secondary amine coupling procedure" was followed with Fmoc-Sar-OH; "Prelude Method A: Secondary Amine Coupling Procedure" was followed with Fmoc-[N-Me]Nle-OH; "Prelude Method A: Secondary Amine Coupling Procedure" was followed with Fmoc-[N-Me]Phe-OH; "Prelude Method A: Secondary Amine Coupling Procedure" was followed with Fmoc-Phe-OH; "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A" was followed; "Global Deprotection Method B" was followed; "Cyclization Method C" was followed.

[00716] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B in A over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 28.6 mg, and its purity was estimated to be 98% by HPLC "Analysis Condition B" using a gradient from 35% to 95% B in A over 30 minutes.

[00717] Analysis Condition A: Retention time = 1.451 min; ESI-MS(+) m/z 899.3 (M+2H). ESI-HRMS(+) m/z: Calculated: 898.4313 (M+2H); Found: 898.4294. EXAMPLE 73 - SYNTHESIS OF COMPOUND NO. 72 Molecular weight: 1720.00

[00718] Example 73 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”.

[00719] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.2 mg, and its purity estimated by LCMS analysis was 100.0%.

[00720] LCMS Analysis Condition A: Retention time = 0.85 min; ESI-MS(+) m/z 860.96 (M+2H).

[00721] HPLC Analysis Condition J: Retention time = 14.696min.EXAMPLE 74 - SYNTHESIS OF COMPOUND NO. 73 Molecular weight: 1720.00

[00722] Example 74 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”.

[00723] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 minutes, followed by a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.4 mg, and its purity estimated by LCMS analysis was 99%.

[00724] LCMS Analysis Condition A: Retention time = 0.87 min; ESI-MS(+) m/z 861.1 (M+2).

[00725] HPLC Analysis Condition J: Retention time = 14.82 min.EXAMPLE 75 - SYNTHESIS OF COMPOUND NO. 74 Molecular weight: 1782.07

[00726] Example 75 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00727] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.7 mg, and its purity estimated by LCMS analysis was 95%.

[00728] LCMS Analysis Condition E: Retention time = 1.98 min; ESI-MS(+) m/z 1783.2 (M+l).EXAMPLE 76 - SYNTHESIS OF COMPOUND NO. 7 Molecular weight: 1754.01

[00729] Example 76 was prepared following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”.

[00730] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 minutes, then a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.9 mg, and its purity estimated by LCMS analysis was 99.6%.

[00731] LCMS Analysis Condition A: Retention time = 0.83 min; ESI-MS(+) m/z 1754.7 (M+H), 878.0 (M+2H).

[00732] HPLC Analysis Condition J: Retention time = 14.44 min.EXAMPLE 77 - SYNTHESIS OF COMPOUND NO. 76 Molecular weight: 1782.07

[00733] Example 77 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00734] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 100%.

[00735] LCMS Analysis Condition D: Retention time = 1.610 min; ESI-MS(+) m/z 1782.75 (M+1), 891.60 (M+2).

[00736] LCMS Analysis Condition E: Retention time = 1.775 min; ESI-MS(+) m/z 892.10 (M+2).EXAMPLE 78 - SYNTHESIS OF COMPOUND NO. 77 Molecular weight: 1810.12

[00737] Example 78 was prepared following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”. Fmoc-N-Me-Ala-OH was used in the eleventh amino acid coupling step.

[00738] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 minutes, then a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.9 mg, and its purity estimated by LCMS analysis was 97.7%.

[00739] LCMS Analysis Condition A: Retention time = 0.94 min; ESI-MS(+) m/z 1811.1 (M+H), 906.0 (M+2H).

[00740] HPLC Analysis Condition J: Retention time = 16.38 min.EXAMPLE 79 - SYNTHESIS OF COMPOUND NO. 78 Molecular weight: 1782.07

[00741] Example 79 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00742] The material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.0 mg, and its purity estimated by LCMS analysis was 97%.

[00743] LCMS Analysis Condition D: Retention time=1.591 min; ESI-MS(+) m/z 1782.80 (M+1), 891.85 (M+2).

[00744] LCMS Analysis Condition E: Retention time=1.634 min; ESI-MS(+) m/z 891.60 (M+2).EXAMPLE 80 - SYNTHESIS OF COMPOUND NO. 79 Molecular weight: 1752.08

[00745] Example 80 was prepared following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”.

[00746] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10 1000% B over 20 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 95.7%.

[00747] LCMS Analysis Condition A: Retention time = 0.94 min; ESI-MS(+) m/z 1753.8 (M+H), 877.0 (M+2H).

[00748] HPLC Analysis Condition J: Retention time = 16.19 min.EXAMPLE 81 - SYNTHESIS OF COMPOUND NO. 80 Molecular weight: 1768.04

[00749] Example 81 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method E”.

[00750] The crude material was purified via preparatory LC under the following conditions: Column: FENOMENEX® Luna C18, 30 x 100 mm; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-1000% B over 20 minutes, followed by a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.7 mg, and its purity estimated by LCMS analysis was 100%.

[00751] LCMS Analysis Condition A: Retention time = 0.86 min; ESI-MS(+) m/z 1769.0 (M+H), 884.8 (M+2H).

[00752] HPLC Analysis Condition J: Retention time = 14.89 min.EXAMPLE 82 - SYNTHESIS OF COMPOUND NO. 81 Molecular weight: 1720.00

[00753] Example 82 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method E".

[00754] The crude material was purified via preparative HPLC with the following conditions: 4 x 2 mL injections on a 30 x 100 C18 column with a gradient of 10 to 100% Acetonitrile in water, 0.1% TFA as modifier over 20 minutes. The yield of the product was 4.0 mg, and its estimated purity by HPLC analysis was 90%.

[00755] LCMS Analysis Condition A: Retention time = 0.85 min; ESI-MS(+) m/z 861.0 (M+2).

[00756] HPLC Analysis Condition J : Retention time = 14.249 min.EXAMPLE 83 - SYNTHESIS OF COMPOUND NO. 82 Molecular weight: 1782.07

[00757] Example 83 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00758] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 100%.

[00759] LCMS Analysis Condition D: Retention time = 1.587 min; ESI-MS(+) m/z 1782.75 (M+1), 891.65 (M+2).

[00760] LCMS Analysis Condition E: Retention time = 1,750 min; ESI-MS(+) m/z 891.70 (M+2).EXAMPLE 84 - SYNTHESIS OF COMPOUND NO. 83 Molecular weight: 1704.00

[00761] Example 84 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method E".

[00762] The crude material was purified via preparative HPLC with the following conditions: 4 x 2 mL injections on a 30 x 100 C18 column with a gradient of 10 to 100% Acetonitrile in water, 0.1% TFA as modifier over 20 minutes. The yield of the product was 1.04 mg, and its estimated purity by HPLC analysis was 91%.

[00763] LCMS Analysis Condition A: Retention time = 0.91min; ESI-MS(+) m/z 852.8 (M+2H).

[00764] HPLC Analysis Condition J: Retention time EXAMPLE 85 - SYNTHESIS OF COMPOUND NO. 84 Molecular weight: 1810.12

[00765] Example 85 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method E".

[00766] The crude material was purified via preparatory HPLC with the following conditions: 4 x 2 mL injections on a 30 x 100 C18 column with a gradient of 10 to 100% Acetonitrile in water, 0.1% TFA as modifier over 20 minutes. The yield of the product was 1.01 mg, and its estimated purity by HPLC analysis was 98%.

[00767] LCMS Analysis Condition A: Retention time = 0.93 min; ESI-MS(+) m/z 906.3 (M+2H).

[00768] HPLC Analysis Condition J: Retention time = 16.484 min.EXAMPLE 86 - SYNTHESIS OF COMPOUND NO. 85 Molecular weight: 1782.07

[00769] Example 86 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00770] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.5 mg, and its purity estimated by LCMS analysis was 96%.

[00771] LCMS Analysis Condition D: Retention time = 1.611 min; ESI-MS(+) m/z 1782.70 (M+1), 891.80 (M+2).

[00772] LCMS Analysis Condition E: Retention time = 1.783 min; ESI-MS(+) m/z 891.95 (M+2).EXAMPLE 87 - SYNTHESIS OF COMPOUND NO. 86 Molecular weight: 1704.00

[00773] Example 87 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method E".

[00774] The crude material was purified via preparatory HPLC with the following conditions: 4 x 2 mL injections on a 30 x 100 C18 column with a gradient of 10 to 100% Acetonitrile in water, 0.1% TFA as modifier over 20 minutes. The yield of the product was 1.53 mg, and its estimated purity by HPLC analysis was 97%.

[00775] LCMS Analysis Condition A: Retention time = 0.92min; ESI-MS(+) m/z 852.3 (M+2).

[00776] HPLC Analysis Condition J: Retention time = 16.044 min.EXAMPLE 88 - SYNTHESIS OF COMPOUND NO. 87 Molecular weight: 1754.01

[00777] Example 88 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method E".

[00778] The crude material was purified via preparative HPLC with the following conditions: 4 x 2 mL injections on a 30 x 100 C18 column with a gradient of 10 to 100% Acetonitrile in water, 0.1% TFA as modifier over 20 minutes. The yield of the product was 1 mg, and its purity estimated by HPLC analysis was 92%.

[00779] LCMS Analysis Condition A: Retention time = 0.88 min; ESI-MS(+) m/z 877.1 (M+2H).

[00780] HPLC Analysis Condition J: Retention time = 15,511 min.TABLE 3 - SULFOXIDE AND LACTAM LINKERS FOR PEPTIDES OF COMPOUNDS NOS. 1 AND 71 *Compounds Nos. 71 through 87 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine. EXAMPLE 72 - SYNTHESIS OF COMPOUND NO. 71

[00783] Compounds Nos. 88 to 90 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine.

[00784] Compounds Nos. 91 to 98 are macrocyclic lactam peptides cyclized via the amino acids mentioned in the comments section. EXAMPLE 89 - SYNTHESIS OF COMPOUND NO. 88 DIASTEREOMERIC MIXTURE OF SULFOCIDES OF COMPOUND NO. 1 Molecular weight: 1868.17

[00785] Example 89 [Compound No. 88] was prepared by oxidation of the macrocyclic peptide from Example 2 using the following procedure: to a solution of the macrocyclic peptide from Example 2 (1.6 mg) in 1 mL of 50 mM NH4HCO4/Acetonitrile (1:1) was added a 1 mg/mL solution of m-chloroperbenzoic acid (0.9 eq.) in acetonitrile. The reaction mixture was stirred at room temperature for 18 h.

[00786] The product was purified via preparatory HPLC using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 20-75% B in A over 55 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 0.91 mg, and its purity estimated by HPLC analysis was 98%.

[00787] LCMS Analysis Condition C: Retention time = 1.16 min; ESI-MS(+) m/z 935.4 (M+2H).

[00788] HPLC Analysis Condition A: Retention time = 9.19 min and 9.41 min for partially resolved diastereomers.EXAMPLE 90. SYNTHESIS OF COMPOUNDS NOS89 AND 90 [SULFOXIDES OF COMPOUND NO. 71] Molecular weight: 1812.09

[00789] The synthesis of the compounds of Example 90 (Compounds Nos. 89 and 90) was carried out by oxidation of the macrocyclic peptide of Example 71 using the following procedure: to a solution of the peptide of Example 71 (1.4 mg) in 1 mL of 50 mM NH4HCO4/Acetonitrile (1:1) was added a 1 mg/mL acetonitrile solution of m-chloroperbenzoic acid (m-CPBA) (0.9 eq.). The reaction mixture was stirred at room temperature for 18 h.

[00790] The product was purified via preparatory HPLC using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in AcCN; gradient: 20-75% B over 55 min.; Flow rate: 15 mL/min. Two isomeric products were separated, Isomer A (Compound No. 89) and Isomer B (Compound No. 90). Fractions containing them were combined and dried by lyophilization.

[00791] The yield of the fastest eluting Isomer A (Compound No. 89) was 0.49 mg, and its estimated purity by HPLC analysis was 98%.

[00792] LCMS Analysis Condition C: Retention time = 1.62 min; ESI-MS(+) m/z 907.4 (M+2H).

[00793] HPLC Analysis Condition G: Retention time

[00794] The yield of the slower eluting Isomer B (Compound No. 90) was 0.49 mg, and its estimated purity by HPLC analysis was 99%.

[00795] LCMS Analysis Condition C: Retention time = 1.65 min; ESI-MS(+) m/z 907.4 (M+2H).

[00796] HPLC Analysis Condition G: Retention time = 13.61 min.EXAMPLE 92 - SYNTHESIS OF COMPOUND NO. 91 Molecular weight: 1806.08

[00797] Example 92 was prepared following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure". Fmoc-Asp(0-2-PhiPr)-OH was used as the orthogonal protection of the Asp14 residue. After removal of the last Fmoc, the peptidyl resin was cleaved from the solid support by treating it four times with DCM/TIS/TFA (96:3:1; v:v:v) (4 mL) for 5 min. This step also removed the 2-phenylisopropyl ester from the Asp14 residue. The protected peptide (70.4 mg) was cyclized using 1 eq. English:of T3P (50% EtOAc) and 2 eq. of DIEA in (1:1) acetonitrile/DCM (20 mL). The reaction was allowed to proceed for 18 h. The solvents were removed under reduced pressure, and the resulting solid was treated with (50:46:4) TFA/DCM/TIS (4 mL) for 1.5 h at room temperature. The reaction mixture was concentrated in vacuo. Addition of ether (20 mL) and cooling to 0 °C for 15 min afforded a solid that was washed with ether and dried to give 27 mg of crude product. The crude material was purified via preparative LC/MS using the following conditions: Column: YMC ODS-AQ, 20 × 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 2060% B over 60 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via lyophilization. The product yield was 1.7 mg, and its purity estimated by HPLC analysis was 93%.

[00798] LCMS analysis Condition A: retention time = 0.97 min.; ESI-MS(+) m/z 904.3 (M+2H).

[00799] HPLC analysis Condition E: retention time = 10.11 min.EXAMPLE 93 - SYNTHESIS OF COMPOUND NO. 92 Molecular weight: 1820.10

[00800] Example 93 was prepared following the general synthetic sequence described for the preparation of Example 92, except that Fmoc-Glu(0-2-PhiPr)-OH was used at position 14. After release of the protected peptide from the solid support, T3P-mediated cyclization of the resulting protected peptide and TFA-mediated side chain deprotection gave the crude product (28 mg), which was purified via preparative LC/MS using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 25-75% B over 75 min; Flow rate: 15 mL/min. The fractions containing the desired product were combined and dried via lyophilization. The product yield was 6.3 mg, and its purity estimated by HPLC analysis was 97.5%.

[00801] LCMS analysis Condition G: retention time = 3.88 min.; ESI-MS(+) m/z 911.08 (M+2H).

[00802] HPLC analysis Condition H. retention time = 12.04 min.EXAMPLE 94 - SYNTHESIS OF COMPOUND NO. 93 Molecular weight: 1863.13

[00803] Example 94 was prepared following the general synthetic sequence described for the preparation of Example 92, except that an additional Fmoc-Gly-OH was coupled to the N-terminus. After release from the solid support, T3P-mediated cyclization of the resulting protected peptide, and TFA-mediated side chain deprotection, the crude product (25 mg) was purified via preparative LC/MS using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 20-60% B over 60 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via freeze-drying. The product yield was 1.0 mg, and its purity estimated by HPLC analysis was 95%.

[00804] LCMS analysis Condition A: retention time = 1.00 min.; ESI-MS(+) m/z 932.8 (M+2H).

[00805] HPLC analysis Condition E: retention time = 11.07 min.EXAMPLE 95 - SYNTHESIS OF COMPOUND NO. 94 Molecular weight: 1877.15

[00806] Example 95 was prepared following the general synthetic sequence described for the preparation of Example 93, except that an additional Fmoc-Gly-OH was coupled to the N-terminus. After release from the solid support, T3P-mediated cyclization of the resulting protected peptide, and TFA-mediated side chain deprotection, the crude product (25 mg) was purified via preparative LC/MS using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 20-60% B over 60 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via freeze-drying. The product yield was 3.8 mg, and its purity estimated by HPLC analysis was 98%.

[00807] LCMS analysis Condition G: retention time = 4.27 min.; ESI-MS(+) m/z 939.5 (M+2H).

[00808] HPLC analysis Condition E: retention time = 13.76 min.EXAMPLE 96 - SYNTHESIS OF COMPOUND NO. 95 Molecular weight: 1807.05

[00809] Example 96 was prepared following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure". Fmoc-Asp(0-2-PhiPr)-OH was used as the orthogonal protection of the Asp13 residue. After removal of the last Fmoc, the peptidyl resin was cleaved from the solid support by treating it five times with DCM/TIS/TFA (96:3:1; v:v:v) (5 mL) for 1 min. This step also removed the 2-phenylisopropyl ester from the Asp13 residue. The filtrates were collected in a flask containing 1.5 mL of pyridine. The filtrates were then extracted with water (3 × 5 mL). The organic phase was dried to give an oil, which was then lyophilized from MeCN/water (1 : 2) to give a solid product (100 mg). A portion of the product (34 mg, 0.017 mmol) was cyclized using 1 eq. of HATU and 2 eq. of DIEA in (1 : 9) DMF/DCM (17 mL). The reaction was allowed to proceed for 18 h. The solvents were removed under reduced pressure, and the resulting solid was treated with (95:5) TFA/TIS (6 mL) for 5 min at room temperature. Addition of ether (20 mL) afforded a solid, which was washed with ether and dried. The product was purified via preparative LC/MS using the following conditions: Column: FENOMENEX® C18 Luna, 20 × 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 30-95% B over 50 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via lyophilization. The product yield was 1.9 mg, and its purity estimated by HPLC analysis was 95%.

[00810] LCMS analysis Condition A: retention time = 1.40 min.; ESI-MS(+) m/z 904.7 (M+2H).

[00811] HPLC analysis Condition G: retention time = 13.54 min.EXAMPLE 97 - SYNTHESIS OF COMPOUND NO. 96 Molecular weight: 1821 .08

[00812] Example 97 was prepared following the general synthetic sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin swelling procedure”, “CEM Method A: Single coupling procedure”, “CEM Method A: Double coupling procedure”. Fmoc-Glu(0-2-PhiPr)-OH was used as the orthogonal protection of the Glu13 residue. After removal of the last Fmoc, the peptidyl resin was cleaved from the solid support by treating it five times with DCM/TIS/TFA (96:3:1; v:v:v) (5 mL) for 1 min. This step also removed the 2-phenylisopropyl ester from the Glu residue. The filtrates were collected in a flask containing 1.5 mL of pyridine and were then extracted with water (3 x 5 mL). The organic phase was evaporated to give an oil, which was then lyophilized from MeCN/water (1:2) to give a solid product (36 mg). The peptide was deprotected using TFA/TIS/water (96:2:2) for 5 min and was then precipitated in ether, washed with ether, and dried. The protected peptide (32 mg, 0.015 mmol) mg) was cyclized using 1 eq. of HATU and 2 eq. of DIEA in DMF (30 mL). The reaction was allowed to proceed for 18 h. The solvent was removed under reduced pressure, and the residue was precipitated with water, washed, and dried. The resulting solid was treated with (48:48:4) TFA/DCM/TIS (3 mL) for 5 min at room temperature. Addition of ether (20 mL) afforded a solid, which was washed with ether and dried to give a solid product. The product was purified via preparative LC/MS using the following conditions: Column: YMC ODS-AQ, 20 × 250 mm, 5 μm particles, heated to 60 °C; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 20-60% B over 60 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via lyophilization. The product yield was 0.4 mg, and its purity estimated by HPLC analysis was 99%.

[00813] LCMS analysis Condition C: retention time = 1.63 min.; ESI-MS(+) m/z 911.9 (M+2H).

[00814] HPLC analysis Condition I: retention time = 12.50 min.EXAMPLE 98 - SYNTHESIS OF COMPOUND NO. 97 Molecular weight: 1750.00

[00815] Example 98 was prepared following the general synthetic sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure". Fmoc-Asp(0-2-PhiPr)-OH was used as the orthogonal protection of the Asp13 residue. After removal of the last Fmoc, the peptidyl resin was cleaved from the solid support by treating it five times with DCM/TIS/TFA (96:3:1; v:v:v) (5 mL) for 1 min. This step also removed the 2-phenylisopropyl ester from the Asp13 residue. The filtrates were collected in a flask containing 1.5 mL of pyridine. The filtrates were then extracted with water (3 × 5 mL). The organic phase was dried to give an oil, which was then lyophilized from MeN/water (1 : 2) to give a solid product (97 mg). A portion of the product (35 mg, 0.017 mmol) was cyclized using 1 eq. of HATU and 2 eq. of DIEA in (1 : 9) DMF/acetonitrile (17 mL). The reaction was allowed to proceed for 18 h. The solvents were removed under reduced pressure, and the residue was redissolved in acetonitrile (1 mL) and then precipitated with water (2 mL). The collected peptide was redissolved in DCM and extracted with water (2 × 5 mL). The organic layer was then dried over sodium sulfate, filtered, and dried to give 97 mg of protected peptide. This was treated with (95:5) TFA/TIS (6 mL) for 5 min at room temperature. Addition of ether (20 mL) yielded a solid, which was washed with ether and dried. The product was purified via preparative LC/MS using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 30-95% B over 50 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via lyophilization. The yield of the product was 1.0 mg, and its purity estimated by HPLC analysis was 82%.

[00816] LCMS analysis Condition A: retention time = 1.42 min.; ESI-MS(+) m/z 876.2 (M+2H).

[00817] HPLC analysis Condition G: retention time = 14.01 min.EXAMPLE 99 - SYNTHESIS OF COMPOUND NO. 98 Molecular weight: 1635.90

[00818] Example 99 was prepared following the general synthesis sequence described for the preparation of Example 6, consisting of the following general procedures: "Prelude Method A: Resin swelling procedure", "Prelude Method A: Simple coupling procedure", "Prelude Method A: Secondary amine coupling procedure". The synthesis was started starting from H-Gly-2-Cl-trityl resin (Novabiochem, 0.6 mmol/g). After removal of the last Fmoc, the peptidyl resin was cleaved from the solid support by treating it five times with DCM/TIS/TFA (96:3:1; v:v:v) (5 mL) for 1 minute. The filtrates were collected in a flask containing 1.5 mL of pyridine. The filtrates were then extracted with water (3 x 5 mL). The organic phase was evaporated to give an oil, which was then lyophilized from MeCN/water (1 : 2) to give a solid product (221 mg). A portion of the product (10 mg, 0.005 mmol) was cyclized using 1 eq. of HATU and 2 eq. of DIEA in (1 : 9) DMF/DCM (17 mL). The reaction was allowed to proceed for 18 h. The solvents were removed under reduced pressure and the residue was redissolved in acetonitrile (1 mL) and then precipitated with water (2 mL). The collected peptide was redissolved in DCM and extracted with water (2 × 5 mL). The organic layer was then dried over sodium sulfate, filtered, and dried to give 17 mg of protected peptide. This was treated with (95:5) TFA/TIS (6 mL) for 5 min at room temperature. Addition of ether (20 mL) and cooling to 0 °C for 10 min yielded a solid, which was washed with ether and dried. The product was purified via preparative LC/MS using the following conditions: Column: FENOMENEX® C18 Luna, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 30-95% B over 50 min; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via lyophilization. The product yield was 0.81 mg, and its purity estimated by HPLC analysis was 99%.

[00819] LCMS analysis Condition A: retention time = 1.55 min.; ESI-MS(+) m/z 819.0 (M+2H).

[00820] HPLC analysis Condition G: retention time = 16.15 min.TABLE 4 - SERIES OF PEPTIDES OF FORMULA III*

[00821] Compounds Nos. 99 through 115 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine. EXAMPLE 100 - SYNTHESIS OF COMPOUND NO. 99 Molecular weight: 1632.97

[00822] Example 100 was prepared by following the general synthetic sequence described for the preparation of Example 19, consisting of the following general procedures: "Prelude Method B: Resin Swelling Procedure", "Prelude Method B: Double Coupling Procedure" for primary amine N-terminal couplings; "Prelude Method B: Secondary Amine Coupling Procedure" for secondary amine N-terminal couplings; "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method A", and "Cyclization Method A".

[00823] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.4 mg, and its purity estimated by HPLC analysis was 99%.

[00824] LCMS analysis Condition A: retention time = 0.90 min.; ESI-MS(+) m/z 817.6 (M+2H).

[00825] HPLC analysis Condition F: retention time = 9.21 min.EXAMPLE 101 - SYNTHESIS OF COMPOUND NO. 100 Molecular weight: 1676.00

[00826] Example 101 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00827] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 15-55% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.0 mg, and its purity estimated by HPLC analysis was 95%.

[00828] LCMS analysis Condition A: retention time = 0.82 min.; ESI-MS(+) m/z 839.1 (M+2H).

[00829] HPLC analysis Condition E: retention time = 10.22 min.EXAMPLE 102 - SYNTHESIS OF COMPOUND NO. 101 Molecular weight: 1666.99

[00830] Example 102 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00831] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.0 mg, and its purity estimated by HPLC analysis was 98%.

[00832] LCMS analysis Condition A: retention time = 0.93 min.; ESI-MS(+) m/z 834.8 (M+2H).

[00833] HPLC analysis Condition F: retention time = 9.57 min.EXAMPLE 103 - SYNTHESIS OF COMPOUND NO. 102 Molecular weight: 1666.99

[00834] Example 103 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00835] The crude material was purified via preparative HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 4.7 mg, and its purity estimated by HPLC analysis was 99%.

[00836] LCMS analysis Condition A: retention time = 1.05 min.; ESI-MS(+) m/z 834.7 (M+2H).

[00837] HPLC analysis Condition F: retention time = 12.03 min.EXAMPLE 104 - SYNTHESIS OF COMPOUND NO. 103 Molecular weight: 1632.97

[00838] Example 104 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00839] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 4.9 mg, and its purity estimated by HPLC analysis was 96%.

[00840] LCMS analysis Condition A: retention time = 0.94 min.; ESI-MS(+) m/z 817.7 (M+2H).

[00841] HPLC analysis Condition F: retention time = 9.61 min.EXAMPLE 105 - SYNTHESIS OF COMPOUND NO. 104 Molecular weight: 1666.99

[00842] Example 105 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00843] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 8.4 mg, and its purity estimated by HPLC analysis was 91%.

[00844] LCMS analysis Condition A: retention time = 0.96 min.; ESI-MS(+) m/z 834.6 (M+2H).

[00845] HPLC analysis Condition F: retention time = 10.20 min.EXAMPLE 106 - SYNTHESIS OF COMPOUND NO. 105 Molecular weight: 1697.01

[00846] Example 106 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00847] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 7.5 mg, and its purity estimated by HPLC analysis was 95%.

[00848] LCMS analysis Condition A: retention time = 0.93 min.; ESI-MS(+) m/z 849.6 (M+2H).

[00849] HPLC analysis Condition F: retention time = 9.43 min.EXAMPLE 107 - SYNTHESIS OF COMPOUND NO. 106 Molecular weight: 1681.02

[00850] Example 107 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00851] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.8 mg, and its purity estimated by HPLC analysis was 96%.

[00852] LCMS analysis Condition A: retention time = 1.00 min.; ESI-MS(+) m/z 841.7 (M+2H).

[00853] HPLC analysis Condition F: retention time = 10.80 min.EXAMPLE 108 - SYNTHESIS OF COMPOUND NO. 107 Molecular weight: 1618.95

[00854] Example 108 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00855] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 8.8 mg, and its purity estimated by HPLC analysis was 98%.

[00856] LCMS analysis Condition A: retention time = 0.90 min.; ESI-MS(+) m/z 810.6 (M+2H).

[00857] HPLC analysis Condition F: retention time = 8.70 min.EXAMPLE 109 - SYNTHESIS OF COMPOUND NO. 108 Molecular weight: 1613.93

[00858] Example 109 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00859] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.3 mg, and its purity estimated by HPLC analysis was 98%.

[00860] LCMS analysis Condition A: retention time = 0.89 min.; ESI-MS(+) m/z 808.1 (M+2H).

[00861] HPLC analysis Condition F: retention time = 8.65 min.EXAMPLE 110 - SYNTHESIS OF COMPOUND NO. 109 Molecular weight: 1589.94

[00862] Example 110 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00863] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 30-80% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.3 mg, and its purity estimated by HPLC analysis was 98%.

[00864] LCMS analysis Condition A: retention time = 1.18 min.; ESI-MS(+) m/z 796.3 (M+2H).

[00865] HPLC analysis Condition J: retention time = 9.00 min.EXAMPLE 111 - SYNTHESIS OF COMPOUND NO. 110 Molecular weight: 1647.00

[00866] Example 111 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00867] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 3.4 mg, and its purity estimated by HPLC analysis was 95%.

[00868] LCMS analysis Condition A: retention time = 0.96 min.; ESI-MS(+) m/z 824.7 (M+2H).

[00869] HPLC analysis Condition F: retention time = 9.98 min.EXAMPLE 112 - SYNTHESIS OF COMPOUND NO. 111 Molecular weight: 1681.02

[00870] Example 112 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00871] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 13 mg, and its purity estimated by HPLC analysis was 95%.

[00872] LCMS analysis Condition A: retention time = 0.98 min.; ESI-MS(+) m/z 841.5 (M+2H).

[00873] HPLC analysis Condition F: retention time = 10.49 min.EXAMPLE 113 - SYNTHESIS OF COMPOUND NO. 112 Molecular weight: 1697.01

[00874] Example 113 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00875] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 5.4 mg, and its purity estimated by HPLC analysis was 98%.

[00876] LCMS analysis Condition A: retention time = 0.95 min.; ESI-MS(+) m/z 849.7 (M+2H).

[00877] HPLC analysis Condition F: retention time = 9.72 min.EXAMPLE 114 - SYNTHESIS OF COMPOUND NO. 113 Molecular weight: 1639.96

[00878] Example 114 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00879] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 2.2 mg, and its purity estimated by HPLC analysis was 94%.

[00880] LCMS analysis Condition A: retention time = 1.02 min.; ESI-MS(+) m/z 821.1 (M+2H).

[00881] HPLC analysis Condition F: retention time = 11.30 min.EXAMPLE 115 - SYNTHESIS OF COMPOUND NO. 114 Molecular weight: 1573.90

[00882] Example 115 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00883] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 12.5 mg, and its purity estimated by HPLC analysis was 99%.

[00884] LCMS Analysis Condition A: Retention time = 1.06 min; ESI-MS(+) m/z 788.0 (M+2H).

[00885] HPLC Analysis Condition F: Retention time = 11.88 min.EXAMPLE 116 - SYNTHESIS OF COMPOUND NO. 115 Molecular weight: 1666.99

[00886] Example 116 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method A”, and “Cyclization Method A”.

[00887] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-60% B over 40 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 8.4 mg, and its purity estimated by HPLC analysis was 96%.

[00888] LCMS Analysis Condition A: Retention time = 0.95 min; ESI-MS(+) m/z 834.5 (M+2H).

[00889] HPLC analysis Condition F: Retention time = 10.01 min.TABLE 5 - C-TERMINALLY PEGYLATED PEPTIDES OF FORMULAS I AND II* *Compounds Nos. 116 through 118 are macrocyclic peptides cyclized via the listed moiety at position A with a downstream cysteine. EXAMPLE 117 - SYNTHESIS OF COMPOUND NO. 116 Molecular weight: 2451.88

[00890] Example 117 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method E”, and “Cyclization Method C”. The starting resin was Fmoc-PEG12-Sieber amide resin (0.05 mmol), which was prepared manually by coupling O-(N-Fmoc-2-aminoethyl)-O'-(2-carboxyethyl)-undecaethylene glycol to Sieber amide resin according to the following procedure: Seiber amide resin (0.60 mmol, 0.846 g, 0.71 mmol/g) was washed with DCM (8 mL) for 5 min and DMF (8 mL) for 5 min. The resin was treated twice with 5% piperazine in DMF (8 mL) for 5 min and then washed once with methanol (8 mL) and six times with DMF (8 mL). To a solution of O-(N-Fmoc-2-aminoethyl)-O’-(2-carboxyethyl)-undecaethylene glycol (0.715 g, 0.851 mmol) in DMF (4 mL) was added 0.45 M HCTU in DMF (1.8 mL, 0.810 mmol) and 2 M DIEA in NMP (0.85 mL, 1.70 mmol). The resulting solution was stirred and added to the resin. The reaction was allowed to proceed for 18 h. The resin was washed three times with DMF (8 mL) and three times with DCM (8 mL) washes. An Fmoc determination on an aliquot of the dried resin gave a substitution of 0.26 mmol/g. This was used to determine the amount of starting resin equivalent to 0.05 or 0.1 mmol, depending on the scale required.

[00891] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-80% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 6.2 mg, and its purity estimated by HPLC analysis was 98%.

[00892] LCMS Analysis Condition A: Retention time = 1.31 min.; ESI-MS(+) m/z 1226.6 (M+2H).

[00893] HPLC Analysis Condition B: Retention time = 16.08 min.EXAMPLE 118 - SYNTHESIS OF COMPOUND NO. 117 Molecular weight: 2517.94

[00894] Example 118 was prepared by following the general synthesis sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method E”, and “Cyclization Method C”. The starting resin was Fmoc-PEG12-Sieber amide resin (0.05 mmol), prepared as described in Example 117.

[00895] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 25-50% B over 50 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 3.2 mg, and its purity estimated by HPLC analysis was 91.4%.

[00896] LCMS Analysis Condition A: Retention time = 1.22 min; ESI-MS(+) m/z 1260.1 (M+2H).

[00897] HPLC Analysis Condition B: Retention time = 14.75 min.EXAMPLE 119 - SYNTHESIS OF COMPOUND NO. 118 Molecular weight: 2395.80

[00898] Example 119 was prepared by following the general synthetic sequence described for the preparation of Example 2, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Single Coupling Procedure”, “CEM Method A: Double Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method F”, and “Cyclization Method C”. The starting resin was Fmoc-PEG12-Sieber amide resin (0.05 mmol), prepared as described in Example 117.

[00899] The crude material was purified via preparatory HPLC using the following conditions: Column: YMC ODS-AQ, 20 x 250 mm, 5 μm particles; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in MeCN; gradient: 20-90% B over 60 min.; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried by lyophilization. The yield of the product was 5.3 mg, and its purity estimated by HPLC analysis was 96%.

[00900] LCMS Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 1198.7 (M+2H).

[00901] HPLC analysis Condition K: Retention time = 14.22 min.Custom amino acids(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclobutanecarboxamido)propanoic acid

[00902] Cyclobutanecarbonyl chloride (72.7 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL x1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (156 mg, 61%).

[00903] LCMS Analysis Condition A: Retention time = 0.94 min; ESI-MS(+) m/z 409.1 (M+H).

[00904] 1H NMR (400MHz, methanol-d4)DDD7.80 (d, J=7.5 Hz, 2H), 7.67 (br s, 2H), 7.44 -7.35 (m, 2H), 7.35 - 7.27 (m, 2H ), 4.37 - 4.31 (m, 2H), 4.23 (s, 1H), 3.55 - 3.48 (m, 1H), 3.14 (s, 2H), 2.31 - 2.08 (m, 7H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclopentanecarboxamido)propanoic acid

[00905] Cyclopentanecarbonyl chloride (81 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0°C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (142 mg, 54%).

[00906] LCMS Analysis Condition A: Retention time = 0.99 min; ESI-MS(+) m/z 423 A (M+H).

[00907] 1H NMR (400MHz, methanol-d4)DDD7.80 (d, J=7.5 Hz, 2H), 7.67 (t, J=6.4 Hz, 2H), 7.44 - 7.37 (m, 2H), 7.35 - 7.27 (m, 2H), 4.38 - 4.31 (m, 2H), 4.27 - 4.19 (m, 1H), 3.69 -3.47 (m, 2H), 2.61 (s, 1H), 1.88 - 1.53 (m, 9H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-benzamidopropanoic acid

[00908] Benzoyl chloride (86 mg, 0.613 mmol) and NaOH (0.735 mL, 0.735 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-aminopropanoic acid (200 mg, 0.613 mmol) in THF (1.5 mL) and NaOH (1N, 0.8 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (149 mg, 52%).

[00909] LCMS Analysis Condition A: Retention time = 0.96 min; ESI-MS(+) m/z 431.0 (M+H).

[00910] 1H NMR (400MHZ, methanol-d4)DDD7.84 - 7.75 (m, 4H), 7.64 (d, J=7.5 Hz, 2H), 7.52 (d, J=7.3 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.31 - 7.22 (m, 2H), 4.54 - 4.47 (m, 1H), 4.33 (dd, J=7.0, 3.3 Hz, 2H), 4.24 - 4.17 (m, 1H), 3.89 - 3.73 (m, 2H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclobutanecarboxamido) butanoic acid

[00911] Cyclobutanecarbonyl chloride (69.7 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and NaOH (1N, 0.7 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (92.6 mg, 37%).

[00912] LCMS Analysis Condition A: Retention time = 0.94 min; ESI-MS(+) m/z 423.1 (M+H).

[00913] 1H NMR (400MHZ, methanol-d4)DDD7.80 (d, J=7.5 Hz, 2H), 7.72 - 7.65 (m, 2H), 7.43 - 7.36 (m, 2H), 7.35 - 7.28 (m, 2H), 4.41 - 4.32 (m, 2H), 4.28 - 4.15 (m, 2H), 3.20 (d, J=7.0 Hz, 1H), 3.08 (s, 1H), 2.31 - 2.04 (m, 6H), 1.97 (d, J=9.9 Hz, 1H), 1.84 (d, J=7.3 Hz, 2H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclopentanecarboxamido) butanoic acid

[00914] Cyclopentanecarbonyl chloride (78 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and NaOH (1N, 0.7 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (84. lmg, 33%).

[00915] LCMS Analysis Condition A: Retention time = 0.98 min; ESI-MS(+) m/z 437.1 (M+H).

[00916] 1H NMR (400MHz, methanol-d4)DDD7.79 (d, J=7.5 Hz, 2H), 7.72 - 7.64 (m, 2H), 7.42 - 7.35 (m, 2H), 7.34 - 7.26 (m, 2H), 4.41 - 4.30 (m, 2H), 4.26 - 4.14 (m, 2H), 3.24 -3.13 (m, 1H), 2.59 (t, J=7.8 Hz, 1H), 2.05 (s, 1H), 1.91 - 1.62 (m, 8H), 1.64 - 1.50 (m, 2H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclohexanecarboxamido)butanoic acid

[00917] Cyclohexanecarbonyl chloride (86 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and NaOH (1N, 0.7 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM (20%) MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (201 mg, 70%).

[00918] LCMS Analysis Condition A: Retention time = 1.01 min; ESI-MS(+) m/z 451.2 (M+H).

[00919] 1H NMR (400MHZ, methanol-d4):DDD7.79 (d, J=7.5 Hz, 2H), 7.73 - 7.65 (m, 2H), 7.43 - 7.35 (m, 2H), 7.34 - 7.26 (m , 2H), 4.42 - 4.30 (m, 2H), 4.27 - 4.15 (m, 2H), 3.18 (d, J=7.3 Hz, 1H), 2.15 (s, 1H), 2.10 - 2.01 (m, 1H), 1.89 - 1.72 (m, 5H), 1.68 (d, J=10.3 Hz, 1H), 1.49 - 1.17 (m, 6H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4- Benzamidobutanoic acid

[00920] Benzoyl chloride (83 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and NaOH (1N, 0.7 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (160 mg, 57%).

[00921] LCMS Analysis Condition A: Retention time = 0.97 min; ESI-MS(+) m/z 445.1 (M+H).

[00922] 1H NMR (400MHz, methanol-d4)DDD7.82 (t, J=8.6 Hz, 4H), 7.74 - 7.67 (m, 2H), 7.56 - 7.50 (m, 1H), 7.49 - 7.42 (m, 2H), 7.42 - 7.36 (m, 2H), 7.35 - 7.26 (m, 2H), 4.39 (dd, J=7.0, 2.0 Hz, 2H), 4.32 - 4.21 (m, 2H), 3.62 - 3.52 (m, 1H), 3.45 - 3.35 (m, 1H), 2.20 (d, J=5.1 Hz, 1H), 1.99 (d, J=8.1 Hz, 1H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(furan-2-carboxamido)butanoic acid

[00923] Furan-2-carbonyl chloride (77 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were added simultaneously to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and NaOH (1N, 0.7 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 1 h at which time LC-MS showed the desired product peak. The reaction solution was acidified with 1 N HCl and extracted with EtOAc (60 mL × 1). The crude product was purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (107 mg, 41%).

[00924] LCMS Analysis Condition A: Retention time = 0.92 min; ESI-MS(+) m/z 435.0 (M+H).

[00925] 1H NMR (400MHz, methanol-d4)DDD7.80 (d, J=7.7 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.63 (s, 1H), 7.44 - 7.35 (m, 2H) , 7.34 - 7.26 (m, 2H), 7.09 (d, J=3.3 Hz, 1H), 6.56 (dd, J=3.4, 1.7 Hz, 1H), 4.41 - 4.35 (m, 2H), 4.28 - 4.19 (m , 2H), 3.51 (dd, J=13.8, 7.4 Hz, 1H), 3.43 - 3.34 (m, 1H), 2.24 - 2.12 (m, 1H), 1.94 (d, J=7.3 Hz, 1H). Intermediate resins for Examples 1001-3000 Preparation of intermediate resin A.

[00926] To a 125 mL reactor was added Sieber resin (1410 mg, 1 mmol) and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin Swelling Procedure” was followed; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Arg(PBF)-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Trp-OH using 2.5 eq for 30 min; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Ser(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp-OH.

[00927] The resulting resin was transferred to a 100 mL polypropylene tube and washed with DCM (40 mL x 3). Finally, the resin was dried under vacuum and used as an intermediate for synthesis.

[00928] Microcleavage A was followed.

[00929] LCMS Analysis Condition A: Retention time = 0.89 min, ESI-MS(+) m/z 1271.2 (M+H). Preparation of intermediate resin B.

[00930] To a 125 mL reactor was added Sieber resin (1410 mg, 1 mmol), and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin Swelling Procedure” was followed; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Arg(PBF)-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Trp(Boc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Ser(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Sar-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Leu-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-His(Trt)-OH; “CEM Method A: Standard coupling procedure" was followed with Fmoc-Pro-OH; “CEM Method A: Double pair coupling procedure" was followed with Fmoc-Asn(tBu)-OFL

[00931] The resulting resin was transferred to a 100 mL polypropylene tube equipped with a frit and washed with DCM (40 mL x 3). Finally, the resin was vacuum dried and used as an intermediate for synthesis.

[00932] Microcleavage A was followed.

[00933] LCMS Analysis Condition A: Retention time = 1.0 min, ESI-MS(+) m/z 966.6 (M+2H + 1C02). Preparation of intermediate resin C.

[00934] To a 125 mL reactor was added Rink Amide resin (1640 mg, 1 mmol), and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin Swelling Procedure” was followed; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Dap(Boc)-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Bzt-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Trp-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Dab(Boc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Hyp(tBu)-OH;

[00935] The resulting resin was transferred to a 100 mL polypropylene tube equipped with a frit and washed with DCM (40 mL x 3). Finally, the resin was vacuum dried and used as an intermediate for synthesis.

[00936] Microcleavage A was followed.

[00937] LCMS Analysis Condition A: Retention time = 0.81 min, ESI-MS(+) m/z 672.2 (M+2H). Preparation of intermediate resin D.

[00938] To a 125 mL reactor was added Rink's resin (1640 mg, 1 mmol), and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin swelling procedure” was followed; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Orn(Boc)-OH; followed with Fmoc-Bzt-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Dab(Boc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Hyp(tBu)-OH.

[00939] The resulting resin was transferred to a 100 mL polypropylene tube equipped with a frit and washed with DCM (40 mL x 3). Finally, the resin was vacuum dried and used as an intermediate for synthesis.

[00940] Microcleavage A was followed.

[00941] LCMS Analysis Condition A: Retention time = 0.77 min, ESI-MS(+) m/z 708.2 (M+2H + 1C02). Preparation of intermediate resin E.

[00942] To a 45 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: "Prelude Method C: Resin Swelling Procedure" was followed; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Gly-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Cys(Trt)-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Orn(Boc)-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-NMeNle-OH; "Prelude Method C: Secondary amine coupling procedure" was followed with Fmoc-MeNleOH; "Prelude Method C: Secondary amine coupling procedure" was followed with Fmoc-Trp(Boc)-OH; "Prelude Method C: Single coupling procedure" was followed with Fmoc-Ser(tBu)-OH; "Prelude Method C: Single coupling procedure" was followed with Fmoc-Trp(Boc)-OH; "Prelude Method C: Single coupling procedure" was followed with Fmoc-Hyp(tBu)-OH; "Prelude Method C: Secondary amine coupling procedure" was followed with Fmoc-Leu-OH; "Prelude Method C: Single coupling procedure" was followed with Fmoc-His(Boc)-OH; "Prelude Method C: Simple coupling procedure" was followed with Fmoc-Pro-OH; "Prelude Method C: Secondary amine coupling procedure" was followed with Fmoc-Asn(tBu)-OH; "Prelude Method C: Final wash procedure" was followed.

[00943] The resulting resin was transferred to a 6 mL Bio-Rad tube equipped with a frit and washed with DCM (4 mL x 3). Finally, the resin was vacuum dried and used as an intermediate for synthesis. The crude material was used as an intermediate for synthesis without analysis. Preparation of intermediate resin F.

[00944] To a 125 mL reactor was added Rink's resin (1640 mg, 1 mmol), and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin swelling procedure” was followed; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Arg(PBF)-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Bzt-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Ser(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Pro-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Leu-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-His(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Pro-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Asn(tBu)-OH.

[00945] The resulting resin was transferred to a 100 mL polypropylene tube equipped with a frit and washed with DCM (40 mL x 3). Finally, the resin was vacuum dried and used as an intermediate for synthesis.

[00946] Microcleavage A was followed.

[00947] LCMS Analysis Condition A: Retention time = 0.83 min, ESI-MS(+) m/z 945 (M+2H). Preparation of intermediate resin G.

[00948] To a 45 mL polypropylene solid phase reaction vessel was added Sieber resin (140 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. The following procedures were then performed in sequence: "Prelude Method C: Resin Swelling Procedure" was followed; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Gly-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Cys(Trt)-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-Orn(Boc)-OH; "Prelude Method C: Simple Coupling Procedure" was followed with Fmoc-NMeNle-OH; "Prelude Method C: Secondary amine coupling procedure" was followed with Fmoc-MeNleOH; "Prelude Method C: Final wash procedure" was followed.

[00949] The resulting resin was transferred to a Bio-Rad tube equipped with a frit and washed with DCM (4 mL x 3).

[00950] Microcleavage A was performed.

[00951] LCMS Analysis Condition A: Retention time = 0.91 min, ESI-MS(+) m/z 810.5 (M+H). Preparation of intermediate resin H.

[00952] To a 125 mL reactor was added Rink's resin (1640 mg, 1 mmol), and the reaction vessel was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin swelling procedure” was followed; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Orn(Alloc)-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-[N-Me]Nle-OH; “CEM Method A: Double pair coupling procedure” was followed with Fmoc-Bzt-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Dab(Alloc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp(Boc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Hyp(tBu)-OH.

[00953] The resulting resin was transferred to a 100 mL polypropylene tube equipped with a frit and washed with DCM (40 mL x 3). Finally, the resin was dried under vacuum and used as an intermediate for synthesis. Preparation of Example 1001 Molecular weight: 1680.96

[00954] Example 1001 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[00955] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00956] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 100%.

[00957] LCMS Analysis Condition D: Retention time 1.49 min; ESI-MS(+) m/z 841.20 (M+2H).

[00958] LCMS Analysis Condition E: Retention time 1.60 min; ESI-MS(+) m/z 841.20 +2H). Preparation of Example 1002 Molecular weight: 1863.19

[00959] Example 1002 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin swelling procedure", "Simphony Method A: Standard-coupling procedure", "Simphony Method A: Secondary amine coupling procedure B", "Chloroacetic acid coupling procedure B", "Global deprotection method C", and "Cyclization method D".

[00960] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.9 mg, and its purity estimated by LCMS analysis was 89%.

[00961] LCMS Analysis Condition D: Retention time = 1.94 min; ESI-MS(+) m/z 932.50 (M+2H).

[00962] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 932.60 (M+2H). Preparation of Example 1003 Molecular weight: 1886.18

[00963] Example 1003 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[00964] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00965] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.1 mg, and its purity estimated by LCMS analysis was 100%.

[00966] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 943.7 (M+2H).

[00967] LCMS Analysis Condition E: Retention time = 1.54 min; ESI-MS(+) m/z 944.0 (M+2H). Preparation of Example 1004 Molecular weight: 1803.10

[00968] Example 1004 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[00969] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00970] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.2 mg, and its purity estimated by LCMS analysis was 100%.

[00971] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 902.1 (M+2H).

[00972] LCMS Analysis Condition E: Retention time = 1.20 min; ESI-MS(+) m/z 902.0 (M+2H). Preparation of Example 1005 Molecular weight: 1822.10

[00973] Example 1005 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[00974] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00975] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.0 mg, and its purity estimated by LCMS analysis was 91%.

[00976] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 911.85 (M+2H).

[00977] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 911.6 (M+2H). Preparation of Example 1006 Molecular weight: 1886.18

[00978] Example 1006 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00979] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 95%.

[00980] LCMS Analysis Condition D: Retention time = 1.64min; ESI-MS(+) m/z 943.90 (M+2H).

[00981] LCMS Analysis Condition E: Retention time = 1.54min; ESI-MS(+) m/z 944.25 (M+2H). Preparation of Example 1007 Molecular weight: 1889.23

[00982] Example 1007 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00983] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.2 mg, and its purity estimated by LCMS analysis was 90%.

[00984] LCMS Analysis Condition D: Retention time = 1.83min; ESI-MS(+) m/z 946.10 (M+2H).

[00985] LCMS Analysis Condition E: Retention time = 1.74min; ESI-MS(+) m/z 945.15 (M+2H). Preparation of Example 1009 Molecular weight: 1863.19

[00986] Example 1009 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[00987] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00988] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.0 mg, and its purity estimated by LCMS analysis was 95%.

[00989] LCMS Analysis Condition D: Retention time = 1.77 min; ESI-MS(+) m/z 932.40 (M+2H).

[00990] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 932.20 (M+2H). Preparation of Example 1010 Molecular weight: 1820.15

[00991] Example 1010 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[00992] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1 mg, and its purity was estimated to be 100% by LCMS analysis.

[00993] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 911.25 (M+2H).

[00994] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 910.60 (M+2H). Preparation of Example 1011 Molecular weight: 1893.18

[00995] Example 1011 was prepared following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclobutanecarboxamido)propanoic acid was used in the "Custom Amino Acid Coupling Procedure".

[00996] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.9 mg, and its purity estimated by LCMS analysis was 98%.

[00997] LCMS Analysis Condition D: Retention time = 1.45min; ESI-MS(+) m/z 947.65 (M+2H).

[00998] LCMS Analysis Condition E: Retention time = 1.39min; ESI-MS(+) m/z 947.35 (M+2H). Preparation of Example 1012 Molecular weight: 1907.20

[00999] Example 1012 was prepared by following the general synthesis sequence described for the preparation of Example 11, consisting of the following general procedures:

[001000] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclopentanecarboxamido)propanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001001] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.3 mg, and its purity estimated by LCMS analysis was 94%.

[001002] LCMS Analysis Condition D: Retention time = 1.50min; ESI-MS(+) m/z 954.30 (M+2H).

[001003] LCMS Analysis Condition E: Retention time = 1.43min; ESI-MS(+) m/z 954.20 (M+2H). Preparation of Example 1013 Molecular weight: 1915.18

[001004] Example 1013 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001005] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-benzamidopropanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001006] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-80% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.4 mg, and its purity estimated by LCMS analysis was 90%.

[001007] LCMS Analysis Condition D: Retention time = 1.48 min; ESI-MS(+) m/z 958.75 (M+2H).

[001008] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 958.35 (M+2H). Preparation of Example 1014 Molecular weight: 1911.25

[001009] Example 1014 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001010] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001011] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-50% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6 mg, and its purity estimated by LCMS analysis was 92%.

[001012] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 956.30 (M+2H).

[001013] LCMS Analysis Condition E: Retention time = 1.57 min; ESI-MS(+) m/z 956.30 (M+2H). Preparation of Example 1015 Molecular weight: 1895.26

[001014] Example 1015 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001015] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001016] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-70% B over 25 min, then a 5 min hold at 70% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.7 mg, and its purity estimated by LCMS analysis was 92%.

[001017] LCMS Analysis Condition D: Retention time = 1.83 min; ESI-MS(+) m/z 948.45 (M+2H).

[001018] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 948.40 (M+2H). Preparation of Example 1016 Molecular weight: 1894.20

[001019] Example 1016 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001020] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001021] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1.6 mg, and its purity was estimated to be 97% by LCMS analysis.

[001022] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 948.20 (M+2H).

[001023] LCMS Analysis Condition E : Retention time = 1.43 min; ESI-MS(+) m/z 948.15 (M+2H). Preparation of Example 1017 Molecular weight: 1921.23

[001024] Example 1017 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001025] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclohexanecarboxamido)propanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001026] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity estimated by LCMS analysis was 95%.

[001027] LCMS analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 961.3 (M+2H).

[001028] LCMS Analysis Condition E: Retention time = 1.42 min; ESI-MS(+) m/z 961.6 (M+2H). Preparation of Example 1018 Molecular weight: 1881.13

[001029] Example 1018 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001030] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001031] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.2 mg, and its purity estimated by LCMS analysis was 99%.

[001032] LCMS Analysis Condition D: Retention time = 1.63 min; ESI-MS(+) m/z 941.3 (M+2H).

[001033] LCMS Analysis Condition E: Retention time = 1.61 min; ESI-MS(+) m/z 942.0 (M+2H).Preparation of Example 1019 Molecular weight: 1963.31

[001034] Example 1019 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001035] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclobutanecarboxamido)butanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001036] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.9 mg, and its purity estimated by LCMS analysis was 97%.

[001037] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 982.50 (M+2H).

[001038] LCMS Analysis Condition E: Retention time = 1.69 min; ESI-MS(+) m/z 982.25 (M+2H). Preparation of Example 1020 Molecular weight: 1977.34

[001039] Example 1020 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001040] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclopentanecarboxamido)butanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001041] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3 mg, and its purity estimated by LCMS analysis was 89%.

[001042] LCMS Analysis Condition D: Retention time = 1.84 min; ESI-MS(+) m/z 989.30 (M+2H).

[001043] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 989.45 (M+2H). Preparation of Example 1021 Molecular weight: 1991.36

[001044] Example 1021 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001045] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclohexanecarboxamido)butanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001046] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.9 mg, and its purity estimated by LCMS analysis was 97%.

[001047] LCMS Analysis Condition D: Retention time = 1.87 min; ESI-MS(+) m/z 996.75 (M+2H).

[001048] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 996.75 (M+2H). Preparation of Example 1022 Molecular weight: 1985.32

[001049] Example 1022 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001050] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-benzamidobutanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001051] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.5 mg, and its purity estimated by LCMS analysis was 96%.

[001052] LCMS Analysis Condition D: Retention time = 1.82 min; ESI-MS(+) m/z 993.35 (M+2H).

[001053] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 993.45 (M+2H). Preparation of Example 1023 Molecular weight: 1975.28

[001054] Example 1023 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001055] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(furan-2-carboxamido)butanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001056] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 95%.

[001057] LCMS Analysis Condition D: Retention time = 1.76 min; ESI-MS(+) m/z 988.75 (M+2H).

[001058] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 988.75 (M+2H). Preparation of Example 1024 Molecular weight: 1921.06

[001059] Example 1024 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001060] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001061] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.6 mg, and its purity estimated by LCMS analysis was 99%.

[001062] LCMS Analysis Condition D: Retention time = 1.87 min; ESI-MS(+) m/z 961.2 (M+2H).

[001063] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 961.3 (M+2H). Preparation of Example 1025 Molecular weight: 1886.61

[001064] Example 1025 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001065] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001066] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.1 mg, and its purity estimated by LCMS analysis was 96%.

[001067] LCMS Analysis Condition D: Retention time = 1.79 min; ESI-MS(+) m/z 944.1 (M+2H).

[001068] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 944 A (M+2H). Preparation of Example 1026 Molecular weight: 1886.61

[001069] Example 1026 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001070] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001071] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.0 mg, and its purity estimated by LCMS analysis was 97%.

[001072] LCMS Analysis Condition D: Retention time = 1.83 min; ESI-MS(+) m/z 944.8 (M+2H).

[001073] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 944.6 (M+2H). Preparation of Example 1028 Molecular weight: 1889.23

[001074] Example 1028 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001075] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001076] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.1 mg, and its purity estimated by LCMS analysis was 92%.

[001077] LCMS Analysis Condition D: Retention time = 1.91 min; ESI-MS(+) m/z 945.7 (M+2H).

[001078] LCMS Analysis Condition E: Retention time = 1.84 min; ESI-MS(+) m/z 945.6 (M+2H). Preparation of Example 1029 Molecular weight: 1889.23

[001079] Example 1029 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001080] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001081] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.7 mg, and its purity estimated by LCMS analysis was 97%.

[001082] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 946.5 (M+2H).

[001083] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 946.5 (M+2H). Preparation of Example 1030 Molecular weight: 1903.25

[001084] Example 1030 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001085] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001086] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.3 mg, and its purity estimated by LCMS analysis was 97%.

[001087] LCMS Analysis Condition D: Retention time = 1.95 min; ESI-MS(+) m/z 953.7 (M+2H).

[001088] LCMS Analysis Condition E: Retention time = 1.91 min; ESI-MS(+) m/z 952.9 (M+2H). Preparation of Example 1031 Molecular weight: 1866.19

[001089] Example 1031 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001090] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001091] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 100%.

[001092] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 934.0 (M+2H).

[001093] LCMS Analysis Condition E: Retention time = 1.57 min; ESI-MS(+) m/z 934.2 (M+2H). Preparation of Example 1032 Molecular weight: 1906.17

[001094] Example 1032 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001095] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001096] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.3 mg, and its estimated purity by LCMS analysis was 99%.

[001097] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 953.9 (M+2H).

[001098] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 954.5 (M+2H). Preparation of Example 1033 Molecular weight: 1851.10

[001099] Example 1033 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001100] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(cyclobutanecarboxamido)propanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001101] The crude material was purified via preparatory LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 25 min, then a 10 min hold at 50% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.8 mg, and its purity estimated by LCMS analysis was 97%.

[001102] LCMS Analysis Condition D: Retention time = 1.31 min; ESI-MS(+) m/z 926.1 (M+2H).

[001103] LCMS Analysis Condition E: Retention time = 1.29 min; ESI-MS(+) m/z 926.2 (M+2H). Preparation of Example 1034 Molecular weight: 1865.12

[001104] Example 1034 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001105] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-(cyclobutanecarboxamido)butanoic acid was used in the “Custom Amino Acid Coupling Procedure”.

[001106] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.3 mg, and its purity estimated by LCMS analysis was 98%.

[001107] LCMS Analysis Condition D: Retention time 1.31 min; ESI-MS(+) m/z 933.3 (M+2H).

[001108] LCMS Analysis Condition E: Retention time 1.30 min; ESI-MS(+) m/z 933.3 (M+2H). Preparation of Example 1035 Molecular weight: 1927.25

[001109] Example 1035 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001110] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001111] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.8 mg, and its purity estimated by LCMS analysis was 95%.

[001112] LCMS analysis Condition D: Retention time 1.69 min; ESI-MS(+) m/z 965.1 (M+2H).

[001113] LCMS Analysis Condition E: Retention time 1.62 min; ESI-MS(+) m/z 964.6 (M+2H). Preparation of Example 1036 Molecular weight: 1947.24

[001115] Example 1036 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001116] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.7 mg, and its purity estimated by LCMS analysis was 95%.

[001117] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 974.9 (M+2H).

[001118] LCMS Analysis Condition E: Retention time = 1.67 min; ESI-MS(+) m/z 974.8 (M+2H). Preparation of Example 1037 Molecular weight: 1926.27

[001119] Example 1037 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001120] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001121] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.6 mg, and its purity estimated by LCMS analysis was 98%.

[001122] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 964.3 (M+2H).

[001123] LCMS Analysis Condition E: Retention time = 1.60 min; ESI-MS(+) m/z 964.0 (M+2H). Preparation of Example 1038 Molecular weight: 1853.16

[001124] Example 1038 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001125] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001126] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.0 mg, and its purity estimated by LCMS analysis was 93%.

[001127] LCMS Analysis Condition D: Retention time = 1.47min; ESI-MS(+) m/z 927.5 (M+2H).

[001128] LCMS Analysis Condition E: Retention time = 1.32min; ESI-MS(+) m/z 927.3 (M+2H). Preparation of Example 1039 Molecular weight: 1870.16

[001129] Example 1039 was following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B",

[001130] “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001131] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.4 mg, and its purity estimated by LCMS analysis was 99%.

[001132] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 936.0 (M+2H).

[001133] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 935.8 (M+2H). Preparation of Example 1040 Molecular weight: 1824.15

[001134] Example 1040 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001135] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001136] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.6 mg, and its purity estimated by LCMS analysis was 99%.

[001137] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 913.7 (M+2H).

[001138] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 912.9 (M+2H). Preparation of Example 1041 Molecular weight: 1883.24

[001139] Example 1041 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001140] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001141] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.8 mg, and its purity estimated by LCMS analysis was 92%.

[001142] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 942.6 (M+2H).

[001143] LCMS Analysis Condition E: Retention time = 1.55 min; ESI-MS(+) m/z 942 (M+2H). Preparation of Example 1042 Molecular weight: 1869.21

[001144] Example 1042 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001145] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001146] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 0.9 mg, and its purity estimated by LCMS analysis was 99%.

[001147] LCMS Analysis Condition D: Retention time = 1.57min; ESI-MS(+) m/z 935.7 (M+2H).

[001148] LCMS Analysis Condition E: Retention time = 1.57min; ESI-MS(+) m/z 935.3 (M+2H). Preparation of Example 1043 Molecular weight: 1904.24

[001149] Example 1043 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001150] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001151] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna Axia C18, 30 x 250; Mobile phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile phase B: 95:5 acetonitrile: water with 0.1% TFA; Gradient: 10-100% B over 30 minutes, followed by a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 15 mg, and its estimated purity by HPLC analysis was 99%.

[001152] LCMS Analysis Condition A: Retention time = 0.9 min; ESI-MS(+) m/z 953.1 (M+2H).

[001153] HPLC Analysis Condition I: Retention time = 14.98 min. Preparation of Example 1044 Molecular weight: 1945.26

[001154] Example 1044 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001155] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001156] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.6 mg, and its purity estimated by LCMS analysis was 100%.

[001157] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 973.6 (M+2H).

[001158] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 973.3 (M+2H). Preparation of Example 1045 Molecular weight: 1928.21

[001159] Example 1045 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001160] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001161] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 10 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.0 mg, and its purity estimated by LCMS analysis was 94%.

[001162] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 964.9 (M+2H).

[001163] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 964.8 (M+2H). Preparation of Example 1046 Example 1046

[001164] Example 1046 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001165] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001166] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.0 mg, and its purity estimated by LCMS analysis was 100%.

[001167] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 964.5 (M+2H).

[001168] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 963.8 (M+2H).Preparation of Example 1047 Molecular weight: 1932.30

[001169] Example 1047 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001170] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001171] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna Axia C18, 30 x 250; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-100% B over 30 minutes, followed by a 5-minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26 mg, and its purity estimated by HPLC analysis was 100%.

[001172] LCMS Analysis Condition A: Retention time = 0.94 min; ESI-MS(+) m/z 967.0 (M+2H).

[001173] HPLC Analysis Condition I: Retention time = 15.58 min. Preparation of Example 1048 Molecular weight: 1947.24

[001174] Example 1048 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001175] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001176] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.3 mg, and its purity estimated by LCMS analysis was 97%.

[001177] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 974.6 (M+2H).

[001178] LCMS Analysis Condition E: Retention time = 1.62 min; ESI-MS(+) m/z 974.8 (M+2H). Preparation of Example 1049 Molecular weight: 1826.15

[001179] Example 1049 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001180] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001181] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 10 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.5 mg, and its purity estimated by LCMS analysis was 93%.

[001182] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 914.1 (M+2H).

[001183] LCMS Analysis Condition E: Retention time = 1.67 min; ESI-MS(+) m/z 913.8 (M+2H). Preparation of Example 1050 Molecular weight: 1902.24

[001184] Example 1050 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001185] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001186] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 10 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 92%.

[001187] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 952.0 (M+2H).

[001188] LCMS Analysis Condition E: Retention time = 1.72 min; ESI-MS(+) m/z 951.7 (M+2H). Preparation of Example 1051 Molecular weight: 1885.21

[001189] Example 1051 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001190] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001191] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg and its purity estimated by LCMS analysis was 99%.

[001192] LCMS Analysis Condition D: Retention time = 1.54 min; ESI-MS(+) m/z 943.3 (M+2H).

[001193] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 943.5 (M+2H).Preparation of Example 1052 Molecular weight: 1911.25

[001194] Example 1052 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001195] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 1.1 mg, and its purity estimated by HPLC analysis was 95%.

[001196] LCMS Analysis Condition A Retention time = 0.8 min, ESI-MS(+) m/z 956.9 (M+H).

[001197] HPLC Analysis Condition G: Retention time = 7.8 min.

[001198] HPLC Analysis Condition H. Retention time = 9.35 min. Preparation of Example 1053 Molecular weight: 1796.06

[001199] Example 1053 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001200] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001201] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 0.5 mg, and its purity estimated by HPLC analysis was 95%.

[001202] LCMS Analysis Condition A: Retention time = 0.78 min; ESI-MS(+) m/z 899.0 (M+2H).

[001203] HPLC Analysis Condition J: Retention time = 12.74 min. Preparation of Example 1054 Molecular weight: 1868.12

[001204] Example 1054 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001205] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001206] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 4.7 mg, and its purity estimated by HPLC analysis was 100%.

[001207] LCMS Analysis Condition A: Retention time = 0.81 min; ESI-MS(+) m/z 935.4 (M+2H).

[001208] HPLC Analysis Condition J: Retention time = 13.48 min. Preparation of Example 1055 Molecular weight: 1810.13

[001209] Example 1055 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001210] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001211] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 1.6 mg, and its purity estimated by HPLC analysis was 100%.

[001212] LCMS Analysis Condition A: Retention time = 0.81 min; ESI-MS(+) m/z 906.2 (M+2H).

[001213] HPLC Analysis Condition J: Retention time = 13.54 min. Preparation of Example 1056 Molecular weight: 1924.19

[001214] Example 1056 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001215] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001216] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 3.6 mg, and its estimated purity by HPLC analysis was 99.2%.

[001217] LCMS Analysis Condition A: Retention time = 0.78 min; ESI-MS(+) m/z 963.1 (M+2H).

[001218] HPLC Analysis Condition J: Retention time = 12.33 min. Preparation of Example 1057 Molecular weight: 1796.06

[001219] Example 1057 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001220] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001221] The crude material was purified via 2 preparatory HPLC injections with the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 30 x 100; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 0-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was dissolved in a minimum of acetonitrile and water, frozen and lyophilized to give a white amorphous solid. The yield of the product was 8.7 mg, and its estimated purity by HPLC analysis was 99.5%.

[001222] LCMS Analysis Condition A: Retention time = 0.71 min; ESI-MS(+) m/z 899.1 (M+2H).

[001223] HPLC Analysis Condition J: Retention time = 11.76 min. Preparation of Example 1058 Molecular weight: 1962.11

[001224] Example 1058 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001225] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001226] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, followed by a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.7 mg, and its purity estimated by LCMS analysis was 96%.

[001227] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 981.6 (M+2H).

[001228] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 981.7 (M+2H). Preparation of Example 1059 Molecular weight: 1829.17

[001229] Example 1059 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001230] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001231] The crude material was purified via preparatory LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.9 mg, and its purity estimated by LCMS analysis was 98%.

[001232] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 915.4 (M+2H).

[001233] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 915.4 (M+2H). Preparation of Example 1060 Molecular weight: 1801 .12

[001234] Example 1060 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001235] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001236] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.8 mg, and its purity estimated by LCMS analysis was 98%.

[001237] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 901.6 (M+2H).

[001238] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 901.3 (M+2H).Preparation of Example 1061 Molecular weight: 1836.

[001239] Example 1061 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001240] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001241] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.6 mg, and its purity estimated by LCMS analysis was 93%.

[001242] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 919.0 (M+2H).

[001243] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 919.0 (M+2H). Preparation of Example 1062 Molecular weight: 1815.15

[001244] Example 1062 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001245] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001246] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg, and its purity estimated by LCMS analysis was 96%.

[001247] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 908.8 (M+2H).

[001248] LCMS Analysis Condition E: Retention time = 1.67 min; ESI-MS(+) m/z 908.8 (M+2H). Preparation of Example 1063 Molecular weight: 1829.13

[001249] Example 1063 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001250] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001251] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5A particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.4 mg, and its purity estimated by LCMS analysis was 98%.

[001252] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 915.8 (M+2H).

[001253] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 915.8 (M+2H). Preparation of Example 1064 Molecular weight: 1830.12

[001254] Example 1064 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001255] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001256] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.7 mg, and its purity estimated by LCMS analysis was 97%.

[001257] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 916.3 (M+2H).

[001258] LCMS Analysis Condition E: Retention time = 1.76 min; ESI-MS(+) m/z 916.2 (M+2H). Preparation of Example 1065 Molecular weight: 1852.17

[001259] Example 1065 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001260] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001261] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7 mg, and its purity estimated by LCMS analysis was 93%.

[001262] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 927.2 (M+2H).

[001263] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 927.2 (M+2H). Preparation of Example 1066 Molecular weight: 1779.12

[001264] Example 1066 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001265] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001266] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 0-100% B over 30 minutes, Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LC analysis was 100%.

[001267] LCMS Analysis Condition A: Retention time = 0.78 min; ESI-MS(+) m/z 890.5 (M+2H).

[001268] HPLC Analysis Condition J: Retention time = 13.4 min. Preparation of Example 1067 Molecular weight: 1869.

[001269] Example 1067 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001270] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001271] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna C18, 30 x 1000 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 0-100% B over 30 minutes, Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.6 mg, and its purity estimated by LC analysis was 95%.

[001272] LCMS Analysis Condition A: Retention time = 0.93 min; ESI-MS(+) m/z 935.7 (M+2H).

[001273] HPLC Analysis Condition J: Retention time = 14.92 min. Preparation of Example 1068 Molecular weight: 1902.23

[001274] Example 1068 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001275] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001276] The crude material was purified via preparative LC with the following conditions: Column; FENOMENEX® Luna C18, 30 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-1000% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min, 2 2 mL injections. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 3.3 mg, and its purity estimated by LC was 100% using analysis condition J.

[001277] LCMS Analysis Condition A: Retention time = 0.79 min; ESI-MS(+) m/z 952.4 (M+2H).

[001278] HPLC Analysis Condition J: Retention time = 12.99 min. Preparation of Example 1069 Molecular weight: 1893.26

[001279] Example 1069 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001280] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001281] The crude material was purified via preparative LC under the following conditions: Column; FENOMENEX® Luna C18, 30 x 1000 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min, 2 2 ml injections. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 4.7 mg, and its purity estimated by LC was 95.5% using 3 LC analysis methods.

[001282] LCMS Analysis Condition A: Retention time = 0.81 min; ESI-MS(+) m/z 947.5 (M+2H).

[001283] HPLC Analysis Condition J: Retention time = 13.13 min.

[001284] HPLC Analysis Condition G: Retention time = 9.14 min.

[001285] HPLC Analysis Condition H. Retention time = 10.76 min. Preparation of Example 1070 Molecular weight: 1879.24

[001286] Example 1070 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001287] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001288] The crude material was purified via preparatory LC under the following conditions: Column; FENOMENEX® Luna C18, 30 x 100 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min, 2 2 ml injections. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 6 mg, and its purity estimated by LC was 100%.

[001289] LCMS Analysis Condition A: Retention time = 0.82 min; ESI-MS(+) m/z 940.7 (M+2H).

[001290] HPLC Analysis Condition J: Retention time = 13.0 min. Preparation of Example 1071 Molecular weight: 1809.14

[001291] Example 1071 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001292] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001293] The crude material was purified via preparatory LC with the following conditions: FENOMENEX® Luna C18 column, 30 x 100 mm, 5 μm particles; 0 to 100% acetonitrile in water with 0.1% TFA as modifier, for 30 minutes. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.5 mg, and its purity estimated by LC was 100%.

[001294] LCMS Analysis Condition A: Retention time = 0.88 min; ESI-MS(+) m/z 905.7 (M+2H).

[001295] HPLC Analysis Condition J: Retention time = 14.83 min. Preparation of Example 1072 Molecular weight: 1842.1

[001296] Example 1072 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001297] The crude material was purified via preparatory LC with the following conditions: FENOMENEX® Luna C18 column, 30 x 100 mm, 5 μm particles; 0 to 100% acetonitrile in water with 0.1% TFA as modifier, for 30 minutes. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.3 mg, and its purity estimated by LC was 100%.

[001298] LCMS Analysis Condition A: Retention time = 0.7 min; ESI-MS(+) m/z 922.9 (M+2H).

[001299] HPLC Analysis Condition J: Retention time = 11.36 min. Preparation of Example 1073 Molecular weight: 1803.10

[001300] Example 1073 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001301] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001302] The crude material was purified via preparatory LC with the following conditions: FENOMENEX® Luna C18 column, 30 x 100 mm, 5 μm particles; 0 to 100% acetonitrile in water with 0.1% TFA as modifier, for 30 minutes. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 3 mg, and its purity estimated by LC was 100%.

[001303] LCMS Analysis Condition A: Retention time = 0.71 min; ESI-MS(+) m/z 902.7 (M+2H).

[001304] HPLC Analysis Condition J: Retention time = 11.15 min. Preparation of Example 1074 Molecular weight: 1909.22

[001305] Example 1074 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001306] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001307] The crude material was purified via preparative LC with the following conditions: FENOMENEX® Luna C18 column, 30 x 100 mm, 5 μm particles; 0 to 100% acetonitrile in water with 0.1% TFA as modifier, for 30 minutes. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.8 mg, and its purity estimated by LC was 100%.

[001308] LCMS Analysis Condition A: Retention time = 0.84 min; ESI-MS(+) m/z 955.8 (M+2H).

[001309] HPLC Analysis Condition J: Retention time = 13.34 min. Preparation of Example 1075 Molecular weight: 1895.19

[001310] Example 1075 was prepared following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001311] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001312] The crude material was purified via preparatory LC with the following conditions: FENOMENEX® Luna C18 column, 30 x 100 mm, 5 μm particles; 0 to 100% acetonitrile in water with 0.1% TFA as modifier, for 30 minutes. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 3.8 mg, and its purity estimated by LC was 100%.

[001313] LCMS Analysis Condition A: Retention time = 0.8 min; ESI-MS(+) m/z 948.9 (M+2H).

[001314] HPLC Analysis Condition J: Retention time = 13.34 min. Preparation of Example 1076 Molecular weight: 1853.1

[001315] Example 1076 was prepared over Fmoc-Gly-O-cltrityl resin, following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001316] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 93%.

[001317] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 927.7 (M+2H).

[001318] LCMS Analysis Condition E: Retention time = 1.66 min; ESI-MS(+) m/z 927.4 (M+2H). Preparation of Example 1077 Molecular weight: 1843.20

[001319] Example 1077 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001320] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001321] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.8 mg, and its purity estimated by LCMS analysis was 94%.

[001322] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 922.4 (M+2H).

[001323] LCMS Analysis Condition E: Retention time = 1.66 min; ESI-MS(+) m/z 922.3 (M+2H).Preparation of Example 1078 Molecular weight: 1866.19

[001324] Example 1078 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001325] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001326] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1 mg, and its purity was estimated to be 89% by LCMS analysis.

[001327] LCMS Analysis Condition D: Retention time 1.54 min; ESI-MS(+) m/z 933.7 (M+2H).

[001328] LCMS Analysis Condition E: Retention time 1.47 min; ESI-MS(+) m/z 933.7 (M+2H). Preparation of Example 1080 Molecular weight: 1873.18

[001329] Example 1080 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001330] "Simphony Method A: Resin swelling procedure", "Simphony Method A: Standard-coupling procedure", "Simphony Method A: Secondary amine coupling procedure B", "Chloroacetic acid coupling procedure B", "Global deprotection method C", and "Cyclization method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-dimethoxyphenyl)propanoic acid was used in the eighth amino acid coupling step.

[001331] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 0.9 mg, and its purity was estimated to be 92% by LCMS analysis.

[001332] LCMS Analysis Condition D: Retention time = 1.55 min; ESI-MS(+) m/z 937.5 (M+2H).

[001333] LCMS Analysis Condition E: Retention time = 1.48 min; ESI-MS(+) m/z 937.5 (M+2H). Preparation of Example 1081 Molecular weight: 1809.14

[001334] Example 1081 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001335] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001336] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.6 mg, and its purity was estimated to be 94% by LCMS analysis.

[001337] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 905.5 (M+2H).

[001338] LCMS Analysis Condition E: Retention time = 1.54 min; ESI-MS(+) m/z 905.5 (M+2H). Preparation of Example 1082 Molecular weight: 1851.22

[001339] Example 1082 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001340] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001341] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.8 mg, and its purity estimated by LCMS analysis was 99%.

[001342] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 926.3 (M+2H).

[001343] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 926.3 (M+2H). Preparation of Example 1083 Molecular weight: 1880.22

[001344] Example 1083 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001345] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (R)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methyl-3-(tritylthio)butanoic acid was used in the second amino acid coupling step.

[001346] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.91 mg and its purity estimated by LCMS analysis was 98%.

[001347] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 941.2 (M+2H).

[001348] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 940.9 (M+2H). Preparation of Example 1084 Molecular weight: 1860.21

[001349] Example 1084 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001350] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001351] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5 mg, and its purity estimated by LCMS analysis was 95%.

[001352] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 930.8 (M+2H).

[001353] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 930.8 (M+2H). Preparation of Example 1085 Molecular weight: 1843.16

[001354] Example 1085 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001355] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoic acid was used in the eighth amino acid coupling step.

[001356] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13 mg and its purity estimated by LCMS analysis was 99%.

[001357] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 922.6 (M+2H).

[001358] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 922.5 (M+2H). Preparation of Example 1086 Molecular weight: 1827.16

[001359] Example 1086 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001360] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methylphenyl)propanoic acid was used in the eighth amino acid coupling step.

[001361] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 100%.

[001362] LCMS Analysis Condition D: Retention time = 1.55 min; ESI-MS(+) m/z 914.2 (M+2H).

[001363] LCMS Analysis Condition E: Retention time = 1.52 min; ESI-MS(+) m/z 914.5 (M+2H). Preparation of Example 1087 Molecular weight: 1894.20

[001364] Example 1087 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001365] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001366] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 99%.

[001367] LCMS Analysis Condition D: Retention time = 1.79 min; ESI-MS(+) m/z 948.3 (M+2H).

[001368] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 947.9 (M+2H). Preparation of Example 1088 Molecular weight: 1802.11

[001369] Example 1088 was prepared from intermediate resin A, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001370] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.6 mg, and its purity estimated by LCMS analysis was 98%.

[001371] LCMS Analysis Condition D: Retention time = 1.81 min; ESI-MS(+) m/z 902.0 (M+2H).

[001372] LCMS Analysis Condition E: Retention time = 1.83 min; ESI-MS(+) m/z 902.0 (M+2H). Preparation of Example 1089 Molecular weight: 1866.19

[001373] Example 1089 was prepared from intermediate resin A, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001374] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.7 mg, and its purity estimated by LCMS analysis was 98%.

[001375] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 934.0 (M+2H).

[001376] LCMS Analysis Condition E: Retention time = 1.59 min; ESI-MS(+) m/z 934.3 (M+2H). Preparation of Example 1090 Molecular weight: 1910.16

[001377] Example 1090 was prepared from intermediate resin A, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001378] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.1 mg, and its purity estimated by LCMS analysis was 93%.

[001379] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 956.0 (M+2H).

[001380] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 955.9 (M+2H). Preparation of Example 1091 Molecular weight: 1859.11

[001381] Example 1091 was prepared from intermediate resin A, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001382] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, then a 10 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.1 mg, and its purity estimated by LCMS analysis was 99%.

[001383] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 930.9 (M+2H).

[001384] LCMS Analysis Condition E: Retention time = 1.47 min; ESI-MS(+) m/z 930.7 (M+2H). Preparation of Example 1092 Molecular weight: 1853.15

[001385] Example 1092 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001386] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001387] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1.4 mg, and its purity was estimated to be 100% by LCMS analysis.

[001388] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 927.3 (M+2H).

[001389] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 927.3 (M+2H). Preparation of Example 1093 Molecular weight: 1931.25

[001390] Example 1093 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-sulfamoylphenyl)propanoic acid was used in the amino acid coupling step.

[001391] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.0 mg, and its purity estimated by LCMS analysis was 99%.

[001392] LCMS Analysis Condition D: Retention time = 1.48 min; ESI-MS(+) m/z 966.7 (M+2H).

[001393] LCMS Analysis Condition E: Retention time = 1.45 min; ESI-MS(+) m/z 966.2 (M+2H). Preparation of Example 1094 Molecular weight: 1891.20

[001394] Example 1094 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-4-yl)propanoic acid was used in the amino acid coupling step.

[001395] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.8 mg, and its purity estimated by LCMS analysis was 100%.

[001396] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 946.6 (M+2H).

[001397] LCMS Analysis Condition E: Retention time = 1.62 min; ESI-MS(+) m/z 946.6 (M+2H). Preparation of Example 1095 Molecular weight: 1896.18

[001398] Example 1095 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid was used in the amino acid coupling step.

[001399] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.0 mg, and its purity estimated by LCMS analysis was 100%.

[001400] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 949.3 (M+2H).

[001401] LCMS Analysis Condition E: Retention time = 1.44 min; ESI-MS(+) m/z 949.2 (M+2H). Preparation of Example 1096 Molecular weight: 1859.18

[001402] Example 1096 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(thiazol-4-yl)propanoic acid was used in the amino acid coupling step.

[001403] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its purity estimated by LCMS analysis was 100%.

[001404] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 930.6 (M+2H).

[001405] LCMS Analysis Condition E: Retention time = 1.45 min; ESI-MS(+) m/z 930.7 (M+2H). Preparation of Example 1097 Molecular weight: 1866.19

[001406] Example 1097 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyl)propanoic acid was used in the amino acid coupling step.

[001407] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.7 mg, and its purity estimated by LCMS analysis was 98%.

[001408] LCMS Analysis Condition D: Retention time = 1.87 min; ESI-MS(+) m/z 934.1 (M+2H).

[001409] LCMS Analysis Condition E: Retention time = 1.79 min; ESI-MS(+) m/z 934.1 (M+2H). Preparation of Example 1098 Molecular weight: 1882.19

[001410] Example 1098 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-methoxyphenyl)propanoic acid was used in the amino acid coupling step.

[001411] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 100%.

[001412] LCMS Analysis Condition D: Retention time = 1.78 min; ESI-MS(+) m/z 942.2 (M+2H).

[001413] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 942.1 (M+2H).Preparation of Example 1099 Molecular weight: 1842.13

[001414] Example 1099 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(furan-2-yl)propanoic acid was used in the amino acid coupling step.

[001415] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.9 mg, and its purity estimated by LCMS analysis was 100%.

[001416] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 922.1 (M+2H).

[001417] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 922.2 (M+2H). Preparation of Example 1100 Molecular weight: 1945.27

[001418] Example 1100 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(methylsulfonamido)phenyl)propanoic acid was used in the amino acid coupling step.

[001419] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.1 mg, and its purity estimated by LCMS analysis was 100%.

[001420] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 973.9 (M+2H).

[001421] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 973.5 (M+2H). Preparation of Example 1101 Molecular weight: 1886.61

[001422] Example 1101 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-chlorophenyl)propanoic acid was used in the amino acid coupling step.

[001423] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.3 mg, and its purity estimated by LCMS analysis was 99%.

[001424] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 945.0 (M+2H).

[001425] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 944.2 (M+2H). Preparation of Example 1102 Molecular weight: 1886.61

[001426] Example 1102 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chlorophenyl)propanoic acid was used in the amino acid coupling step.

[001427] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.6 mg, and its purity estimated by LCMS analysis was 98%.

[001428] LCMS Analysis Condition D: Retention time = 1.77 min; ESI-MS(+) m/z 944.7 (M+2H).

[001429] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 944.4 (M+2H). Preparation of Example 1103 Molecular weight: 1921.06

[001430] Example 1103 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-dichlorophenyl)propanoic acid was used in the amino acid coupling step.

[001431] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.5 mg, and its purity estimated by LCMS analysis was 98%.

[001432] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 961.9 (M+2H).

[001433] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 961.3 (M+2H). Preparation of Example 1104 Molecular weight: 1888.15

[001434] Example 1104 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-difluorophenyl)propanoic acid was used in the amino acid coupling step.

[001435] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 98%.

[001436] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 945.2 (M+2H).

[001437] LCMS Analysis Condition E: Retention time = 1.66 min; ESI-MS(+) m/z 945.2 (M+2H). Preparation of Example 1105 Molecular weight: 1912.22

[001438] Example 1105 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,4-dimethoxyphenyl)propanoic acid was used in the amino acid coupling step.

[001439] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.9 mg, and its purity estimated by LCMS analysis was 100%.

[001440] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 956.9 (M+2H).

[001441] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 956.9 (M+2H). Preparation of Example 1106 Molecular weight: 1866.19

[001442] Example 1106 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(o-tolyl)propanoic acid was used in the amino acid coupling step.

[001443] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.0 mg, and its purity estimated by LCMS analysis was 99%.

[001444] LCMS Analysis Condition D: Retention time = 1.79 min; ESI-MS(+) m/z 934.2 (M+2H).

[001445] LCMS Analysis Condition E: Retention time = 1.72 min; ESI-MS(+) m/z 934.0 (M+2H). Preparation of Example 1107 Molecular weight: 1920.17

[001446] Example 1107 was prepared starting from intermediate resin B, using "Manual Coupling Procedure A", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used in the amino acid coupling step.

[001447] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.7 mg, and its purity estimated by LCMS analysis was 95%.

[001448] LCMS Analysis Condition D: Retention time = 1.78 min; ESI-MS(+) m/z 961.2 (M+2H).

[001449] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 961.0 (M+2H). Preparation of Example 1108 Molecular weight: 1858.13

[001450] Example 1108 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001451] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-N-Me-Ala-OH was used in the fourth amino acid coupling step, and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-phenylpentanoic acid was used in the fifth amino acid coupling step.

[001452] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2 mg, and its purity estimated by LCMS analysis was 91%.

[001453] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 930.1 (M+2H).

[001454] LCMS Analysis Condition E: Retention time = 1.48 min; ESI-MS(+) m/z 930.0 (M+2H). Preparation of Example 1110 Molecular weight: 1866.19

[001455] Example 1110 was prepared starting from intermediate resin A, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". 2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-methylpropanoic acid was used in the first coupling step to intermediate resin A.

[001456] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.0 mg, and its purity estimated by LCMS analysis was 100%.

[001457] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS(+) m/z 934.0 (M+2H).

[001458] LCMS Analysis Condition E: Retention time = 1.52 min; ESI-MS(+) m/z 933.9 (M+2H). Preparation of Example 1112 Molecular weight: 1888.15

[001459] Example 1112 was prepared starting from intermediate resin A, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid was used in the fourth coupling step.

[001460] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 100%.

[001461] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 944.9 (M+2H).

[001462] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 944.9 (M+2H). Preparation of Example 1113 Molecular weight: 1843.16

[001463] Example 1113 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001464] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001465] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.5 mg, and its purity estimated by LCMS analysis was 100%.

[001466] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 922.7 (M+2H).

[001467] LCMS Analysis Condition E: Retention time = 1.43 min; ESI-MS(+) m/z 922.4(M+2H). Preparation of Example 1114 Molecular weight: 1859.16

[001468] Example 1114 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001469] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001470] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.4 mg, and its purity estimated by LCMS analysis was 100%.

[001471] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 930.6 (M+2H).

[001472] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 930.2 (M+2H). Preparation of Example 1115 Molecular weight: 1927.21

[001473] Example 1115 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001474] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001475] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.6 mg, and its purity estimated by LCMS analysis was 100%.

[001476] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 964.8 (M+2H).

[001477] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 964.4 (M+2H). Preparation of Example 1116 Molecular weight: 1850.19

[001478] Example 1116 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001479] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001480] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.2 mg, and its purity estimated by LCMS analysis was 100%.

[001481] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 926.7 (M+2H).

[001482] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 926.2 (M+2H). Preparation of Example 1117 Molecular weight: 1912.65

[001483] Example 1117 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001484] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001485] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 100%.

[001486] LCMS Analysis Condition D: Retention time = 1.86 min; ESI-MS(+) m/z 957.0 (M+2H).

[001487] LCMS Analysis Condition E: Retention time = 1.79 min; ESI-MS(+) m/z 956.8 (M+2H). Preparation of Example 1118 Molecular weight: 1876.21

[001488] Example 1118 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001489] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001490] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.2 mg, and its purity estimated by LCMS analysis was 100%.

[001491] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 939.0 (M+2H).

[001492] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 938.7 (M+2H).

[001493] ESI-HRMS(+) m/z: Calculated: 938.4553 (M+2H); Found: 938.4529 (M+2H). Preparation of Example 1119 Molecular weight: 1910.20

[001494] Example 1119 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001495] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001496] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.1 mg, and its purity estimated by LCMS analysis was 97%.

[001497] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 955.7 (M+2H).

[001498] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 955.6 (M+2H). Preparation of Example 1120 Molecular weight: 1934.29

[001499] Example 1120 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001500] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001501] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.3 mg, and its purity estimated by LCMS analysis was 99%.

[001502] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 967.8 (M+2H).

[001503] LCMS Analysis Condition E: Retention time = 1.67 min; ESI-MS(+) m/z 968.2 (M+2H). Preparation of Example 1121 Molecular weight: 1810.08

[001504] Example 1121 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001505] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001506] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.6 mg, and its purity estimated by LCMS analysis was 96%.

[001507] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 906.2 (M+2H).

[001508] LCMS Analysis Condition E: Retention time = 1.59 min; ESI-MS(+) m/z 906.2 (M+2H). Preparation of Example 1122 Molecular weight: 1895.19

[001509] Example 1122 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001510] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001511] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.2 mg, and its purity estimated by LCMS analysis was 99%.

[001512] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 948.8 (M+2H).

[001513] LCMS Analysis Condition E: Retention time = 1.49 min; ESI-MS(+) m/z 948.8 (M+2H). Preparation of Example 1123 Molecular weight: 1868.16

[001514] Example 1123 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001515] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001516] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.0 mg, and its purity estimated by LCMS analysis was 100%.

[001517] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 935.3 (M+2H).

[001518] LCMS Analysis Condition E: Retention time = 1.44 min; ESI-MS(+) m/z 935.3 (M+2H). Preparation of Example 1124 Molecular weight: 1929.70

[001519] Example 1124 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001520] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001521] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity estimated by LCMS analysis was 95%.

[001522] LCMS Analysis Condition D: Retention time = 2.03 min; ESI-MS(+) m/z 966.0 (M+2H).

[001523] LCMS Analysis Condition E: Retention time = 1.99 min; ESI-MS(+) m/z 965.9 (M+2H). Preparation of Example 1125 Molecular weight: 1945.70

[001524] Example 1125 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001525] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001526] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.7 mg, and its purity estimated by LCMS analysis was 100%.

[001527] LCMS Analysis Condition D: Retention time = 1.97 min; ESI-MS(+) m/z 974.5 (M+2H).

[001528] LCMS Analysis Condition E: Retention time = 1.90 min; ESI-MS(+) m/z 973.4 (M+2H). Preparation of Example 1126 Molecular weight: 1930.19

[001529] Example 1126 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001530] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001531] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.7 mg, and its purity estimated by LCMS analysis was 98%.

[001532] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 965.8 (M+2H).

[001533] LCMS Analysis Condition E: Retention time = 1.59 min; ESI-MS(+) m/z 966.3 (M+2H). Preparation of Example 1127 Molecular weight: 1876.1

[001534] Example 1127 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001535] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001536] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.9 mg, and its purity estimated by LCMS analysis was 95%.

[001537] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 939.4 (M+2H).

[001538] LCMS Analysis Condition E: Retention time = 1.6 min; ESI-MS(+) m/z 938.9 (M+2H). Preparation of Example 1128 Molecular weight: 1892.16

[001539] Example 1128 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001540] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001541] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 95%.

[001542] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 947.3 (M+2H).

[001543] LCMS Analysis Condition E: Retention time = 1.60 min; ESI-MS(+) m/z 947.1 (M+2H). Preparation of Example 1129 Molecular weight: 1912.24

[001544] Example 1129 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001545] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001546] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 90%.

[001547] LCMS Analysis Condition D: Retention time = 1.55 min; ESI-MS(+) m/z 957.3 (M+2H).

[001548] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 956.7 (M+2H). Preparation of Example 1130 Molecular weight: 1908.23

[001549] Example 1130 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001550] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". Fmoc-(D/L)-Trp(Me)-OH was used in the sixth amino acid coupling step.

[001551] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.2 mg, and its purity estimated by LCMS analysis was 97%.

[001552] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 955.5 (M+2H).

[001553] LCMS Analysis Condition E: Retention time = 1.61 min; ESI-MS(+) m/z 955.4 (M+2H). Preparation of Example 1131 Molecular weight: 1854.14

[001554] Example 1131 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001555] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001556] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.7 mg, and its purity estimated by LCMS analysis was 99%.

[001557] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 928.2 (M+2H).

[001558] LCMS Analysis Condition E: Retention time = 1.44 min; ESI-MS(+) m/z 928.1 (M+2H). Preparation of Example 1132 Molecular weight: 1840.11

[001559] Example 1132 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001560] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001561] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 100%.

[001562] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 921.2 (M+2H).

[001563] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 921.2 (M+2H). Preparation of Example 1133 Molecular weight: 1937.27

[001564] Example 1133 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001565] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001566] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 92%.

[001567] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 969.9 (M+2H).

[001568] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 969.8 (M+2H). Preparation of Example 1134 Molecular weight: 1923.25

[001569] Example 1134 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001570] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001571] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.9 mg, and its purity estimated by LCMS analysis was 100%.

[001572] LCMS Analysis Condition D: Retention time 1.41 min; ESI-MS(+) m/z 962.8 (M+2H).

[001573] LCMS Analysis Condition E: Retention time 1.35 min; ESI-MS(+) m/z 962 A (M+2H). Preparation of Example 1135 Molecular weight: 1909.22

[001574] Example 1135 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001575] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001576] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.2 mg, and its purity estimated by LCMS analysis was 98%.

[001577] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 955.8 (M+2H).

[001578] LCMS Analysis Condition E: Retention time = 1.31 min; ESI-MS(+) m/z 955.5 (M+2H). Preparation of Example 1136 Molecular weight: 1906.22

[001579] Example 1136 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001580] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001581] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.2 mg, and its purity estimated by LCMS analysis was 94%.

[001582] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 954.1 (M+2H).

[001583] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 953.8 (M+2H). Preparation of Example 1137 Molecular weight: 1906.22

[001584] Example 1137 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001585] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001586] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.2 mg, and its purity estimated by LCMS analysis was 100%.

[001587] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 954.3 (M+2H).

[001588] LCMS Analysis Condition E: Retention time = 1.43 min; ESI-MS(+) m/z 953.8 (M+2H). Preparation of Example 1138 Molecular weight: 1775.03

[001589] Example 1138 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001590] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.0 mg, and its purity estimated by LCMS analysis was 98%.

[001591] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 888.1 (M+2H).

[001592] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 888.2 (M+2H). Preparation of Example 1139 Molecular weight: 1834.17

[001593] Example 1139 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001594] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001595] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.2 mg, and its estimated purity by LCMS analysis was 97%.

[001596] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 917.8 (M+2H).

[001597] LCMS Analysis Condition E: Retention time = 1.52 min; ESI-MS(+) m/z 917.8 (M+2H). Preparation of Example 1140 Molecular weight: 1827.07

[001598] Example 1140 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001599] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001600] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 30.4 mg, and its estimated purity by LCMS analysis was 91%.

[001601] LCMS Analysis Condition D: Retention time = 1.42 min; ESI-MS(+) m/z 914.2 (M+2H).

[001602] LCMS Analysis Condition E: Retention time = 1.36 min; ESI-MS(+) m/z 914.6 (M+2H). Preparation of Example 1141 Molecular weight: 1877.19

[001603] Example 1141 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001604] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001605] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.5 mg, and its purity estimated by LCMS analysis was 93%.

[001606] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 939.3 (M+2H).

[001607] LCMS Analysis Condition E: Retention time = 1.57 min; ESI-MS(+) m/z 940.4 (M+2H). Preparation of Example 1142 Molecular weight: 1844.14

[001608] Example 1142 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001609] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001610] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then 7-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.3 mg, and its estimated purity by LCMS analysis was 99%.

[001611] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 923.3 (M+2H).

[001612] LCMS Analysis Condition E: Retention time = 1.49 min; ESI-MS(+) m/z 923.3 (M+2H). Preparation of Example 1143 Molecular weight: 1816.13

[001613] Example 1143 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001614] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001615] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 10 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.4 mg, and its purity estimated by LCMS analysis was 92%.

[001616] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 908.9 (M+2H).

[001617] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 909.3 (M+2H). Preparation of Example 1144 Molecular weight: 1908.23

[001618] Example 1144 was prepared starting from intermediate resin G following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-methyl-1H-indol-3-yl)propanoic acid was used in the first coupling to intermediate resin G.

[001619] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.0 mg, and its purity estimated by LCMS analysis was 96%.

[001620] LCMS Analysis Condition D: Retention time = 1.54 min; ESI-MS(+) m/z 955.1 (M+2H).

[001621] LCMS Analysis Condition E: Retention time = 1.49 min; ESI-MS(+) m/z 955.0 (M+2H). Preparation of Example 1145 Molecular weight: 1817.12

[001622] Example 1145 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001623] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001624] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.1 mg, and its purity estimated by LCMS analysis was 92%.

[001625] LCMS Analysis Condition D: Retention time = 1.39 min; ESI-MS(+) m/z 909.3 (M+2H).

[001626] LCMS Analysis Condition E: Retention time = 1.4 min; ESI-MS(+) m/z 909.5 (M+2H). Preparation of Example 1146 Molecular weight: 1844.19

[001627] Example 1146 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001628] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001629] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge shield rpl 8, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-55% B over 25 min, then a 5 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.4 mg, and its purity estimated by LCMS analysis was 98%.

[001630] LCMS Analysis Condition D: Retention time = 1.31 min; ESI-MS(+) m/z 922.8 (M+2H).

[001631] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 922.8 (M+2H). Preparation of Example 1147 Molecular weight: 1860.14

[001632] Example 1147 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001633] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001634] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its estimated purity by LCMS analysis was 99%.

[001635] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 931.3 (M+2H).

[001636] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 931.1 (M+2H). Preparation of Example 1148 Molecular weight: 1922.21

[001637] Example 1148 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001638] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001639] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.0 mg, and its estimated purity by LCMS analysis was 93%.

[001640] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 962.2 (M+2H).

[001641] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 961.8 (M+2H). Preparation of Example 1149 Molecular weight: 1830.11

[001642] Example 1149 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001643] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001644] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 55.2 mg, and its purity estimated by LCMS analysis was 96%.

[001645] LCMS Analysis Condition D: Retention time = 1.32 min; ESI-MS(+) m/z 915.8 (M+2H).

[001646] LCMS Analysis Condition E: Retention time = 1.31 min; ESI-MS(+) m/z 916.0 (M+2H). Preparation of Example 1150 Molecular weight: 1800.09

[001647] Example 1150 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001648] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001649] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 47.7 mg, and its purity estimated by LCMS analysis was 98%.

[001650] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 901.0 (M+2H).

[001651] LCMS Analysis Condition E: Retention time = 1.34 min; ESI-MS(+) m/z 900.7 (M+2H). Preparation of Example 1151 Molecular weight: 1815.06

[001652] Example 1151 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001653] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001654] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 53.0 mg, and its purity estimated by LCMS analysis was 100%.

[001655] LCMS Analysis Condition D: Retention time = 1.31 min; ESI-MS(+) m/z 908.2 (M+2H).

[001656] LCMS Analysis Condition E: Retention time = 1.30 min; ESI-MS(+) m/z 908.4 (M+2H). Preparation of Example 1152 Molecular weight: 1787.04

[001657] Example 1152 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001658] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001659] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.0 mg, and its purity estimated by LCMS analysis was 94%.

[001660] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 894.1 (M+2H).

[001661] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 894.1 (M+2H). Preparation of Example 1153 Molecular weight: 1844.16

[001662] Example 1153 was prepared by following the general synthesis sequence described for the preparation of Example 1, starting from Fmoc-Gly-O-chlorotrityl resin, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method E", and "Cyclization Method D".

[001663] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.9 mg and its purity estimated by LCMS analysis was 92%.

[001664] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 922.7 (M+2H).

[001665] LCMS Analysis Condition E: Retention time = 1.60 min; ESI-MS(+) m/z 923.3 (M+2H). Preparation of Example 1154 Molecular weight: 1827.11

[001666] Example 1154 was prepared by following the general synthetic sequence described for the preparation of Example 1, starting from Fmoc-Gly-O-chlorotrityl Resin, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method E", and "Cyclization Method D".

[001667] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.7 mg, and its purity was estimated to be 100% by LCMS analysis.

[001668] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 914.2 (M+2H).

[001669] LCMS Analysis Condition E: Retention time = 1.44 min; ESI-MS(+) m/z 914.2 (M+2H).

[001670] ESI-HRMS(+) m/z: Calculated: 913.9560 (M+2H); Found: 913.9529 (M+2H). Preparation of Example 1155 Molecular weight: 1846.12

[001671] Example 1155 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001672] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001673] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.2 mg, and its purity estimated by LCMS analysis was 96%.

[001674] LCMS Analysis Condition D: Retention time = 1.4 min; ESI-MS(+) m/z 923.8 (M+2H).

[001675] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 923.9 (M+2H). Preparation of Example 1156 Molecular weight: 1869.11

[001676] Example 1156 was prepared by treating Example 1140 (29 mg, 0.016 mmol) with a previously made solution of HATU (7.24 mg, 0.019 mmol) in DMF (2 mL), and DIEA (6.93 μL, 0.040 mmol). Stir at room temperature overnight.

[001677] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.9 mg, and its purity estimated by LCMS analysis was 97%.

[001678] LCMS Analysis Condition D: Retention time = 1.42 min; ESI-MS(+) m/z 935.2 (M+2H).

[001679] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 935.2 (M+2H). Preparation of Example 1157 Molecular weight: 1881.21

[001680] Example 1157 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001681] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001682] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.4 mg, and its purity estimated by LCMS analysis was 98%.

[001683] LCMS Analysis Condition D: Retention time = 1.35 min; ESI-MS(+) m/z 941.6 (M+2H).

[001684] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 941.4 (M+2H). Preparation of Example 1158 Molecular weight: 1789.06

[001685] Example 1158 was prepared using Rink resin following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001686] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.5 mg, and its purity estimated by LCMS analysis was 92%.

[001687] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 895.2 (M+2H).

[001688] LCMS Analysis Condition E: Retention time = 1.48 min; ESI-MS(+) m/z 895.8 (M+2H). Preparation of Example 1159 Molecular weight: 1926.16

[001689] Example 1159 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001690] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.1 mg, and its purity was estimated to be 100% by LCMS analysis.

[001691] LCMS Analysis Condition D: Retention time = 1.42 min; ESI-MS(+) m/z 964.2 (M+2H).

[001692] LCMS Analysis Condition E: Retention time = 1.39 min; ESI-MS(+) m/z 964.0 (M+2H). Preparation of Example 1160 Molecular weight: 1875.11

[001693] Example 1160 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001694] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 4.2 mg, and its purity estimated by LCMS analysis was 99%.

[001695] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 938.4 (M+2H).

[001696] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 938.5 (M+2H). Preparation of Example 1161 Molecular weight: 1806.11

[001697] Example 1161 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001698] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.7 mg, and its purity estimated by LCMS analysis was 100%.

[001699] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 903.8 (M+2H).

[001700] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 904.0 (M+2H).Preparation of Example 1162 Molecular weight: 1822.07

[001701] Example 1162 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001702] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.3 mg, and its purity estimated by LCMS analysis was 100%.

[001703] LCMS Analysis Condition D: Retention time 1.61 min; ESI-MS(+) m/z 912.3 (M+2H).

[001704] LCMS Analysis Condition E: Retention time 1.57 min; ESI-MS(+) m/z 911.7 (M+2H). Preparation of Example 1163 Molecular weight: 1807.10

[001705] Example 1163 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001706] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.8 mg, and its purity estimated by LCMS analysis was 100%.

[001707] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 904.4 (M+2H).

[001708] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 904.3 (M+2H). Preparation of Example 1164 Molecular weight: 1824.11

[001709] Example 1164 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001710] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 92%.

[001711] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 912.8 (M+2H).

[001712] LCMS Analysis Condition E: Retention time = 1.50 min; ESI-MS(+) m/z 912.5 (M+2H). Preparation of Example 1165 Molecular weight: 1826.08

[001713] Example 1165 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001714] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge Shield RP18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.4 mg, and its purity estimated by LCMS analysis was 100%.

[001715] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 913.8 (M+2H).

[001716] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 913.7 (M+2H). Preparation of Example 1166 Molecular weight: 1911.19

[001717] Example 1166 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001718] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge Shield RP18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 1060% B over 25 min, then 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.6 mg, and its purity estimated by LCMS analysis was 100%.

[001719] LCMS Analysis Condition D: Retention time 1.38 min; ESI-MS(+) m/z 956.2 (M+2H).

[001720] LCMS Analysis Condition E: Retention time 1.38 min; ESI-MS(+) m/z 956.4 (M+2H). Preparation of Example 1167 Molecular weight: 1909.22

[001721] Example 1167 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001722] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.2 mg, and its purity estimated by LCMS analysis was 99%.

[001723] LCMS Analysis Condition D: Retention time = 1.4 min; ESI-MS(+) m/z 955.3 (M+2H).

[001724] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 955.3 (M+2H). Preparation of Example 1168 Molecular weight: 1841.05

[001725] Example 1168 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001726] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.6 mg, and its purity estimated by LCMS analysis was 93%.

[001727] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 921.7 (M+2H).

[001728] LCMS Analysis Condition E: Retention time = 1.42 min; ESI-MS(+) m/z 921.2 (M+2H). Preparation of Example 1169 Molecular weight: 1840.11

[001729] Example 1169 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001730] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge Shield RP18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-65% B over 25 min, then 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.6 mg, and its purity was estimated to be 90% by LCMS analysis.

[001731] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 921.1 (M+2H).

[001732] LCMS Analysis Condition E: Retention time = 1.42 min; ESI-MS(+) m/z 921.5 (M+2H). Preparation of Example 1170 Molecular weight: 1775.98

[001733] Example 1170 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001734] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 8.8 mg, and its purity was estimated to be 95% by LCMS analysis.

[001735] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 889.3 (M+2H).

[001736] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 888.7 (M+2H). Preparation of Example 1171 Exact mass: 1788.83

[001737] Example 1171 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001738] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.6 mg, and its purity estimated by LCMS analysis was 98%.

[001739] LCMS Analysis Condition D: Retention time 1.43 min; ESI-MS(+) m/z 895.7 (M+2H).

[001740] LCMS Analysis Condition E: Retention time 1.43 min; ESI-MS(+) m/z 895.7 (M+2H). Preparation of Example 1172 Molecular weight: 1732.01

[001741] Example 1172 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “Chloroacetic Acid Coupling Procedure B”, “Global Deprotection Method C”, and “Cyclization Method D”.

[001742] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.9 mg, and its purity was estimated to be 100% by LCMS analysis.

[001743] LCMS Analysis Condition D: Retention time = 1.53 min; ESI-MS(+) m/z 867.0 (M+2H).

[001744] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 867.0 (M+2H). Preparation of Example 1173 Molecular weight: 1880.17

[001745] Example 1173 was prepared using Rink resin by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001746] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 40.2 mg, and its purity estimated by LCMS analysis was 99%.

[001747] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 940.9 (M+2H).

[001748] LCMS Analysis Condition E: Retention time = 1.32 min; ESI-MS(+) m/z 941.0 (M+2H). Preparation of Example 1174 Molecular weight: 1916.16

[001749] Example 1174 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001750] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.3 mg, and its purity estimated by LCMS analysis was 91%.

[001751] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 958.7 (M+2H).

[001752] LCMS Analysis Condition E: Retention time = 1.39 min; ESI-MS(+) m/z 959.2 (M+2H). Preparation of Example 1175 Molecular weight: 1925.22

[001753] Example 1175 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001754] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.2 mg, and its purity estimated by LCMS analysis was 100%.

[001755] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 963.7 (M+2H).

[001756] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 963.6 (M+2H). Preparation of Example 1176 Molecular weight: 1866.15

[001757] Example 1176 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001758] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.8 mg, and its purity estimated by LCMS analysis was 98%.

[001759] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 934.1 (M+2H).

[001760] LCMS Analysis Condition E: Retention time = 1.32 min; ESI-MS(+) m/z 933.9 (M+2H).

[001761] ESI-HRMS(+) m/z: Calculated: 933.4614 (M+2H); Found: 933.4596 (M+2H). Preparation of Example 1177 Molecular weight: 1894.20

[001762] Example 1177 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001763] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.2 mg, and its purity estimated by LCMS analysis was 99%.

[001764] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 948.0 (M+2H).

[001765] LCMS Analysis Condition E: Retention time = 1.39 min; ESI-MS(+) m/z 947.7 (M+2H). Preparation of Example 1178 Molecular weight: 1841.10

[001766] Example 1178 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001767] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.8 mg, and its purity was estimated to be 100% by LCMS analysis.

[001768] LCMS Analysis Condition D: Retention time = 1.39 min; ESI-MS(+) m/z 921.1 (M+2H).

[001769] LCMS Analysis Condition E: Retention time = 1.32 min; ESI-MS(+) m/z 921.0 (M+2H). Preparation of Example 1179 Molecular weight: 1841.10

[001770] Example 1179 was prepared using Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Prelude Method D: Resin Swelling Procedure", "Prelude Method D: Simple Coupling Procedure", "Prelude Method D: Secondary Amine Coupling Procedure", "Prelude Method D: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method F", and "Cyclization Method D".

[001771] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-61% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.2 mg, and its purity estimated by LCMS analysis was 92%.

[001772] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 921.6 (M+2H).

[001773] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 921.6 (M+2H). Preparation of Example 1180 Molecular weight: 1819.16

[001774] Example 1180 was prepared from intermediate resin C, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001775] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.1 mg, and its purity estimated by LCMS analysis was 100%.

[001776] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 910.4 (M+2H).

[001777] LCMS Analysis Condition E: Retention time = 1.45 min; ESI-MS(+) m/z 910.1 (M+2H). Preparation of Example 1181 Molecular weight: 1862.13

[001778] Example 1181 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001779] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 30.4 mg, and its purity estimated by LCMS analysis was 99%.

[001780] LCMS Analysis Condition D: Retention time = 1.34 min; ESI-MS(+) m/z 931.9 (M+2H).

[001781] LCMS Analysis Condition E: Retention time = 1.28 min; ESI-MS(+) m/z 932.0 (M+2H).

[001782] ESI-HRMS(+) m/z: Calculated: 931.4236 (M+2H); Found: 931.4212 (M+2H). Preparation of Example 1182 Molecular weight: 1863.17

[001783] Example 1182 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001784] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.7 mg, and its purity estimated by LCMS analysis was 99%.

[001785] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 932.1 (M+2H).

[001786] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 932.5 (M+2H).

[001787] ESI-HRMS(+) m/z: Calculated: 931.9395 (M+2H); Found: 931.9369 (M+2H). Preparation of Example 1183 Molecular weight: 1864.15

[001788] Example 1183 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001789] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.3 mg, and its purity estimated by LCMS analysis was 91%.

[001790] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 932.6 (M+2H).

[001791] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 932 (M+2H).

[001792] ESI-HRMS(+) m/z: Calculated: 932.4315 (M+2H); Found: 932.4284 (M+2H). Preparation of Example 1184 Molecular weight: 1850.12

[001793] Example 1184 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001794] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity estimated by LCMS analysis was 97%.

[001795] LCMS Analysis Condition D: Retention time = 1.36 min; ESI-MS(+) m/z 926.3 (M+2H).

[001796] LCMS Analysis Condition E: Retention time = 1.39 min; ESI-MS(+) m/z 926.9 (M+2H).

[001797] ESI-HRMS(+) m/z: Calculated: 925.4236 (M+2H); Found: 925.4208 (M+2H). Preparation of Example 1185 Molecular weight: 1863.17

[001798] Example 1185 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001799] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.9 mg, and its purity estimated by LCMS analysis was 99%.

[001800] LCMS Analysis Condition D: Retention time = 1.36 min; ESI-MS(+) m/z 932.6 (M+2H).

[001801] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 932.3 (M+2H).

[001802] ESI-HRMS(+) m/z: Calculated: 931.9395 (M+2H); Found: 931.9371 (M+2H). Preparation of Example 1186 Molecular weight: 1849.14

[001803] Example 1186 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001804] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.8 mg, and its purity estimated by LCMS analysis was 98%.

[001805] LCMS Analysis Condition D: Retention time = 1.31 min; ESI-MS(+) m/z 925.0 (M+2H).

[001806] LCMS Analysis Condition E: Retention time = 1.42 min; ESI-MS(+) m/z 925.3 (M+2H).

[001807] ESI-HRMS(+) m/z: Calculated: 924.9316 (M+2H); Found: 924.9286 (M+2H). Preparation of Example 1187 Molecular weight: 1875.18

[001808] Example 1187 was prepared from intermediate resin D, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001809] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.0 mg, and its estimated purity by LCMS analysis was 97%.

[001810] LCMS Analysis Condition D: Retention time = 1.27 min; ESI-MS(+) m/z 937.5 (M+2H).

[001811] LCMS Analysis Condition E: Retention time = 1.29 min; ESI-MS(+) m/z 938.0 (M+2H). Preparation of Example 1188 Molecular weight: 1895.19

[001812] Example 1188 was prepared from intermediate resin E by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: End Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D". (2S,4S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid was used in the first amino acid coupling step to intermediate resin E.

[001813] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 27.6 mg, and its purity estimated by LCMS analysis was 100%.

[001814] LCMS Analysis Condition D: Retention time = 1.21 min; ESI-MS(+) m/z 948.1 (M+2H).

[001815] LCMS Analysis Condition E: Retention time = 1.18 min; ESI-MS(+) m/z 948.2 (M+2H).

[001816] ESI-HRMS(+) m/z: Calculated: 947.9747 (M+2H); Found: 947.9706 (M+2H). Preparation of Example 1189 Molecular weight: 1926.20

[001817] Example 1189 was prepared from intermediate resin B following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Custom Amino Acid Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D". Fmoc-N-Me-Glu(tBu)-OH was used in the first amino acid coupling step to intermediate resin B.

[001818] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 100%.

[001819] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 963.7 (M+2H).

[001820] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 963.6 (M+2H).

[001821] ESI-HRMS(+) m/z: Calculated: 963.4776 (M+2H); Found: 963.4749 (M+2H). Preparation of Example 1190 Molecular weight: 1955.26

[001822] Example 1190 was prepared from intermediate resin F by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Custom Amino Acid Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D". Fmoc-N-Me-Asp(tBu)-OH was used in the first step of coupling the amino acid to intermediate resin F.

[001823] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 97%.

[001824] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 978.5 (M+2H).

[001825] LCMS Analysis Condition E: Retention time = 1.49 min; ESI-MS(+) m/z 978.8 (M+2H).

[001826] ESI-HRMS(+) m/z: Calculated: 977.9582 (M+2H); Found: 977.9561 (M+2H). Preparation of Example 1191 Molecular weight: 1969.29

[001827] Example 1191 was prepared from intermediate resin F by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Custom Amino Acid Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D". Fmoc-N-Me-Glu(tBu)-OH was used in the first step of coupling the amino acid to the intermediate resin F.

[001828] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.3 mg, and its purity estimated by LCMS analysis was 92%.

[001829] LCMS Analysis Condition D: Retention time = 1.48 min; ESI-MS(+) m/z 985.3 (M+2H).

[001830] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 985.1 (M+2H).

[001831] ESI-HRMS(+) m/z: Calculated: 984.9660 (M+2H); Found: 984.9631(M+2H). Preparation of Example 1192 Molecular weight: 1895.19

[001832] Example 1192 was prepared from intermediate resin E by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: End Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D". (2S,4R)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-((tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid was used in the first amino acid coupling step to intermediate resin E.

[001833] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.4 mg, and its purity estimated by LCMS analysis was 98%.

[001834] LCMS Analysis Condition D: Retention time = 1.14 min; ESI-MS(+) m/z 948.0 (M+2H).

[001835] LCMS Analysis Condition E: Retention time = 1.19 min; ESI-MS(+) m/z 948.1 (M+2H).

[001836] ESI-HRMS(+) m/z: Calculated: 947.9747 (M+2H); Found: 947.9710 (M+2H). Preparation of Example 1193 Molecular weight: 1876.16

[001837] Example 1193 was prepared from intermediate resin D following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001838] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.6 mg, and its purity was estimated to be 100% by LCMS analysis.

[001839] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 938.9 (M+2H).

[001840] LCMS Analysis Condition E: Retention time = 1.28 min; ESI-MS(+) m/z 938.8 (M+2H).

[001841] ESI-HRMS(+) m/z: Calculated: 938.4315 (M+2H); Found: 938.4283 (M+2H). Preparation of Example 1194 Molecular weight: 1847.21

[001842] Example 1194 was prepared from intermediate resin D, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001843] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 12.9 mg, and its purity was estimated to be 97% by LCMS analysis.

[001844] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 924.4 (M+2H).

[001845] LCMS Analysis Condition E: Retention time = 1.44 min; ESI-MS(+) m/z 924.2 (M+2H).

[001846] ESI-HRMS(+) m/z: Calculated: 923.9602 (M+2H); Found: 923.9567 (M+2H). Preparation of Example 1195 Molecular weight: 1862.18

[001847] Example 1195 was prepared from intermediate resin D, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001848] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[001849] LCMS Analysis Condition D: Retention time = 1.36 min; ESI-MS(+) m/z 932.0 (M+2H).

[001850] LCMS Analysis Condition E: Retention time = 1.39 min; ESI-MS(+) m/z 931.9 (M+2H).

[001851] ESI-HRMS(+) m/z: Calculated: 931.4475 (M+2H); Found: 931.4443 (M+2H). Preparation of Example 1196 Molecular weight: 1892.23

[001852] Example 1196 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001853] "Prelude Method C: Resin swelling procedure", "Prelude Method C: Single-coupling procedure", "Prelude Method C: Secondary amine coupling procedure", "Prelude Method C: Final wash procedure", "Chloroacetic acid coupling procedure B", "Global deprotection method C", and "Cyclization method D".

[001854] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 22-72% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.6 mg, and its purity estimated by LCMS analysis was 99%.

[001855] LCMS Analysis Condition D: Retention time 1.75 min; ESI-MS(+) m/z 947.0 (M+2H).

[001856] LCMS Analysis Condition E: Retention time 1.71 min; ESI-MS(+) m/z 947.3 (M+2H). Preparation of Example 1197 Molecular weight: 1914.19

[001857] Example 1197 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001858] "Prelude Method C: Resin Swelling Procedure", "Prelude Method C: Simple Coupling Procedure", "Prelude Method C: Secondary Amine Coupling Procedure", "Prelude Method C: Final Wash Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001859] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 22-72% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 98%.

[001860] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 957.5 (M+2H).

[001861] LCMS Analysis Condition E: Retention time = 1.76 min; ESI-MS(+) m/z 958.1 (M+2H). Preparation of Example 1198 Molecular weight: 1825.10

[001862] Example 1198 was prepared by following the general synthetic sequence described for the preparation of Example 1, consisting of the following general procedures:

[001863] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001864] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.8 mg, and its purity estimated by LCMS analysis was 97%.

[001865] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 913.4 (M+2H).

[001866] LCMS Analysis Condition E: Retention time = 1.46 min; ESI-MS(+) m/z 913.1 (M+2H). Preparation of Example 1199 Molecular weight: 1774.05

[001867] Example 1199 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001868] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001869] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.8 mg, and its purity estimated by LCMS analysis was 96%.

[001870] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 887.8 (M+2H).

[001871] LCMS Analysis Condition E: Retention time = 1.48 min; ESI-MS(+) m/z 887.8 (M+2H). Preparation of Example 1200 Molecular weight: 1827.03

[001872] Example 1200 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001873] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001874] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.4 mg, and its purity was estimated to be 100% by LCMS analysis.

[001875] LCMS Analysis Condition D: Retention time = 1.34 min; ESI-MS(+) m/z 914.8 (M+2H).

[001876] LCMS Analysis Condition E: Retention time = 1.43 min; ESI-MS(+) m/z 914.4 (M+2H). Preparation of Example 1201 Molecular weight: 1966.23

[001877] Example 1201 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001878] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.7 mg, and its purity estimated by LCMS analysis was 91%.

[001879] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 984.3 (M+2H).

[001880] LCMS Analysis Condition E: Retention time = 1.30 min; ESI-MS(+) m/z 983.8 (M+2H). Preparation of Example 1202 Molecular weight: 1841.10

[001881] Example 1202 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001882] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001883] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.0 mg, and its purity estimated by LCMS analysis was 93%.

[001884] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 921.1 (M+2H).

[001885] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 921 A (M+2H). Preparation of Example 1203 Molecular weight: 1982.23

[001886] Example 1203 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001887] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001888] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.8 mg, and its purity estimated by LCMS analysis was 98%.

[001889] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 992.1 (M+2H).

[001890] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 991.8 (M+2H). Preparation of Example 1204 Molecular weight: 1792.09

[001891] Example 1204 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001892] "Simphony Method A: Resin Swelling Procedure", "Simphony Method A: Standard Coupling Procedure", "Simphony Method A: Secondary Amine Coupling Procedure B", "Custom Amino Acid Coupling Procedure", "Chloroacetic Acid Coupling Procedure B", "Global Deprotection Method C", and "Cyclization Method D".

[001893] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.0 mg, and its purity estimated by LCMS analysis was 100%.

[001894] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 897.0 (M+2H).

[001895] LCMS Analysis Condition E: Retention time = 1.50 min; ESI-MS(+) m/z 896.7 (M+2H). Preparation of Example 1205 Molecular weight: 1839.12

[001896] Example 1205 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001897] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001898] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.2 mg, and its purity estimated by LCMS analysis was 99%.

[001899] LCMS Analysis Condition D: Retention time = 1.44 min; ESI-MS(+) m/z 920.2 (M+2H).

[001900] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 920.2 (M+2H). Preparation of Example 1206 Molecular weight: 1809.10

[001901] Example 1206 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001902] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001903] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.5 mg, and its purity estimated by LCMS analysis was 100%.

[001904] LCMS Analysis Condition D: Retention time = 1.55 min; ESI-MS(+) m/z 905.2 (M+2H).

[001905] LCMS Analysis Condition E: Retention time = 1.52 min; ESI-MS(+) m/z 905.4 (M+2H). Preparation of Example 1207 Molecular weight: 1825.10

[001906] Example 1207 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001907] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001908] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 97%.

[001909] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 913.0 (M+2H).

[001910] LCMS Analysis Condition E: Retention time = 1.36 min; ESI-MS(+) m/z 913.5 (M+2H). Preparation of Example 1208 Molecular weight: 1799.06

[001911] Example 1208 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001912] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001913] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.6 mg, and its purity estimated by LCMS analysis was 100%.

[001914] LCMS Analysis Condition D: Retention time = 1.40 min; ESI-MS(+) m/z 900.1 (M+2H).

[001915] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 900.1 (M+2H). Preparation of Example 1209 Molecular weight: 1800.04

[001916] Example 1209 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001917] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001918] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1.9 mg, and its purity was estimated to be 99% by LCMS analysis.

[001919] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 900.5 (M+2H).

[001920] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 900.7 (M+2H). Preparation of Example 1210 Molecular weight: 1786.02

[001921] Example 1210 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001922] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001923] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.8 mg, and its purity estimated by LCMS analysis was 96%.

[001924] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 893.6 (M+2H).

[001925] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 893.6 (M+2H). Preparation of Example 1211 Molecular weight: 1798.07

[001926] Example 1211 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001927] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001928] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.5 mg, and its purity estimated by LCMS analysis was 99%.

[001929] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 899.7 (M+2H).

[001930] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 899.6 (M+2H). Preparation of Example 1212 Molecular weight: 1801.03

[001931] Example 1212 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001932] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001933] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 3.6 mg, and its purity was estimated to be 92% by LCMS analysis.

[001934] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 901.1 (M+2H).

[001935] LCMS Analysis Condition E: Retention time = 1.25 min; ESI-MS(+) m/z 901.4 (M+2H). Preparation of Example 1213 Molecular weight: 1814.07

[001936] Example 1213 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001937] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001938] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 2.9 mg, and its purity estimated by LCMS analysis was 99%.

[001939] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 907.4 (M+2H).

[001940] LCMS Analysis Condition E: Retention time = 1.23 min; ESI-MS(+) m/z 907.9 (M+2H). Preparation of Example 1214 Molecular weight: 1843.11

[001941] Example 1214 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001942] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001943] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.0 mg, and its purity was estimated to be 92% by LCMS analysis.

[001944] LCMS Analysis Condition D: Retention time = 1.33 min; ESI-MS(+) m/z 922.2 (M+2H).

[001945] LCMS Analysis Condition E: Retention time = 1.22 min; ESI-MS(+) m/z 922.7 (M+2H). Preparation of Example 1215 Molecular weight: 1851.09

[001946] Example 1215 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001947] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001948] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 5.5 mg, and its purity was estimated to be 99% by LCMS analysis.

[001949] LCMS Analysis Condition D: Retention time = 1.40 min; ESI-MS(+) m/z 926.5 (M+2H).

[001950] LCMS Analysis Condition E: Retention time = 1.35 min; ESI-MS(+) m/z 926.2 (M+2H). Preparation of Example 1216 Molecular weight: 1894.16

[001951] Example 1216 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001952] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001953] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 3.8 mg, and its purity was estimated to be 93% by LCMS analysis.

[001954] LCMS Analysis Condition D: Retention time = 1.32 min; ESI-MS(+) m/z 948.1 (M+2H).

[001955] LCMS Analysis Condition E: Retention time = 1.23 min; ESI-MS(+) m/z 948.0 (M+2H). Preparation of Example 1217 Molecular weight: 1952.24

[001956] Example 1217 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001957] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001958] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.5 mg, and its purity estimated by LCMS analysis was 100%.

[001959] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 977.6 (M+2H).

[001960] LCMS Analysis Condition E: Retention time = 1.31 min; ESI-MS(+) m/z 976.7 (M+2H). Preparation of Example 1218 Molecular weight: 1938.21

[001961] Example 1218 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001962] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001963] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.9 mg, and its purity estimated by LCMS analysis was 99%.

[001964] LCMS Analysis Condition D: Retention time = 1.43 min; ESI-MS(+) m/z 969.7 (M+2H).

[001965] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 969.7 (M+2H). Preparation of Example 1219 Molecular weight: 1911.14

[001966] Example 1219 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001967] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001968] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1.6 mg, and its purity estimated by LCMS analysis was 99%.

[001969] LCMS Analysis Condition D: Retention time = 1.40 min; ESI-MS(+) m/z 956.7 (M+2H).

[001970] LCMS Analysis Condition E: Retention time = 1.43 min; ESI-MS(+) m/z 956.7 (M+2H). Preparation of Example 1220 Molecular weight: 1895.19

[001971] Example 1220 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001972] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001973] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-50% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity estimated by LCMS analysis was 100%.

[001974] LCMS Analysis Condition D: Retention time = 1.32 min; ESI-MS(+) m/z 948.5 (M+2H).

[001975] LCMS Analysis Condition E: Retention time = 1.21 min; ESI-MS(+) m/z 948.7 (M+2H). Preparation of Example 1221 Molecular weight: 1842.04

[001976] Example 1221 was prepared by following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures:

[001977] "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001978] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 0-50% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 0-45% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 95%.

[001979] LCMS Analysis Condition D: Retention time = 0.94 min; ESI-MS(+) m/z 922.1 (M+2H).

[001980] LCMS Analysis Condition E: Retention time = 0.97 min; ESI-MS(+) m/z 921.5 (M+2H). Preparation of Example 1222 Molecular weight: 1834.08

[001981] Example 1222 was prepared starting from intermediate resin C following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001982] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.6 mg, and its purity estimated by LCMS analysis was 95%.

[001983] LCMS Analysis Condition D: Retention time = 1.37 min; ESI-MS(+) m/z 917.7 (M+2H).

[001984] LCMS Analysis Condition E: Retention time = 1.31 min; ESI-MS(+) m/z 918.0 (M+2H).

[001985] ESI-HRMS(+) m/z: Calculated: 917.4080 (M+2H); Found: 917.4042 (M+2H). Preparation of Example 1223 Molecular weight: 1835.11

[001986] Example 1223 was prepared starting from intermediate resin C, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001987] The crude material was purified via preparatory LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.0 mg, and its purity estimated by LCMS analysis was 95%.

[001988] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 918.6 (M+2H).

[001989] LCMS Analysis Condition E: Retention time = 1.38 min; ESI-MS(+) m/z 918.7 (M+2H).

[001990] ESI-HRMS(+) m/z: Calculated: 917.9238 (M+2H); Found: 917.9207 (M+2H). Preparation of Example 1224 Molecular weight: 1822.07

[001991] Example 1224 was prepared starting from intermediate resin C, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001992] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.8 mg, and its purity estimated by LCMS analysis was 95%.

[001993] LCMS Analysis Condition D: Retention time = 1.39 min; ESI-MS(+) m/z 911.8 (M+2H).

[001994] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 911.5 (M+2H).

[001995] ESI-HRMS(+) m/z: Calculated: 911.4080 (M+2H); Found: 911.4052 (M+2H). Preparation of Example 1225 Molecular weight: 1834.13

[001996] Example 1225 was prepared starting from intermediate resin C, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[001997] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.8 mg, and its purity estimated by LCMS analysis was 98%.

[001998] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 917.7 (M+2H).

[001999] LCMS Analysis Condition E: Retention time = 1.41 min; ESI-MS(+) m/z 917.9 (M+2H).

[002000] ESI-HRMS(+) m/z: Calculated: 917.4318 (M+2H); Found: 917.4290 (M+2H). Preparation of Example 1226 Molecular weight: 1821.09

[002001] Example 1226 was prepared starting from intermediate resin C, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002002] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 95%.

[002003] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 911.2 (M+2H).

[002004] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 911.3 (M+2H).

[002005] ESI-HRMS(+) m/z: Calculated: 910.9160 (M+2H); Found: 910.9128 (M+2H). Preparation of Example 1227 Molecular weight: 1939.26

[002006] Example 1227 was prepared starting from intermediate resin F, following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin swelling procedure", "Simphony Method B: Standard coupling procedure", "Simphony Method B: Secondary amine-coupling procedure", "Simphony Method B: Final capping procedure", "Global deprotection method F", and "Cyclization method D".

[002007] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 1.6 mg, and its purity estimated by LCMS analysis was 97%.

[002008] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 970.1 (M+2H).

[002009] LCMS Analysis Condition E: Retention time = 1.47 min; ESI-MS(+) m/z 970.2 (M+2H).

[002010] ESI-HRMS(+) m/z: Calculated: 969.9607 (M+2H); Found: 969.9592 (M+2H). Preparation of Example 1228 Molecular weight: 1847.12

[002011] Example 1228 was prepared starting from intermediate resin C following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002012] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.8 mg, and its purity estimated by LCMS analysis was 98%.

[002013] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 924.5 (M+2H).

[002014] LCMS Analysis Condition E: Retention time = 1.34 min; ESI-MS(+) m/z 924.6 (M+2H).

[002015] ESI-HRMS(+) m/z: Calculated: 923.9238 (M+2H); Found: 923.9242 (M+2H). Preparation of Example 1229 Molecular weight: 1813.09

[002016] Example 1229 was prepared over Fmoc-Gly-Chlortritil Resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method E", and "Cyclization Method D".

[002017] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.2 mg, and its purity estimated by LCMS analysis was 91%.

[002018] LCMS Analysis Condition D: Retention time = 1.48 min; ESI-MS(+) m/z 907.3 (M+2H).

[002019] LCMS Analysis Condition E: Retention time = 1.43 min; ESI-MS(+) m/z 907.2 (M+2H). Preparation of Example 1230 Molecular weight: 2082.40

[002020] Example 1230 was prepared starting from intermediate resin H following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002021] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; Gradient: 10-65% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.9 mg, and its purity estimated by LCMS analysis was 99%.

[002022] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 1041.4 (M+2H). Preparation of Example 1231 Molecular weight: 1770.02

[002023] Example 1231 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002024] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.3 mg, and its purity estimated by LCMS analysis was 100%.

[002025] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 886.4 (M+2H).

[002026] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 886.0 (M+2H). Preparation of Example 1232 Molecular weight: 1827.07

[002027] Example 1232 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002028] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.3 mg, and its purity estimated by LCMS analysis was 92%.

[002029] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 914.6 (M+2H). Preparation of Example 1233 Molecular weight: 1886.18

[002030] Example 1233 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002031] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.7 mg, and its purity estimated by LCMS analysis was 98%.

[002032] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 944.1 (M+2H).

[002033] LCMS Analysis Condition E: Retention time = 1.56 min; ESI-MS(+) m/z 944.0 (M+2H). Preparation of Example 1234 Molecular weight: 1910.16

[002034] Example 1234 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002035] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-100% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.9 mg, and its purity estimated by LCMS analysis was 98%.

[002036] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 956.3 (M+2H).

[002037] LCMS Analysis Condition E: Retention time = 1.50 min; ESI-MS(+) m/z 956.0 (M+2H). Preparation of Example 1235 Molecular weight: 1844.14

[002038] Example 1235 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002039] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.5 mg, and its purity estimated by LCMS analysis was 100%.

[002040] LCMS Analysis Condition D: Retention time = 1.54 min; ESI-MS(+) m/z 923.0 (M+2H).

[002041] LCMS Analysis Condition E: Retention time = 1.52 min; ESI-MS(+) m/z 923.2 (M+2H). Preparation of Example 1236 Molecular weight: 1885.19

[002042] Example 1236 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002043] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.2 mg, and its purity estimated by LCMS analysis was 82%.

[002044] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 943.7 (M+2H).

[002045] LCMS Analysis Condition E: Retention time = 1.55 min; ESI-MS(+) m/z 943.8 (M+2H). Preparation of Example 1237 Molecular weight: 1952.20

[002046] Example 1237 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002047] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.7 mg, and its purity estimated by LCMS analysis was 97%.

[002048] LCMS Analysis Condition D: Retention time = 1.54 min; ESI-MS(+) m/z 977.0 (M+2H).

[002049] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 977.0 (M+2H). Preparation of Example 1238 Molecular weight: 1841.14

[002050] Example 1238 was prepared on Gly-Chlortrityl resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method E", and "Cyclization Method D".

[002051] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.4 mg, and its purity was estimated to be 88% by LCMS analysis.

[002052] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 921 A (M+2H).

[002053] LCMS Analysis Condition E: Retention time = 1.42 min; ESI-MS(+) m/z 921.3 (M+2H).

[002054] ESI-HRMS(+) m/z: Calculated: 920.9638 (M+2H); Found: 920.9628 (M+2H). Preparation of Example 1239 Molecular weight: 1770.02

[002055] Example 1239 was prepared on Rink resin following the general synthesis sequence described for the preparation of Example 1, consisting of the following general procedures: "Simphony Method B: Resin Swelling Procedure", "Simphony Method B: Standard Coupling Procedure", "Simphony Method B: Secondary Amine Coupling Procedure", "Simphony Method B: Final Capping Procedure", "Global Deprotection Method F", and "Cyclization Method D".

[002056] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 1.7 mg, and its purity was estimated to be 93% by LCMS analysis.

[002057] LCMS Analysis Condition D: Retention time = 1.42 min; ESI-MS(+) m/z 885.7 (M+2H).

[002058] LCMS Analysis Condition E: Retention time = 1.36 min; ESI-MS(+) m/z 885.8 (M+2H).

[002059] ESI-HRMS(+) m/z: Calculated: 885.4270 (M+2H); Found: 885.4269 (M+2H). Analytical Data:

[002060] Mass Spectrometry: "ESI-MS(+)" means electrospray ionization mass spectrometry performed in positive ion mode; "ESI-MS(-)" means electrospray ionization mass spectrometry performed in negative ion mode; "ESI-HRMS(+)" means electrospray ionization high-resolution mass spectrometry performed in positive ion mode; "ESI-HRMS(-)" means electrospray ionization high-resolution mass spectrometry performed in negative ion mode. Detected masses are reported using the “m/z” unit designation. Compounds with exact masses greater than 1000 were frequently detected as doubly or triply charged ions. LCMS Analysis Condition A:

[002061] Column: BEH C18, 2.1 x 50 mm, 1.7-μm particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Temperature: 50 °C; Gradient: 2% B to 98% B over 2 min, then a 0.5 min hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm. LCMS Analysis Condition C:

[002062] Column: BEH C18, 2.1 × 50 mm, 1.7-μm particles; Mobile phase A: water with 0.2% formic acid and 0.01% TFA; Mobile phase B: Acetonitrile with 0.2% formic acid and 0.01% TFA; Temperature: 50 °C; Gradient: 2% B to 80% B over 2 min, 80% B to 98% B over 0.1 min, then a 0.5 min hold at 98% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm. LCMS analysis Condition D:

[002063] Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7- μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0- 100% B over 3 min, then a 0.75 min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm. LCMS Analysis Condition E:

[002064] Column: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7- μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; temperature: 50 °C; Gradient: 0-100% B over 3 min, then a 0.75 min hold at 100% B; Flow rate: 1.11 mL/min; Detection: UV at 220 nm. LCMS Analysis Condition F:

[002065] Column: Waters XBridge C18, 2.1 x 50 mm; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 35 °C; Gradient: 0-100%) B for 4 minutes, then a 1 minute hold at 100% B; Flow rate: 4 mL/min; Detection: UV at 220 nm. HPLC analysis Condition B:

[002066] Column: YMC Pack ODS-AQ 3μm 150x4.6mm Mobile phase A: water with 0.1% TFA; Mobile phase B: Acetonitrile with 0.1% TFA; Temperature: 40 °C; Gradient: from 10% B to 100% B over 10 to 40 minutes; Flow rate: 1 mL/min; Detection: UV at 220 nm. General Procedures: Prelude Method A:

[002067] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 or 45 mL polypropylene tube equipped with a bottom frit. The tube is connected to the Prelude peptide synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly coats the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube. "Periodic agitation" describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[002068] The “Prelude Method A” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Coupling of amino acids to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Coupling of amino acids to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. Coupling of the chloroacetyl group to the N-terminus of the peptide is described by the “Chloroacetyl Chloride Coupling Procedure” or "Chloroacetic acid coupling procedure" detailed below. Resin swelling procedure:

[002069] To a 40 mL polypropylene solid phase reaction vessel was added Merrifield:Sieber resin (140 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel were added DMF (5.0 mL) and DCM (5.0 mL), and thereafter the mixture was stirred periodically with N2 bubbling from the bottom of the reaction vessel for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[002070] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 60 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 5.0 mL, 10 eq.), followed by HATU (0.2 M in DMF, 5.0 mL, 10 eq.), and finally DIPEA (0.8 M in DMF, 2.5 mL, 20 eq.). The mixture was stirred periodically for 60 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Secondary amine coupling procedure:

[002071] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), followed by HATU (0.2 M in DMF, 2.5 mL, 5 eq.), and finally DIPEA (0.8 M in DMF, 1.5 mL, 12 eq.). The mixture was stirred periodically for 300 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. A solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[002072] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 0.5 to 2.5 mL, 1 to 5 eq.), followed by HATU (0.2 M in DMF, 0.5 to 2.5 mL, 1 to 5 eq.), and finally DIPEA (0.8 M in DMF, 0.5 to 1.5 mL, 4 to 12 eq.). The mixture was stirred periodically for 60 min to 600 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (4.0 mL) was added from the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetyl chloride coupling procedure A:

[002073] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added 3.0 mL of a solution of DIPEA (4.0 mmol, 0.699 mL, 40 eq.), and chloroacetyl chloride (2.0 mmol, 0.160 mL, 20 eq.) in DMF. The mixture was stirred periodically for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. Chloroacetic acid coupling procedure A:

[002074] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively five times as follows: for each wash, DMF (4.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel were added DMF (2.0 mL), chloroacetic acid (1.2 mmol, 113 mg, 12 eq.), and N,N'-Diisopropylcarbodiimide (1.2 mmol, 0.187 mL, 12 eq.). The mixture was stirred periodically for 12 to 18 h, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (4.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. CEM Method A:

[002075] All manipulations were performed with automation on a CEM Liberty microwave peptide synthesizer (CEM Corporation, Matthews, NC). All procedures, unless noted, were performed in a 30 or 125 mL polypropylene tube equipped with a bottom frit for a CEM Liberty microwave unit. The tube is connected to the CEM Liberty synthesizer through the bottom and top of the tube. DMF and DCM can be added through the bottom and top of the tube, which evenly flushes the sides of the tube. All solutions are removed through the bottom of the tube except while resin is being transferred from the top. "Periodic bubbling" describes a brief bubbling of N2 gas through the bottom frit. Amino acid solutions were generally not used beyond three weeks after preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HCTU = 2-(6-Chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Sieber = Fmoc-amino-xanthen-3-yloxy, where "3-yloxy" describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Sieber linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.71 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala- OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[002076] The “CEM Method A” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin. This scale corresponds to approximately 140 mg of the Sieber-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure.” Coupling of amino acids to the N-terminus of a primary amine used the “Simple Coupling Procedure” described below. Coupling of amino acids to the N-terminus of a secondary amine used the “Secondary Amine Coupling Procedure” described below. Coupling of the chloroacetyl group to the N-terminus of the peptide is described by the “Chloroacetyl Chloride Coupling Procedure” or "Chloroacetic acid coupling procedure" detailed above. Resin swelling procedure:

[002077] To a 50 mL polypropylene conical tube was added Merrifield:Sieber resin (140 mg, 0.100 mmol). Then DMF (7 mL) was added to the tube followed by DCM (7 mL). The resin was then transferred to the reaction vessel from the top of the vessel. The procedure was repeated two more times. DMF (7 mL) was added followed by DCM (7 mL). The resin was allowed to swell with N2 bubbling from the bottom of the reaction vessel for 15 min before the solvent was drained through the frit. Standard coupling procedure:

[002078] To the reaction vessel containing the resin from the previous step was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH, which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. Double-pair coupling procedure:

[002079] To the reaction vessel containing the resin from the previous step was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a piperidine:DMF solution (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by bubbling N2 for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel were added the amino acid (0.2 M in DMF, 2.5 mL, 5 eq.), HATU (0.5 M in DMF, 1.0 mL, 5 eq.), and DIPEA (2 M in NMP, 0.5 mL, 10 eq.). The mixture was mixed by N2 bubbling for 5 min at 75 °C for all amino acids except Fmoc-Cys(Trt)-OH and Fmoc-His(Trt)-OH which were coupled at 50 °C, the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom, and finally washing with DMF (7 mL) from the top. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. Custom amino acid coupling procedure:

[002080] To the reaction vessel containing the resin from the previous step was added a solution of piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added a solution of piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the top, followed by washing with DMF (7 mL) from the bottom and finally washing with DMF (7 mL) from the top. To the reaction vessel was added the amino acid solution (1.25 mL to 5 mL, 2.5 eq. to 10 eq.) containing HATU (2.5 eq. to 10 eq.), and finally DIPEA (2 M in NMP, 0.5 mL to 1 mL, 10 to 20 eq.). The mixture was mixed by bubbling N2 for 5 min to 2 h at a temperature of 25 °C to 75 °C, and then the reaction solution was drained through the frit. The resin was washed successively three times as follows: washing with DMF (7 mL) from the upper part, followed by washing with DMF (7 mL) from the lower part, and finally washing with DMF (7 mL) from the upper part. To the reaction vessel was added a solution of acetic anhydride:DIEA:DMF (10:1:89 v/v/v, 5.0 mL). The mixture was bubbled periodically for 2 min at 65 °C, and then the solution was drained through the frit. The resin was washed successively three times as follows: DMF wash (7 mL) from the top, followed by DMF wash (7 mL) from the bottom, and finally DMF wash (7 mL) from the top. The resulting resin was used directly in the next step. N-methylation on-resin methylation Method A (Turner, R. A. et al., Org. Lett., 15(19):5012–5015 (2013)):

[002081] All manipulations were done manually unless otherwise indicated. The "N-methylation methylation on resin Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of resin-bound Sieber linker that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple.

[002082] The resin was transferred to a 25 mL fritted syringe. To the resin was added piperidine:DMF (20:80 v/v, 5.0 mL). The mixture was stirred for 3 min and then the solution was drained through the frit. The resin was washed 3 times with DMF (4.0 mL). To the reaction vessel was added piperidine:DMF (20:80 v/v, 4.0 mL). The mixture was stirred for 3 min and then the solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). The resin was suspended in DMF (2.0 mL) and ethyl trifluoroacetate (0.119 mL, 1.00 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.181 mL, 1.20 mmol). The mixture was placed on a shaker for 60 min. The solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL).

[002083] The resin was washed three times with dry THF (2.0 mL) to remove any residual water. To an oven-dried 4.0 mL vial was added THF (1.0 mL) and triphenylphosphine (131 mg, 0.500 mmol) over 4 Å molecular sieves (20 mg). The solution was transferred to the resin and diisopropyl azodicarboxylate (0.097 mL, 0.5 mmol) was added slowly. The resin was stirred for 15 min. The solution was drained through the frit and the resin was washed three times with dry THF (2.0 mL) to remove any residual water. To an oven-dried 4.0 mL vial was added THF (1.0 mL), triphenylphosphine (131 mg, 0.500 mmol) over 4 Å molecular sieves (20 mg). The solution was transferred to the resin, and diisopropyl azodicarboxylate (0.097 mL, 0.5 mmol) was added slowly. The resin was stirred for 15 min. The solution was drained through the frit. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). The resin was suspended in ethanol (1.0 mL) and THF (1.0 mL), and sodium borohydride (37.8 mg, 1.000 mmol) was added. The mixture was stirred for 30 min and drained. The resin was washed successively three times with DMF (4.0 mL) and three times with DCM (4.0 mL). Global deprotection method B:

[002084] All manipulations were done manually unless indicated. The "Global Deprotection Method B" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the volumes described by the multiple of the scale. A "deprotection solution" was prepared using trifluoroacetic acid:triisopropylsilane:dithiothreitol (94:3 :3 v:v:w). The resin was removed from the reaction vessel and transferred to a 25 mL fritted syringe to which “deprotection solution” (5.0 mL) was added. The mixture was shaken for 5 min. The solution was filtered, and the filtrate was poured into diethyl ether (30 mL). The precipitated solid was centrifuged for 3 min. The supernatant solution was decanted, and the solid was resuspended in diethyl ether (25 mL). The suspension was centrifuged for 3 min. The procedure was repeated one more time, and the remaining solid was dried under high vacuum to give a white to off-white solid. Cyclization method C:

[002085] All manipulations were done manually unless otherwise noted. The "Cyclization Method C" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Sieber linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. The crude peptide solids were redissolved in a solution of acetonitrile:0.1 M aqueous ammonium bicarbonate buffer (11 mL:24 mL or similar ratio), and the solution was then cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then stirred for 12 to 18 hours. The reaction solution was concentrated, and the residue was then dissolved in acetonitrile:water. This solution was subjected to purification by reversed-phase HPLC to give the desired cyclic peptide. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(naphthalen-1-yl)propanoic acid (Freidinger, R. M. et al., J. Org. Chem., 48(1):77-81 (1983)) Scheme: Step 1:

[002086] To a suspension of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalen-1-yl)propanoic acid (1.00 g, 2.286 mmol) in toluene (50 mL) was added paraformaldehyde (0.500 g, 16.65 mmol) and p-toluenesulfonic acid monohydrate (0.435 g, 2.286 mmol). The reaction mixture was heated to reflux for 16 h with water azeotropic removal using a Dean-Stark trap. The mixture was cooled to room temperature and diluted with 20 mL of EtOAc. The organic phase was washed with 2 x 50 mL of a saturated aqueous NaHCO3 solution and then dried over anhydrous sodium sulfate. After filtration and concentration a colorless oil was obtained. Purification by column chromatography on silica gel using 30% EtOAc/Hexanes led to the desired product as a colorless oil. (S)-(9H-fluoren-9-yl)methyl 4-(naphthalen-1-ylmethyl)-5-oxo-oxazolidine-3-carboxylate 0.750 g (73%) 1H NMR (400MHz, DMSO-dβ)DDD7.88 (d, J=7.5 Hz, 3H), 7.82 (d, J=8.1 Hz, 2H), 8 - 7.51 (m, 2H), 7.49 - 7.21 (m, 8H), 5.18 (d, J=4.0 Hz, 1H), 4.40 (br. s., 4H), 3.31 (br. s., 4H). Step 2:

[002087] To a solution of (S)-(9H-fluoren-9-yl)methyl 4-(naphthalen-1-ylmethyl)-5-oxo-oxazolidine-3-carboxylate (0.750 g, 1.0β9 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (8.0 mL, 104 mmol) followed by triethylsilane (0.799 mL, 5.01 mmol). The reaction mixture was allowed to stir at room temperature for 24 h. The reaction mixture was dried on a rotovaporizer. The crude oil was dissolved in 15.0 mL of DCM and rotovaporized twice. The crude product was obtained as an off-white gum and was purified by chromatography on silica gel using dichloromethane and methanol as eluent.

[002088] The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(naphthalen-1-yl)propanoic acid, was obtained as a colorless gum (0.β92 g, 4β%). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid (Ross, A. J. et al., J. Org. Chem., 75:245-248 (2010)) Scheme: Step 1:

[002089] To an oven-dried 8 mL vial with a N2-purged Teflon cap was added zinc dust (298 mg, 4.5β mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2'6-dimethoxybiphenyl (62.4 mg, 0.152 mmol), and 4-bromo-2-chloro-1-fluorobenzene (477 mg, 2.279 mmol) were then added and the reaction mixture was allowed to stir at 50 °C for 3 h. The crude mixture was diluted in 30 mL of EtOAc, and DMF was removed with 4 aqueous layers. The organic layer was dried over anhydrous sodium sulfate. The solution was filtered and concentrated, and the product was purified by chromatography on silica gel using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (0.174 g, 35%). 1H NMR (400MHz, chloroform-d)DDD7.27 (s, 1H), 7.17 (dd, J=6.9, 1.4 Hz, 1H), 7.11 - 6.93 (m, 1H), 5.03 (d, J=6.8 Hz, 1H), 4.55 (d, J=6.4 Hz, 1H), 3.73 (s, 3H), 3.19 - 3.04 (m, 1H), 2.98 (dd, J=13.9, 5.9 Hz, 1H), 1.49 - 1.37 (m, 10H). Step 2:

[002090] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoate (174 mg, 0.524 mmol) in THF (1967 μL)/H2θ (656 μL) was added LiOH (37.7 mg, 1.573 mmol) and the reaction was allowed to stir for 2 h. The THF was removed by rotovap before the solution was diluted with EtOAc (10 mL) and the aqueous phase was acidified to pH 3 using 1 N aqueous HCl solution. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product, (S)-2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a yellow gum (0.183 mg, 99%). Step 3:

[002091] (S)-2-((tert-Butoxycarbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid (183.0 mg, 0.576 mmol) was suspended in a solution of 4 M hydrochloric acid (1440 μL, 5.76 mmol) in dioxane at room temperature for 2 h. After evaporation of the solvent, the crude product was cooled to 0 °C using an ice bath before being dissolved in MeCN (288 μL) and a 2.0 M aqueous Na2CO3 solution (288 μL, 0.576 mmol). (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidin-1-yl)carbonate (194 mg, 0.576 mmol) was added to the solution and the reaction mixture was allowed to stir for 30 min. The mixture was diluted with 5.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of a 1 N aqueous HCl solution. The organic solvents were evaporated and the crude product was then distributed between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, a yellow crystalline solid was obtained. Purification by chromatography on silica gel using 100% hexanes to 30% EtO-Ac/Hexanes gave the desired product as a white crystalline solid. A second purification on silica gel was done using 100% DCM to 20% MeOH/DCM as eluent. The desired product, (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid, was obtained as a white solid (0.111 g, 44%). 1H NMR (400MHz, methanol-d4)DDD7.79 (d, J=7.5 Hz, 2H), 7.60 (t, J=6.8 Hz, 2H), 7.47 -7.23 (m, 5H), 7.25 - 7.14 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.52 - 4. 11 (m, 4H), 3.19 (dd, J=14.3, 4.6 Hz, 1H), 2.92 (dd, J=13.9, 9.7 Hz, 1H). (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (Ley, SV et al., Tetrahedron, 48(6): 1145-1174 (1992)) Scheme: Step 1:

[002092] (R)-2-Amino-5-(tert-butoxy)-5-oxopentanoic acid (1.00 g, 4.92 mmol) was suspended in THF (18.45 mL)/water (6.15 mL) and cooled to 0 °C using an ice bath. To the cold suspension was slowly added benzyl chloroformate (0.773 mL, 5.41 mmol) and the reaction mixture was allowed to stir for 2.5 h. The suspension was diluted with 50 mL of EtOAc before being acidified to pH 3 using 1 N aqueous HCl solution. The crude product was extracted three times with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was obtained as a clear oil and was chromatographed on silica gel using 100% hexanes to 100% ethyl acetate as eluent. The product, (R)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid, was obtained as a colorless oil (1.41 g, 71%). 1H NMR (400MHz, chloroform-d)DDD7.44 - 7.29 (m, 5H), 5.53 (d, J=7.5 Hz, 1H), 5.13 (s, 2H), 4.41 (d, J=5.1 Hz, 1H), 2.56 - 2.30 (m, 2H), 2.21 (dd, J=13.5, 6.5 Hz, 1H), 2.06 - 1.88 (m, 2H), 1.45 (s, 9H). Step 2:

[002093] To a solution of (R)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (1.41 g, 4.18 mmol) and Mel (2.091 mL, 33.4 mmol) in THF (12.66 mL) at 0 °C was slowly added NaH (0.501 g, 12.54 mmol) and the suspension was allowed to stir while warming to room temperature over 24 h. The reaction mixture was cooled to 0 °C before 10 mL of EtOAc was added along with 5 mL of water to quench the excess NaH. The crude product was partitioned between a saturated aqueous NaHCO3 solution and Et2O. The two phases were separated and the organic phase was washed with a saturated NaHCO3 solution and the two aqueous extracts were combined. The aqueous solution was brought to pH 3 using 6 N aqueous HCl solution. The aqueous phase was extracted with EtOAc, the organic extracts were combined, and dried over anhydrous sodium sulfate. After filtration and concentration, (R)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid was obtained as a yellow oil, 1.4 g (78%). LCMS showed the m/z of the desired product, (M+Na)+ 374. Step 3:

[002094] To a solution of (R)-2-(((benzyloxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (1.40 g, 3.98 mmol) in MeOH (18.79 mL) was added 10% Pd/C (0.424 g, 0.398 mmol) and the reaction mixture was placed under a hydrogen atmosphere using . The reaction was allowed to stir at room temperature for 18 h. The catalyst was removed by filtration over CELITE® and the filtrate was concentrated under reduced pressure to give a white solid. The crude material was dissolved in acetonitrile (9.40 mL), water (9.40 mL), and TEA (1.111 mL, 7.97 mmol). The solution was cooled to 0 °C using an ice bath, and FMOC-OSU (1.344 g, 3.98 mmol) was added. The reaction mixture was allowed to stir while warming to room temperature for 18 h. The crude product was diluted in 200 mL of EtOAc and washed with 1 N aqueous HCl solution and brine. The organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, a clear oil was obtained, which was purified by chromatography on silica gel using 100% hexanes–100% EtOAc. (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid was obtained as a colorless oil (0.481 g, 28%). - 4.48 (m, 1H), 4.47 - 4.32 (m, 2H), 4.29 - 4.10 (m, 1H), 2.87 (s, 3H), 2.43 - 1.82 (m, 4H), 1.51 - 1.36 (m, 9H). Step 1:

[002095] A solution of L-phenylalanine benzyl ester hydrochloride (2 g, 6.85 mmol), Z-Phe-OH (2.257 g, 7.54 mmol), DIPEA (2.99 mL, 17.14 mmol), and DCM (100 mL) was treated with 1-hydroxy-7-azabenzotriazole (1.120 g, 8.23 mmol) and EDC (1.577 g, 8.23 mmol) and stirred at room temperature for 15 h. The mixture was washed with saturated NaHCO3 (2 × 100 mL), 1 M HCl (2 × 50 mL), and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-benzyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-3-phenylpropanoate (3.2 g, 5.96 mmol, 87% yield) as a white solid. 1H NMR (400MHz, DMSO-dβ)DDD7.42 - 7.11 (m, 21H), 4.96 (d, J=2.0 Hz, 4H), 4.63 - 4.45 (m, 1H), 4.06 - 3.91 (m, 2H), 3.34 - 2.9β (m, 3H), 2.85 (br. , 4H). Step 2 (Schroeder, G.M. et al., Tetrahedron Lett, 51:1404-140β (2010)):

[002096] A pressure flask was charged with (S)-benzyl 2-((S)-2-(((benzyloxy)carbonyl)amino)-3-phenylpropanamido)-3-phenylpropanoate (1.0 g, 1.8β4 mmol) and diphenyl-2-pyridylphosphine (3.17 g, 7.45 mmol) in THF (9.32 mL) under a N2 atmosphere. The solution was purged with N2 before DIAD (1.449 mL, 7.45 mmol) was added dropwise. The reaction was allowed to stir for 5 min. Diphenylphosphoryl azide (1.0β0β mL, 7.45 mmol) was then added dropwise over 30 min. After the addition was complete and no more nitrogen was being formed, the sealed tube was capped and the reaction was allowed to stir at 55 °C for 4 h.

[002097] The reaction was cooled to room temperature and poured into ethyl acetate (200 mL), washed with cold 1 N HCl (100 mL), saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give an orange oil. Purification by silica gel chromatography using 100% hexanes to β0% ethyl acetate in hexanes as eluent gave ββ0 mg of (S)-benzyl 2-(5-((S)-1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-1H-tetrazol-1-yl)-3-phenylpropanoate in low purity. A second preparatory HPLC purification using the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 100A 250x21.2mm Axia spiked (10-100mg) #520551-2. Mobile phase A: 0.1 TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 50-80% B over 20 min, then 10-min gradient 95% B; Flow rate: 15 mL/min; Detection: UV at 220 nm. Fractions containing the desired product were combined and dried. (S)-benzyl 2-(5-((S)-1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-1H-tetrazol-1-yl)-3-phenylpropanoate was obtained as a beige hygroscopic solid in 60.0 mg yield and 70% purity by LC/MS analysis.

[002098] LCMS Analysis Condition A: Retention time = 1.82 min; ESI-MS(+) m/z 562.5 (M+H). Step 3:

[002099] A solution of (S)-benzyl 2-(5-((S)-1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-1H-tetrazol-1-yl)-3-phenylpropanoate (60 mg, 0.107 mmol) in MeOH (534 μL) was hydrogenated over 10% Pd/C (22.74 mg, 0.021 mmol) using hydrogen from a latex balloon for 2 h.

[002100] The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a white gummy solid. The product was dissolved in MeCN (2 mL) and water (2 mL) and Et3N (100 μL) and treated with FMOC-OSU (36.0 mg, 0.107 mmol). The mixture was stirred at room temperature for 15 h.

[002101] The reaction mixture was diluted with EtOAc (50 mL), washed with 1 M HCl (2 x 20 mL) and brine (20 mL), dried (sodium sulfate), and concentrated under reduced pressure to give (S)-2-(5-((S)-1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylethyl)-1H-tetrazol-1-yl)-3-phenylpropanoic acid (42 mg, 0.075 mmol, 70.3% yield) as a yellow solid. The product is 64% pure by LC/MS analysis. Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z 560.5 (M+H). (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichlorophenyl)propanoic acid (Ross, AJ et al., J. Org. Chem., 75:245-248 (2010)) Scheme: Step 1:

[002102] To an oven-dried 8 mL vial with a Teflon cap purged with N2 was added zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((/er/-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1,3-dichloro-5-iodobenzene (622 mg, 2.279 mmol) and the reaction mixture were allowed to stir at room temperature for 16 h. The crude mixture was diluted in EtOAc (30 mL) and DMF was removed with four aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated, and the crude product was purified by chromatography on silica gel using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichlorophenyl)propanoate, 0.160 g yield in 77% purity by LCMS analysis. LCMS Analysis Condition F: Retention time = 2.84 min; ESI-MS(+) m/z 348.1 (M+H). Step 2:

[002103] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichlorophenyl)propanoate (160 mg, 0.459 mmol) in THF (2 mL)/H2O (0.667 mL) was added LiOH (33.0 mg, 1.378 mmol) and the reaction was allowed to stir for 2 h. THF was evaporated before the solution was diluted with EtOAc (10 mL) and the aqueous phase was acidified to pH 3 using 1 N aqueous HCl solution. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained as a yellow gum. The solid was taken directly to Step 3. Step 3:

[002104] To the solids from the previous step was added 4 M HCl in dioxane (1.149 mL, 4.59 mmol) and the solution was allowed to stir for 2 h. After evaporation of the solvent, the crude product was cooled to 0 °C and dissolved in 5% aqueous Na2CO3/AcCN (2:1) (30 mL). (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidin-1-yl)carbonate (170 mg, 0.505 mmol) was added and the reaction mixture was allowed to stir for 16 h. The mixture was diluted in 15.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of a 1 N aqueous HCl solution. The organic solvents were evaporated and the crude product was then distributed between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The product was purified by preparative LCMS using the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 35-100% B over 50 min, then a 10 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichlorophenyl)propanoic acid was 50 mg; purity, 87% by LCMS analysis. Condition A: rt = 1.73 min; ESI-MS(+) m/z 478.0 (M+Na)+. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4,5-difluorophenyl)propanoic acid (Ross, AJ et al., J. Org. Chem., 75:245-248 (2010)) Scheme: Step 1:

[002105] To an oven-dried 8 mL vial with a Teflon cap purged with N2 was added zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 5-bomo-1chloro-2,3-diflurobenzene (518 mg, 2.279 mmol) and the reaction mixture were allowed to stir at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed with four aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated and the crude product was purified by chromatography on silica gel using 100% hexanes to 30% EtO-Ac/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4,5-difluorophenyl)propanoate, 0.165 g, which was taken directly to the next step. Step 2:

[002106] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3-chloro-4,5-difluorophenyl)propanoate (165 mg, 0.472 mmol) in THF (2 mL)/H2O (0.667 mL) was added LiOH (33.9 mg, 1.415 mmol) and the reaction was allowed to stir for 2 h. THF was removed before the solution was diluted with EtOAc (10 mL). The aqueous phase was acidified to pH 3 using 1 N aqueous HCl solution. The crude product was extracted with EtOAc. The organic fractions were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained as a yellow gum, which was taken directly to Step 3. Step 3:

[002107] To the solids was added 4 M HCl in dioxane (1.179 mL, 4.72 mmol) and the reaction mixture was allowed to stir for 2 h. After evaporation of the solvent, the crude product was cooled to 0 °C and dissolved in 5% aqueous Na2CO3/ACN (2:1) (30 mL). (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (175 mg, 0.519 mmol) was added to the solution and the reaction mixture was allowed to stir for 16 h. The mixture was diluted with 15.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of 1 N aqueous HCl. The organic solvents were evaporated and the crude product was then distributed between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic extracts were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting product was then purified by preparative LCMS using the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 35-100% B over 50 min, then a 10 min hold at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried to give 62 mg of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4,5-difluorophenyl)propanoic acid. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoic acid (Ross, AJ et al., J. Org. Chem., 75:245-248 (2010)) Scheme: Step 1:

[002108] To an oven-dried 8 mL vial with a Teflon cap purged with N2 was added zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 5-bromo-1,3-dichloro-2-fluorobenzene (556 mg, 2.279 mmol) and the reaction mixture were allowed to stir at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated and the product was purified by chromatography on silica gel using 100% hexanes to 30% EtO-Ac/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoate, 0.102 g which was taken directly to the next step. Step 2:

[002109] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoate (102 mg, 0.279 mmol) in THF (2 mL)/H2O (0.667 mL) was added LiOH (20.01 mg, 0.836 mmol) and the reaction was stirred for 2 h. THF was removed and the solution was diluted with EtOAc (10 mL). The aqueous phase was acidified to pH 3 using 1 N aqueous HCl. The crude product was extracted with EtOAc. The organic extracts were combined and dried over anhydrous sodium sulfate. After filtration and concentration the crude product was obtained as a yellow gum, and was taken directly to Step 3. Step 3:

[002110] To the product from Step 2 was added 4 M HCl in dioxane (0.696 mL, 2.79 mmol) and the reaction mixture was allowed to stir for 2 h. After evaporation of the solvent, the crude product was cooled to 0 °C and dissolved in 5% aqueous Na2CO3/MeCN (2:1) (30 mL). (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (103 mg, 0.306 mmol) was added to the solution and the reaction mixture was stirred for 16 h. The mixture was diluted with 15.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of 1 N aqueous HCl. The organic solvents were evaporated and the crude product was then partitioned between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic extracts were combined, dried over anhydrous sodium sulfate, concentrated and then purified by preparative LCMS using the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 35-100% B over 50 min, then a 10 min retention at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried to give 36 mg of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoic acid. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoic acid (Ross, AJ et al., J. Org. Chem., 75:245-248 (2010)) Scheme: Step 1:

[002111] To an oven-dried 8 mL vial with a Teflon cap purged with N2 was added zinc dust (298 mg, 4.56 mmol), DMF (1.5 mL), and iodine (57.8 mg, 0.228 mmol). To this mixture was added (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (500 mg, 1.519 mmol), immediately followed by iodine (57.8 mg, 0.228 mmol). Pd2(dba)3 (69.6 mg, 0.076 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (62.4 mg, 0.152 mmol), 1-chloro-2-fluoro-4-iodobenzene (584 mg, 2.279 mmol), and the reaction mixture were stirred at room temperature for 16 h. The crude mixture was diluted in 30 mL of EtOAc and DMF was removed using four aqueous washes. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the product was purified by chromatography on silica gel using 100% hexanes to 30% EtOAc/Hexanes. The desired product was obtained as a pale yellow oil, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate, 0.220 g; purity, 93% by LCMS analysis. LCMS Analysis Condition F: rt = 2.59 min; ESI-MS(+) m/z 332.2 (M+H). Step 2:

[002112] To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoate (220mg, 0.663 mmol) in THF (2 mL)/Water (0.667 mL) was added LiOH (47.6 mg, 1.989 mmol) and the reaction was allowed to stir for 2 h. THF was removed and the solution was diluted in EtOAc (10 mL). The aqueous phase was acidified to pH 3 using 1 N aqueous HCl. The crude product was extracted with EtOAc. The organic extracts were combined and dried over anhydrous sodium sulfate. After filtration and concentration the crude product was obtained as a yellow gum and taken directly to Step 3. Step 3:

[002113] To the solid from Step 2 was added 4M HCl in dioxane (1.658 mL, 6.63 mmol) and the mixture was stirred for 2 h. After evaporation of the solvent, the crude product was cooled to 0 °C and dissolved in 5% aqueous Na2CO3/AcCN (2:1) (30 mL). (9H-fluoren-9-yl)methyl(2,5-dioxopyrrolidin-1-yl)carbonate (246 mg, 0.729 mmol) was added to the solution and the reaction mixture was stirred for 16 h. The mixture was diluted with 15.0 mL of EtOAc and the aqueous phase was neutralized with a few drops of 1 N HCl. The organic solvents were evaporated and the crude product was then partitioned between a saturated aqueous NH4Cl solution and EtOAc. The crude product was extracted with EtOAc. The organic extracts were combined, dried over anhydrous sodium sulfate, concentrated and then purified by preparative LCMS under the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 35-100% B over 50 min, then a 10 min retention at 100% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried to give 30 mg of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoic acid. LCMS analysis Condition A: rt = 1.65 min, 85% purity; ESI-MS(+) m/z 462.0 (M+Na). Preparation of Example 3052 Example 3052

[002114] Example 3052 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002115] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002116] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B in A for 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 5 mg, and its purity was estimated to be 99% by HPLC "Analysis Condition B" using a gradient from 35% to 95% buffer B for 30 minutes.

[002117] LCMS Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 825.2 (M+2H). Preparation of Example 3053 Example 3053

[002118] Example 3053 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002119] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002120] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B in A over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 15 mg, and its estimated purity was 92% by “HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B in A over 30 minutes.

[002121] LCMS Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 818.2 (M+2H). Preparation of Example 3054 Example 3054

[002122] Example 3054 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002123] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002124] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B in A over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 21 mg, and its purity was estimated to be 99% by “HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B in A over 30 minutes.

[002125] LCMS Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 842.2 (M+2H). Preparation of Example 3055 Example 3055

[002126] Example 3055 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002127] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002128] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B in A over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 19 mg, and its estimated purity was 92% by “HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B in A over 30 minutes.

[002129] LCMS Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 760.6 (M+2H). Preparation of Example 3056 Example 3056

[002130] Example 3056 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002131] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002132] The crude material was purified via preparatory LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 25-95% B over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3056-A and isomer 3056-B) were obtained. The yield of isomer 3056-A and isomer 3056-B products was 3.6 mg and 5.7 mg, respectively, and their purity estimated by "Analysis Condition B" using a gradient of 20% to 85% buffer B in A over 30 min at 60°C was 83% and 96%, respectively.

[002133] LCMS Analysis Condition A: isomer 3056-A, Retention Time = 1.21 min; ESI-MS(+) m/z 894.2 (M+2H); isomer 3056-B, 1.31 min; ESI-MS(+) m/z 894.2 (M+2H). Preparation of Example 3057 Example 3057

[002134] Example 3057 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002135] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002136] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 20-85% B in A for 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 10.3 mg, and its estimated purity was 91% by “HPLC Analysis Condition B" using a gradient of 20% to 85% buffer B in A at 60° C for 30 minutes.

[002137] LCMS Analysis Condition A : Retention time = 1.23 min; ESI-MS(+) m/z 894.1 (M+2H). Preparation of Example 3058 Example 3058

[002138] Example 3058 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002139] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002140] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250, 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 20-85% B in A over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3058-A and isomer 3058-B) were obtained. The yield of isomer 3058-A and isomer 3058-B products was 4.3 mg and 7.6 mg respectively, and their purity estimated by “HPLC Analysis Condition B” using a gradient of 20% to 85% buffer B in A over 30 min at 60°C was 93% and 92%, respectively.

[002141] LCMS Analysis Condition A: isomer 3058-A, retention time = 0.99 min; ESI-MS(+) m/z 889.1 (M+2H); isomer 3058-B, 1.10 min; ESI-MS(+) m/z 889.1 (M+2H). Preparation of Example 3059 Example 3059

[002142] Example 3059 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002143] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002144] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B in A over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried to obtain 9.2 mg of product with 96% purity.

[002145] LCMS Analysis Condition D: Retention time = 1.573 min; ESI-MS(+) m/z 1811.80 (M+H).

[002146] LCMS Analysis Condition E: Retention time = 1.711 min; ESI-MS(+) m/z 906.80 (M+2H), 1811.80 (M+H). Preparation of Example 3060 Example 3060

[002147] Example 3060 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002148] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002149] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B in A over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3060-A and isomer 3060-B) were obtained. The yield of isomer 3060-A and isomer 3060-B products was 5.5 mg and 1.7 mg respectively, and their purity estimated by "Analysis Conditions D and E" was 95% and 86%, respectively.

[002150] Analysis Condition D: 3060-A isomer: Retention time = 1.455 min; ESI-MS(+) m/z 923.65 (M+2H).

[002151] Analysis Condition D: 3060-B isomer: Retention time = 1,570 min; ESI-MS(+) m/z 923.60 (M+2H).

[002152] Analysis Condition E: 3060-A isomer: Retention time = 1.549 min; ESI-MS(+) m/z 923.45 (M+2H).

[002153] Analysis Condition E: isomer 3060-B: Retention time = 1.666 min; m/z 923.70 (M+2H). Preparation of Example 3061 Example 3061

[002154] Example 3061 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002155] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002156] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried to give 3.2 mg in 98% purity.

[002157] LCMS Analysis Condition D: Retention time = 1.573 min; ESI-MS(+) m/z 1811.80 (M+H).

[002158] LCMS Analysis Condition E: Retention time = 1.711 min; ESI-MS(+) m/z 906.80 (M+2H), 1811.80 (M+H). Preparation of Example 3062 Example 3062

[002159] Example 3062 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002160] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002161] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried to obtain 5.7 mg in 95% purity.

[002162] LCMS Analysis Condition D: Retention time = 1.698 min; ESI-MS(+) m/z 1813.70 (M+H).

[002163] LCMS Analysis Condition E: Retention time = 1.853 min; ESI-MS(+) m/z 1813.65 (M+H). Preparation of Example 3063 Example 3063

[002164] Example 3063 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002165] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002166] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.4 mg, and its purity was estimated to be 99% by LCMS analysis.

[002167] LCMS Analysis Condition D: Retention time = 1.439 min; ESI-MS(+) m/z 1825.90 (M+H).

[002168] LCMS Analysis Condition E: Retention time = 1,490 min; ESI-MS(+) m/z 1825.85 (M+H). Preparation of Example 3064 Example 3064

[002169] Example 3064 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002170] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002171] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.31 mg, and its purity was estimated to be 98% by LCMS analysis.

[002172] LCMS Analysis Condition D: Retention time = 1.468 min; ESI-MS(+) m/z 1777.95 (M+H).

[002173] LCMS Analysis Condition E: Retention time = 1.671 min; ESI-MS(+) m/z 1778.80 (M+H). Preparation of Example 3065 Example 3065

[002174] Example 3065 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002175] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002176] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-80% B over 50 minutes, then a 5 minute hold at 80% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.1 mg, and its purity estimated by HPLC "Analysis Condition B" using a gradient from 35% to 75% buffer B over 30 minutes giving 96% purity.

[002177] LCMS Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 907.2 (M+2H). Preparation of Example 3066 Example 3066

[002178] Example 3066 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002179] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002180] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-70% B over 50 minutes, then a 5-minute hold at 70% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 2.5 mg, and its purity was estimated to be 91% by HPLC "HPLC Analysis Condition B" using a gradient from 35% to 70% buffer B over 30 minutes.

[002181] LCMS Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 947.1 (M+2H). Preparation of Example 3067 Example 3067

[002182] Example 3067 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002183] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002184] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-70% B over 50 minutes, then a 5-minute hold at 70% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 11.8 mg, and its purity estimated by HPLC was 99% "HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 minutes.

[002185] LCMS Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 916.5 (M+2H). Preparation of Example 3068 Example 3068

[002186] Example 3068 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002187] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002188] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 11.8 mg, and its purity was estimated to be 99% by “HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 minutes.

[002189] LCMS Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 912.3 (M+2H). Preparation of Example 3069 Example 3069

[002190] Example 3069 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002191] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002192] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.1 mg, and its purity was estimated to be 98% by “HPLC Analysis Condition B" using a gradient of 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 912.3 (M+2H). Preparation of Example 3070 Example 3070

[002193] Example 3070 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002194] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002195] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.9 mg, and its purity was estimated to be 98% by “HPLC Analysis Condition B" using a gradient of 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 925.5 (M+2H). Preparation of Example 3071 Example 3071

[002196] Example 3071 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002197] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002198] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.3 mg, and its purity was estimated to be 99% by “HPLC Analysis Condition B" using a gradient of 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 899.3 (M+2H). Preparation of Example 3072 Example 3072

[002199] Example 3072 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002200] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002201] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.5 mg, and its purity was estimated to be 99% by “HPLC Analysis Condition B" using a gradient of 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 870.7 (M+2H). Preparation of Example 3073 Example 3073

[002202] Example 3073 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002203] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002204] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .35-95% B over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 5.9 mg, and its purity was estimated to be 98% by “HPLC Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 minutes.

[002205] LCMS Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 943.9 (M+2H). Preparation of Example 3074 Example 3074

[002206] Example 3074 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002207] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002208] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 50 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.8 mg, and its purity was estimated to be 99% by “HPLC Analysis Condition B" using a gradient of 30% to 90% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 915.9 (M+2H). Preparation of Example 3075 Example 3075

[002209] Example 3075 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002210] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002211] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .30-90% B over 60 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 9.5 mg, and its purity estimated by HPLC "Analysis Condition B" using a gradient from 30% to 85% buffer B over 30 minutes giving 97% purity.

[002212] LCMS Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 926.3 (M+2H). Preparation of Example 3076 Example 3076

[002213] Example 3076 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002214] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002215] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .35-95% B over 60 min, then a 5-min hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.9 mg, and its purity was estimated by HPLC "Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 min giving 99% purity.

[002216] LCMS Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 900.3 (M+2H). Preparation of Example 3077 Example 3077

[002217] Example 3077 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002218] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002219] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .35-95% B over 60 min, then a 5-min hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 12.3 mg, and its purity was estimated by HPLC "Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 min giving 99% purity.

[002220] LCMS Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 900.3 (M+2H). Preparation of Example 3078 Example 3078

[002221] To a 50 mL polypropylene tube was added Sieber resin (140 mg, 0.100 mmol), and the tube was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin swelling procedure” was followed; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Leu-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Tyr(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Trp(Boc)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Sar-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Tyr(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-[N-Me]Phe-OH; “CEM Method A: Custom amino acid coupling procedure” was followed with Fmoc-Val-OH using 10 eq. for 2 h at 75 °C; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Asp(OtBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Sar-OH; “CEM Method A: Custom amino acid coupling procedure” was followed with Fmoc-[N-Me]Nle-OH using 5 eq. for 10 min; “CEM Method A: Custom amino acid coupling procedure” was followed with Fmoc-[N-Me]Phe-OH using 5 eq. for 10 min; “CEM Method A: Custom amino acid coupling procedure” was followed with Fmoc-Phe(penta-F)-OH using 5 eq. for 10 min; “Prelude Method A: Chloroacetyl chloride coupling procedure A” was followed; “Global deprotection method B” was followed; “Cyclization method C” was followed.

[002222] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.7 mg, and its purity estimated by LCMS analysis was 97%.

[002223] LCMS Analysis Condition D: Retention time = 1.79 min; ESI-MS(+) m/z 944.4 (M+2H).

[002224] LCMS Analysis Condition E: Retention time = 1.98 min; ESI-MS(+) m/z 944.3 (M+2H). Preparation of Example 3079 Example 3079

[002225] Example 3079 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002226] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 35-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.3 mg, and its purity estimated by LCMS analysis was 99%.

[002227] LCMS Analysis Condition D: Retention time = 1.87 min; ESI-MS(+) m/z 936.5 (M+2H).

[002228] LCMS Analysis Condition E: Retention time = 2.09 min; ESI-MS(+) m/z 935.8 (M+2H). Preparation of Example 3080 Example 3080

[002229] Example 3080 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002230] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.71 mg, and its purity estimated by LCMS analysis was 98%.

[002231] LCMS Analysis Condition D: Retention time = 1.90 min; ESI-MS(+) m/z 935.9 (M+2H).

[002232] LCMS Analysis Condition E: Retention time = 2.11 min; ESI-MS(+) m/z 936.0 (M+2H).

[002233] Preparation of Example 3081 Example 3081

[002234] Example 3081 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002235] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002236] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.0 mg, and its purity estimated by LCMS analysis was 98%.

[002237] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 938.8 (M+2H).

[002238] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 938.9 (M+2H). Preparation of Example 3082 Example 3082

[002239] Example 3082 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002240] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002241] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.8 mg, and its purity estimated by LCMS analysis was 99%.

[002242] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 906.1 (M+2H).

[002243] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 906.2 (M+2H). Preparation of Example 3083 Example 3083

[002244] Example 3083 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002245] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002246] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.4 mg, and its purity estimated by LCMS analysis was 95%.

[002247] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 882.0 (M+2H).

[002248] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 881.7 (M+2H). Preparation of Example 3086 Example 3086

[002249] Example 3086 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002250] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002251] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.1 mg, and its purity estimated by LCMS analysis was 95%.

[002252] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 916.3 (M+2H).

[002253] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 916.5 (M+2H). Preparation of Example 3087 Example 3087

[002254] Example 3087 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002255] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002256] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC AQ-ODS 250 x 20mm column; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 30-90% B over 55 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The peptide was not very clean and therefore another preparatory HPLC with the following conditions was performed: Column: YMC AQ-ODS 250 x 20mm column; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 40-80% B over 50 min, then a 5 min hold at 80% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 2.5 mg, and its purity was estimated to be 97% by HPLC "Analysis Condition B" using a gradient from 35% to 85% buffer B over 30 min.

[002257] LCMS Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 913.5 (M+2H). Preparation of Example 3088 Example 3088

[002258] Example 3088 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002259] The crude material was purified via preparatory HPLC with the following conditions: Column: YMC AQ-ODS 250 x 20mm column; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 30-90% B over 55 minutes, then a 5 minute hold at 90% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The peptide was not very clean and therefore another preparatory HPLC with the following conditions was performed: Column: YMC AQ-ODS 250 x 20mm column; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 40-80% B over 50 min, then a 5 min hold at 80% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3088-A and isomer 3088-B) were obtained. The yield of the product s isomer 3088-A and isomer 3088-B was 1.1 mg and 0.81 mg respectively, and their purity estimated by HPLC "Analysis Condition B" using a gradient from 35% to 85% buffer B over 30 min giving 99% and 93% purity for isomer 3088-A and isomer 3088-B, respectively. LC/MS confirmed product using LCMS "Analysis Condition A".

[002260] Isomer 3088- A: LCMS analysis Condition A: Retention time = 1.45 min; MS(+) m/z 918.7 (M+2H).

[002261] Isomer 3088-B LCMS Analysis Condition A: Retention time = 1.51 min, MS(+) m/z 918.8 (M+2H). Preparation of Example 3089 Example 3089

[002262] Example 3089 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002263] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002264] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.0 mg, and its purity estimated by LCMS analysis was 95%.

[002265] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS(+) m/z 914.1 (M+2H).

[002266] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 914.2 (M+2H). Preparation of Example 3090 Example 3090

[002267] Example 3090 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002268] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.11 mg, and its purity estimated by LCMS analysis was 99%.

[002269] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 918.6 (M+2H).

[002270] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 918.9 (M+2H). Preparation of Example 3091 Example 3091

[002271] Example 3091 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002272] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002273] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.9 mg, and its purity estimated by LCMS analysis was 92%.

[002274] LCMS Analysis Condition D: Retention time = 1.40 min; ESI-MS(+) m/z 894.4 (M+2H).

[002275] LCMS Analysis Condition E: Retention time = 1.53 min; ESI-MS(+) m/z 893.9 (M+2H). Preparation of Example 3092 Example 3092

[002276] Example 3092 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002277] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002278] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.8 mg, and its purity estimated by LCMS analysis was 95%.

[002279] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 902.6 (M+2H).

[002280] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 902.6 (M+2H). Preparation of Example 3093 Example 3093

[002281] Example 3093 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002282] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002283] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 10 min hold at 60% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.8 mg, and its purity estimated by LCMS analysis was 93%.

[002284] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 933.1 (M+2H).

[002285] LCMS Analysis Condition E: Retention time = 1.94 min; ESI-MS(+) m/z 933.4 (M+2H). Preparation of Example 3094 Example 3094

[002286] Example 3094 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002287] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002288] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.7 mg, and its purity estimated by LCMS analysis was 100%.

[002289] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 906.4 (M+2H).

[002290] LCMS Analysis Condition E: Retention time = 1.88 min; ESI-MS(+) m/z 906.8 (M+2H). Preparation of Example 3095 Example 3095

[002291] Example 3095 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002292] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002293] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.6 mg, and its purity estimated by LCMS analysis was 100%.

[002294] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 914.5 (M+2H).

[002295] LCMS Analysis Condition E: Retention time = 1.80 min; ESI-MS(+) m/z 914.1 (M+2H). Preparation of Example 3096 Example 3096

[002296] Example 3096 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002297] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002298] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.8 mg, and its purity estimated by LCMS analysis was 100%.

[002299] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 919.3 (M+2H).

[002300] LCMS Analysis Condition E: Retention time = 1.93 min; ESI-MS(+) m/z 919.0 (M+2H). Preparation of Example 3097 Example 3097

[002301] Example 3097 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002302] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002303] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.4 mg, and its purity estimated by LCMS analysis was 100%.

[002304] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 898.8 (M+2H).

[002305] LCMS Analysis Condition E: Retention time = 1.84 min; ESI-MS(+) m/z 898.9 (M+2H). Preparation of Example 3098 Example 3098

[002306] Example 3098 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002307] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002308] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.2 mg, and its purity estimated by LCMS analysis was 100%.

[002309] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 934.0 (M+2H).

[002310] LCMS Analysis Condition E: Retention time = 1.91 min; ESI-MS(+) m/z 932.8 (M+2H). Preparation of Example 3099 Example 3099

[002311] Example 3099 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002312] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002313] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 97%.

[002314] LCMS Analysis Condition D: Retention time = 1.78 min; ESI-MS(+) m/z 908.2 (M+2H).

[002315] LCMS Analysis Condition E: Retention time = 2.03 min; ESI-MS( +) m/z 908.0 (M+2H). Preparation of Example 3100 Example 3100

[002316] Example 3100 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002317] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002318] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.2 mg, and its purity estimated by LCMS analysis was 91%.

[002319] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 925.3 (M+2H).

[002320] LCMS Analysis Condition E: Retention time = 2.09 min; ESI-MS( +) m/z 925.6 (M+2H). Preparation of Example 3101 Example 3101

[002321] Example 3101 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002322] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002323] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 96%.

[002324] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 893.6 (M+2H).

[002325] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 893.8 (M+2H). Preparation of Example 3102 Example 3102

[002326] Example 3102 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002327] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002328] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.5 mg, and its purity estimated by LCMS analysis was 96%.

[002329] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 928.7 (M+2H).

[002330] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 928.6 (M+2H). Preparation of Example 3103 Example 3103

[002331] Example 3103 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002332] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002333] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5A particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.0 mg, and its purity estimated by LCMS analysis was 96%.

[002334] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 918.9 (M+2H).

[002335] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 918.1 (M+2H). Preparation of Example 3104 Example 3104

[002336] Example 3104 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002337] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002338] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.3 mg, and its purity estimated by LCMS analysis was 99%.

[002339] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 916.0 (M+2H).

[002340] LCMS Analysis Condition E: Retention time = 1.88 min; ESI-MS(+) m/z 916.0 (M+2H). Preparation of Example 3105 Example 3105

[002341] Example 3105 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002342] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002343] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.6 mg, and its purity estimated by LCMS analysis was 97%.

[002344] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 906.0 (M+2H).

[002345] LCMS Analysis Condition E: Retention time = 1.88 min; ESI-MS(+) m/z 905.6 (M+2H). Preparation of Example 3106 Example 3106

[002346] Example 3106 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002347] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002348] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.4 mg, and its purity estimated by LCMS analysis was 99%.

[002349] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 933.0 (M+2H).

[002350] LCMS Analysis Condition E: Retention time = 1.93 min; ESI-MS(+) m/z 932.9 (M+2H). Preparation of Example 3107 Example 3107

[002351] Example 3107 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002352] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002353] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.1 mg, and its purity estimated by LCMS analysis was 100%.

[002354] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS( +) m/z 922.7 (M+2H).

[002355] LCMS Analysis Condition E: Retention time = 1.88 min; ESI-MS(+) m/z 922.8 (M+2H). Preparation of Example 3109 Example 3109

[002356] Example 3109 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002357] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002358] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 96%.

[002359] LCMS Analysis Condition D: Retention time = 1.77 min; ESI-MS(+) m/z 927.5 (M+2H).

[002360] LCMS Analysis Condition E: Retention time = 2.03 min; ESI-MS(+) m/z 927.9 (M+2H). Preparation of Example 3110 Example 3110

[002361] Example 3110 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002362] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002363] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 35-80% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.4 mg, and its purity estimated by LCMS analysis was 100%.

[002364] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS( +) m/z 910.7 (M+2H).

[002365] LCMS Analysis Condition E: Retention time = 1.93 min; ESI-MS(+) m/z 910.8 (M+2H). Preparation of Example 3111 Example 3111

[002366] Example 3111 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002367] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002368] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.9 mg, and its purity estimated by LCMS analysis was 88%.

[002369] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 962.5 (M+2H).

[002370] LCMS Analysis Condition E: Retention time = 1.94 min; ESI-MS(+) m/z 962.2 (M+2H). Preparation of Example 3112 Example 3112

[002371] Example 3112 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002372] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002373] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 35-80% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.2 mg, and its purity estimated by LCMS analysis was 100%.

[002374] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 977.8 (M+2H).

[002375] LCMS Analysis Condition E: Retention time = 1.97 min; ESI-MS(+) m/z 978.1 (M+2H). Preparation of Example 3113 Example 3113

[002376] Example 3113 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002377] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002378] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.6 mg, and its purity estimated by LCMS analysis was 97%.

[002379] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 977.9 (M+2H).

[002380] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 977.7 (M+2H). Preparation of Example 3114 Example 3114

[002381] Example 3114 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002382] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.3 mg, and its purity estimated by LCMS analysis was 96%.

[002383] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 924.2 (M+2H).

[002384] LCMS Analysis Condition E: Retention time = 1.99 min; ESI-MS(+) m/z 925.4 (M+2H). Preparation of Example 3115 Example 3115

[002385] Example 3115 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002386] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.7 mg, and its purity estimated by LCMS analysis was 94%.

[002387] LCMS Analysis Condition D: Retention time = 1.81 min; ESI-MS(+) m/z 924.4 (M+2H).

[002388] LCMS Analysis Condition E: Retention time = 2.02 min; ESI-MS( +) m/z 924.6 (M+2H). Preparation of Example 3116 Example 3116

[002389] Example 3116 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002390] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.5 mg, and its purity estimated by LCMS analysis was 98%.

[002391] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 916.3 (M+2H).

[002392] LCMS Analysis Condition E: Retention time = 1.95 min; ESI-MS(+) m/z 916.3 (M+2H). Preparation of Example 3117 Example 3117

[002393] Example 3117 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002394] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.1 mg, and its purity estimated by LCMS analysis was 98%.

[002395] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 916.2 (M+2H).

[002396] LCMS Analysis Condition E: Retention time = 1.93 min; ESI-MS(+) m/z 916.7 (M+2H). Preparation of Example 3118 Example 3118

[002397] Example 3118 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002398] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 94%.

[002399] LCMS Analysis Condition D: Retention time = 1.82 min; ESI-MS(+) m/z 931.6 (M+2H).

[002400] LCMS Analysis Condition E: Retention time = 1.91 min; ESI-MS(+) m/z 931.3 (M+2H). Preparation of Example 3119 Example 3119

[002401] Example 3119 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002402] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 96%.

[002403] LCMS Analysis Condition D: Retention time = 1.83 min; ESI-MS(+) m/z 931.6 (M+2H).

[002404] LCMS Analysis Condition E: Retention time = 1.94 min; ESI-MS(+) m/z 931.3 (M+2H). Preparation of Example 3120 Example 3120

[002405] Example 3120 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002406] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.2 mg, and its purity estimated by LCMS analysis was 93%.

[002407] LCMS Analysis Condition D: Retention time = 1.77 min; ESI-MS( +) m/z 923.0 (M+2H).

[002408] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 923.1 (M+2H). Preparation of Example 3121 Example 3121

[002409] Example 3121 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002410] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.2 mg, and its purity estimated by LCMS analysis was 96%.

[002411] LCMS Analysis Condition D: Retention time = 1.76 min; ESI-MS( +) m/z 922.7 (M+2H).

[002412] LCMS Analysis Condition E: Retention time = 1.85 min; ESI-MS(+) m/z 923.0 (M+2H). Preparation of Example 3122 Example 3122

[002413] Example 3122 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002414] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.1 mg, and its purity estimated by LCMS analysis was 94%.

[002415] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 922.6 (M+2H).

[002416] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 922.6 (M+2H). Preparation of Example 3123 Example 3123

[002417] Example 3123 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002418] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.3 mg, and its purity estimated by LCMS analysis was 91%.

[002419] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 914.2 (M+2H).

[002420] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 914.4 (M+2H). Preparation of Example 3124 Example 3124

[002421] Example 3124 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002422] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.0 mg, and its purity estimated by LCMS analysis was 93%.

[002423] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 914.2 (M+2H).

[002424] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 914.3 (M+2H). Preparation of Example 3125 Example 3125

[002425] Example 3125 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002426] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.8 mg, and its purity estimated by LCMS analysis was 96%.

[002427] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 908.0 (M+2H).

[002428] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 907.8 (M+2H). Preparation of Example 3130 Example 3130

[002429] Example 3130 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002430] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.8 mg, and its purity estimated by LCMS analysis was 99%.

[002431] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 917.4 (M+2H).

[002432] LCMS Analysis Condition E: Retention time = 1.86 min; ESI-MS(+) m/z 916.5 (M+2H). Preparation of Example 3131 Example 3131

[002433] Example 3131 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002434] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002435] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.3 mg, and its purity estimated by LCMS analysis was 100%.

[002436] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS( +) m/z 908.6 (M+2H).

[002437] LCMS Analysis Condition E: Retention time = 1.83 min; ESI-MS(+) m/z 909.3 (M+2H). Preparation of Example 3132 Example 3132

[002438] Example 3132 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002439] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002440] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-65% B over 25 min, then a 10 min hold at 65% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.5 mg, and its purity estimated by LCMS analysis was 99%.

[002441] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 909.0 (M+2H).

[002442] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS( +) m/z 909.7 (M+2H). Preparation of Example 3133 Example 3133

[002443] Example 3133 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002444] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002445] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.7 mg, and its purity estimated by LCMS analysis was 98%.

[002446] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 898.8 (M+2H).

[002447] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 898.8 (M+2H). Preparation of Example 3134 Example 3134

[002448] Example 3134 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002449] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002450] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.7 mg, and its purity estimated by LCMS analysis was 98%.

[002451] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 898.8 (M+2H).

[002452] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 898.8 (M+2H). Preparation of Example 3135 Example 3135

[002453] Example 3135 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002454] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002455] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 10 min hold at 55% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.8 mg, and its purity estimated by LCMS analysis was 94%.

[002456] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS(+) m/z 898.7 (M+2H).

[002457] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 898.8 (M+2H). Preparation of Example 3136 Example 3136

[002458] Example 3136 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002459] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002460] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.6 mg, and its purity estimated by LCMS analysis was 96%.

[002461] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 898.6 (M+2H).

[002462] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 899.0 (M+2H). Preparation of Example 3138 Example 3138

[002463] Example 3138 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002464] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002465] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 94%.

[002466] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 924.6 (M+2H).

[002467] LCMS Analysis Condition E: Retention time = 2.03 min; ESI-MS(+) m/z 924.8 (M+2H). Preparation of Example 3139 Example 3139

[002468] Example 3139 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002469] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002470] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 14.2 mg, and its purity estimated by LCMS analysis was 100%.

[002471] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 898.2 (M+2H).

[002472] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 898.3 (M+2H). Preparation of Example 3140 Example 3140

[002473] Example 3140 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002474] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002475] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 14.6 mg, and its purity estimated by LCMS analysis was 94%.

[002476] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 898.5 (M+2H).

[002477] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 898.2 (M+2H). Preparation of Example 3141 Example 3141

[002478] Example 3141 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002479] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002480] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.8 mg, and its purity estimated by LCMS analysis was 97%.

[002481] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 914.0 (M+2H).

[002482] LCMS Analysis Condition E: Retention time = 1.83 min; ESI-MS(+) m/z 913.7 (M+2H). Preparation of Example 3142 Example 3142

[002483] Example 3142 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002484] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002485] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.5 mg, and its purity estimated by LCMS analysis was 87%.

[002486] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 899.4 (M+2H).

[002487] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 899.0 (M+2H). Preparation of Example 3143 Example 3143

[002488] Example 3143 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002489] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .25-95% B over 50 min, then a 5 min retention at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 5.3 mg, and its purity was estimated to be 96% by HPLC "Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 916.9 (M+2H). Preparation of Example 3144 Example 3144

[002490] Example 3144 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002491] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .25-95% B over 50 min, then a 5 min retention at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 5.1 mg, and its purity was estimated to be 95% by HPLC "Analysis Condition B" using a gradient from 35% to 95% buffer B over 30 min. LCMS Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 925.8 (M+2H). Preparation of Example 3145 Example 3145

[002492] Example 3145 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002493] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002494] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 18.1 mg, and its purity estimated by LCMS analysis was 93%.

[002495] LCMS Analysis Condition D: Retention time = 1.63 min; ESI-MS(+) m/z 909.6 (M+2H).

[002496] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 908.6 (M+2H). Preparation of Example 3146 Example 3146

[002497] Example 3146 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002498] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002499] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.5 mg, and its purity estimated by LCMS analysis was 91%.

[002500] LCMS Analysis Condition D: Retention time = 1.90 min; ESI-MS(+) m/z 883.8 (M+2H).

[002501] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 883.8 (M+2H). Preparation of Example 3147 Example 3147

[002502] Example 3147 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002503] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002504] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.9 mg, and its purity estimated by LCMS analysis was 94%.

[002505] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 906.9 (M+2H).

[002506] LCMS Analysis Condition E: Retention time = 1.69 min; ESI-MS(+) m/z 907.2 (M+2H). Preparation of Example 3148 Example 3148

[002507] Example 3148 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002508] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002509] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.5 mg, and its purity estimated by LCMS analysis was 90%.

[002510] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS( +) m/z 918.7 (M+2H).

[002511] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 918.4 (M+2H). Preparation of Example 3149 Example 3149

[002512] Example 3149 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002513] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002514] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.6 mg, and its purity estimated by LCMS analysis was 96%.

[002515] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 905.8 (M+2H).

[002516] LCMS Analysis Condition E: Retention time = 1.88 min; ESI-MS(+) m/z 905.8 (M+2H). Preparation of Example 3150 Example 3150

[002517] Example 3150 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002518] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002519] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 12.6 mg, and its purity estimated by LCMS analysis was 98%.

[002520] LCMS Analysis Condition D: Retention time = 1.35 min; ESI-MS(+) m/z 913.8 (M+2H).

[002521] LCMS Analysis Condition E: Retention time = 1.60 min; ESI-MS(+) m/z 913.9 (M+2H). Preparation of Example 3151 Example 3151

[002522] Example 3151 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002523] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002524] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparative LC/MS under the following conditions: Column: Waters XBridge Phenyl, 19 × 150 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-55% B over 20 min, then a 10 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The product yield was 5.1 mg, and its purity estimated by LCMS analysis was 96%.

[002525] LCMS Analysis Condition D: Retention time = 1.45 min; ESI-MS(+) m/z 927.0 (M+2H).

[002526] LCMS Analysis Condition E: Retention time = 1.49 min; ESI-MS(+) m/z 927.3 (M+2H). Preparation of Example 3152 Example 3152

[002527] Example 3152 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002528] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.1 mg, and its purity estimated by LCMS analysis was 93% purity.

[002529] LCMS Analysis Condition D: Retention time 1.67 min; ESI-MS(+) m/z 884.3 (M+2H).

[002530] LCMS Analysis Condition E: Retention time 1.66 min; ESI-MS(+) m/z 884.3 (M+2H). Preparation of Example 3153 Example 3153

[002531] Example 3153 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002532] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.3 mg, and its purity estimated by LCMS analysis was 95% purity.

[002533] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 891.3 (M+2H).

[002534] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 891.4 (M+2H). Preparation of Example 3154 Example 3154

[002535] Example 3154 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002536] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.4 mg, and its purity estimated by LCMS analysis was 94% purity.

[002537] LCMS Analysis Condition D: Retention time = 1.87 min; ESI-MS(+) m/z 922.8 (M+2H).

[002538] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 923.1 (M+2H). Preparation of Example 3155 Example 3155

[002539] Example 3155 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002540] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 15.3 mg, and its purity estimated by LCMS analysis was 98% purity.

[002541] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 900.3 (M+2H).

[002542] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS( +) m/z 899.7 (M+2H). Preparation of Example 3156 Example 3156

[002543] Example 3156 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002544] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-60% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 × 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The product yield was 2.3 mg, and its purity estimated by LCMS analysis was 99%.

[002545] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 893.1 (M+2H).

[002546] LCMS Analysis Condition E: Retention time = 1.61 min; ESI-MS(+) m/z 892.8 (M+2H). Preparation of Example 3157 Example 3157

[002547] Example 3157 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002548] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.1 mg, and its purity estimated by LCMS analysis was 94% purity.

[002549] LCMS Analysis Condition D: Retention time = 1.55 min; ESI-MS(+) m/z 906.9 (M+2H).

[002550] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 907.1 (M+2H). Preparation of Example 3158 Example 3158

[002551] Example 3158 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002552] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.9 mg, and its purity estimated by LCMS analysis was 93% purity.

[002553] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 919.3 (M+2H).

[002554] LCMS Analysis Condition E: Retention time = 1.97 min; ESI-MS(+) m/z 919.2 (M+2H). Preparation of Example 3159 Example 3159

[002555] Example 3159 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002556] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 13.7 mg, and its purity estimated by LCMS analysis was 97% purity.

[002557] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 926.3 (M+2H).

[002558] LCMS Analysis Condition E: Retention time = 2.09 min; ESI-MS( +) m/z 926.1 (M+2H). Preparation of Example 3160 Example 3160

[002559] Example 3160 was prepared following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, and “Custom Amino Acid Coupling Procedure”.

[002560] The above peptidyl resin (0.033 mmol) was purged with N2 and placed in a 15 mL conical flask (equipped with a stirrer) for a microwave reactor. Then 0.033 mmol of Hoveyda-Grubb second generation catalyst dissolved in 5 mL of 1,2-Dichloroethane was added. The mixture was then heated at 120°C for 1 hour. After the reaction, the resin was filtered and washed with 2x5 mL DMF followed by 3x5 mL DCM in a syringe equipped with a filter. The procedure for global deprotection and cyclization was repeated in the manner performed in Example 3078 "Global Deprotection Method B", and "Cyclization Method C".

[002561] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .35-95% B over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 0.77 mg, and its purity was estimated to be 86% by HPLC "Analysis Condition B" using a gradient from 35% to 85% buffer B over 30 minutes.

[002562] LCMS Analysis Condition A: Retention time = 1.78 min; ESI-MS(+) m/z 888.9 (M+2H). Preparation of Example 3161 Example 3161

[002563] Example 3161 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002564] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002565] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.2 mg, and its purity estimated by LCMS analysis was 96%.

[002566] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 885.3 (M+2H).

[002567] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 885.3 (M+2H). Preparation of Example 3162 Example 3162

[002568] Example 3162 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002569] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002570] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 95%.

[002571] LCMS Analysis Condition D: Retention time = 1.59 min; ESI-MS(+) m/z 892.7 (M+2H).

[002572] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 892.3 (M+2H). Preparation of Example 3163 Example 3163

[002573] Example 3163 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002574] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002575] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 94%.

[002576] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 899.7 (M+2H).

[002577] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 899.5 (M+2H). Preparation of Example 3164 Example 3164

[002578] Example 3164 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002579] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002580] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.9 mg, and its purity estimated by LCMS analysis was 98%.

[002581] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 906.8 (M+2H).

[002582] LCMS Analysis Condition E: Retention time = 1.69 min; ESI-MS(+) m/z 906.4 (M+2H). Preparation of Example 3165 Example 3165

[002583] Example 3165 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002584] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002585] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.7 mg, and its purity estimated by LCMS analysis was 94%.

[002586] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 910.8 (M+2H).

[002587] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 910.9 (M+2H). Preparation of Example 3166 Example 3166

[002588] Example 3166 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002589] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002590] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 18.2 mg, and its purity estimated by LCMS analysis was 97%.

[002591] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 901.2 (M+2H).

[002592] LCMS Analysis Condition E: Retention time = 2.03 min; ESI-MS(+) m/z 900.9 (M+2H). Preparation of Example 3167 Example 3167

[002593] Example 3167 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002594] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002595] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.2 mg, and its purity estimated by LCMS analysis was 97%.

[002596] LCMS Analysis Condition D: Retention time = 1.93 min; ESI-MS(+) m/z 900.7 (M+2H).

[002597] LCMS Analysis Condition E: Retention time = 2.14 min; ESI-MS(+) m/z 900.8 (M+2H). Preparation of Example 3168 Example 3168

[002598] Example 3168 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002599] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002600] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 17.7 mg, and its purity estimated by LCMS analysis was 96%.

[002601] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 907.3 (M+2H).

[002602] LCMS Analysis Condition E: Retention time = 1.69 min; ESI-MS(+) m/z 907.2 (M+2H). Preparation of Example 3171 Example 3171

[002603] Example 3171 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002604] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002605] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 95%.

[002606] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 881.9 (M+2H).

[002607] LCMS Analysis Condition E: Retention time = 1.85 min; ESI-MS(+) m/z 881.9 (M+2H). Preparation of Example 3172 Example 3172

[002608] Example 3172 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002609] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002610] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.5 mg, and its purity estimated by LCMS analysis was 97%.

[002611] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 891.1 (M+2H).

[002612] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 891.1 (M+2H). Preparation of Example 3173 Example 3173

[002613] Example 3173 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002614] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002615] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge c-18, 19 x 250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 35-80% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.5 mg, and its estimated purity by LCMS analysis was 97%.

[002616] LCMS Analysis Condition D: Retention time = 2.26 min; ESI-MS(+) m/z 903.3 (M+2H).

[002617] LCMS Analysis Condition E: Retention time = 2.25 min; ESI-MS(+) m/z 903.2 (M+2H). Preparation of Example 3174 Example 3174

[002618] Example 3174 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002619] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002620] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge c-18, 19 x 250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.3 mg, and its purity estimated by LCMS analysis was 100%.

[002621] LCMS Analysis Condition D: Retention time = 1.94 min; ESI-MS(+) m/z 911.0 (M+2H).

[002622] LCMS Analysis Condition E: Retention time = 1.94 min; ESI-MS(+) m/z 911.2 (M+2H). Preparation of Example 3175 Example 3175

[002623] Example 3175 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002624] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002625] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge c-18, 19 x 250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.8 mg, and its estimated purity by LCMS analysis was 95%.

[002626] LCMS Analysis Condition D: Retention time = 1.85 min; ESI-MS(+) m/z 910.3 (M+2H).

[002627] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 910.8 (M+2H). Preparation of Example 3176 Example 3176

[002628] Example 3176 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002629] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002630] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.2 mg, and its purity was estimated to be 100% by LCMS analysis.

[002631] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 879.1 (M+2H).

[002632] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 878.8 (M+2H). Preparation of Example 3177 Example 3177

[002633] Example 3177 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002634] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002635] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[002636] LCMS Analysis Condition D: Retention time = 1.52 min; ESI-MS(+) m/z 887.2 (M+2H).

[002637] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 886.6 (M+2H). Preparation of Example 3178 Example 3178

[002638] Example 3178 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002639] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002640] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.8 mg, and its purity estimated by LCMS analysis was 93%.

[002641] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 887.0 (M+2H).

[002642] LCMS Analysis Condition E: Retention time = 1.69 min; ESI-MS(+) m/z 886.2 (M+2H). Preparation of Example 3179 Example 3179

[002643] Example 3179 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002644] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichlorophenyl)propanoic acid was used.

[002645] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.2 mg, and its purity estimated by LCMS analysis was 99%.

[002646] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 933.3 (M+2H).

[002647] LCMS Analysis Condition E: Retention time = 1.97 min; ESI-MS(+) m/z 933.6 (M+2H). Preparation of Example 3180 Example 3180

[002648] Example 3180 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002649] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-chloro-3-fluorophenyl)propanoic acid was used.

[002650] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.4 mg, and its purity estimated by LCMS analysis was 94%.

[002651] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 924.8 (M+2H).

[002652] LCMS Analysis Condition E: Retention time = 1.91 min; ESI-MS(+) m/z 925.3 (M+2H). Preparation of Example 3181 Example 3181

[002653] Example 3181 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002654] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002655] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 97%.

[002656] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 925.6 (M+2H).

[002657] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS( +) m/z 925.7 (M+2H). Preparation of Example 3182 Example 3182

[002658] Example 3182 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002659] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002660] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge c-18, 19 x 250 mm, 5-μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.9 mg, and its purity estimated by LCMS analysis was 100%.

[002661] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 982.9 (M+2H).

[002662] LCMS Analysis Condition E: Retention time = 1.85 min; ESI-MS(+) m/z 982.8 (M+2H).

[002663] ESI-HRMS(+) m/z: Calculated: 982.4330 (M+2H); Found: 982.4307 (M+2H). Preparation of Example 3183 Example 3183

[002664] Example 3183 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002665] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002666] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge c-18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[002667] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 960.2 (M+2H).

[002668] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 960.2 (M+2H). Preparation of Example 3184 Example 3184

[002669] Example 3184 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002670] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002671] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 25-75% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 21.8 mg, and its estimated purity by LCMS analysis was 97%.

[002672] LCMS Analysis Condition D: Retention time 1.71 min; ESI-MS(+) m/z 925.9 (M+2H).

[002673] LCMS Analysis Condition E: Retention time 1.95 min; ESI-MS(+) m/z 926.0 (M+2H). Preparation of Example 3185 Example 3185

[002674] Example 3185 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002675] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3,5-dichloro-4-fluorophenyl)propanoic acid was used.

[002676] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 6 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.6 mg, and its purity estimated by LCMS analysis was 98%.

[002677] LCMS Analysis Condition D: Retention time 1.76 min; ESI-MS(+) m/z 942.0 (M+2H).

[002678] LCMS Analysis Condition E: Retention time 1.96 min; ESI-MS(+) m/z 942.2 (M+2H). Preparation of Example 3186 Example 3186

[002679] Example 3186 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002680] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4,5-difluorophenyl)propanoic acid was used.

[002681] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: .35-85% B over 50 min, then a 5 min retention at 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product yield was 6.3 mg, and its purity was estimated to be 99% by HPLC "Analysis Condition B" using a gradient from 30% to 85% buffer B over 20 min. LCMS Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 933.9 (M+2H). Preparation of Example 3187 Example 3187

[002682] Example 3187 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002683] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002684] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.4 mg and its purity estimated by LCMS analysis was 100%.

[002685] LCMS Analysis Condition D: Retention time 1.75 min; ESI-MS(+) m/z 907.3 (M+2H).

[002686] LCMS Analysis Condition E: Retention time 1.79 min; ESI-MS(+) m/z 907.5 (M+2H). Preparation of Example 3188 Example 3188

[002687] Example 3188 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002688] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002689] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7 mg and its purity estimated by LCMS analysis was 95%.

[002690] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 900.3 (M+2H).

[002691] LCMS Analysis Condition E: Retention time = 1.79 min; ESI-MS(+) m/z 900.6 (M+2H). Preparation of Example 3189 Example 3189

[002692] Example 3189 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002693] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002694] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.6 mg and its purity estimated by LCMS analysis was 92%.

[002695] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 893.4 (M+2H).

[002696] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 893.2 (M+2H). Preparation of Example 3190 Example 3190

[002697] Example 3190 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002698] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002699] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.8 mg and its estimated purity by LCMS analysis was 94%.

[002700] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 914.8 (M+2H).

[002701] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 914.4 (M+2H). Preparation of Example 3191 Example 3191

[002702] Example 3191 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002703] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002704] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.4 mg, and its purity was estimated to be 92% by LCMS analysis.

[002705] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 893.4 (M+2H).

[002706] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 893.6 (M+2H). Preparation of Example 3192 Example 3192

[002707] Example 3192 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002708] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002709] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-75% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.4 mg, and its purity estimated by LCMS analysis was 94%.

[002710] LCMS Analysis Condition D: Retention time = 1.89 min; ESI-MS(+) m/z 943.4 (M+2H).

[002711] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 943.2 (M+2H). Preparation of Example 3193 Example 3193

[002712] Example 3193 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002713] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002714] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-75% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.9 mg, and its purity estimated by LCMS analysis was 91%.

[002715] LCMS Analysis Condition D: Retention time = 1.90 min; ESI-MS(+) m/z 950.6 (M+2H).

[002716] LCMS Analysis Condition E: Retention time = 1.72 min; ESI-MS(+) m/z 950.4 (M+2H). Preparation of Example 3194 Example 3194

[002717] Example 3194 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002718] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002719] The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.6 mg, and its purity estimated by LCMS analysis was 95%.

[002720] LCMS Analysis Condition D: Retention time = 1.99 min; ESI-MS(+) m/z 957.3 (M+2H).

[002721] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS( +) m/z 957.3 (M+2H). Preparation of Example 3195 Example 3195

[002722] Example 3195 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002723] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002724] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.4 mg, and its purity estimated by LCMS analysis was 90%.

[002725] LCMS Analysis Condition D: Retention time 1.78 min; ESI-MS(+) m/z 951.2 (M+2H).

[002726] LCMS Analysis Condition E: Retention time 1.64 min; ESI-MS(+) m/z 951.2 (M+2H). Preparation of Example 3196 Example 3196

[002727] Example 3196 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002728] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002729] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.2 mg, and its purity estimated by LCMS analysis was 98%.

[002730] LCMS Analysis Condition D: Retention time = 1.86 min; ESI-MS(+) m/z 965.4 (M+2H).

[002731] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 965.3 (M+2H). Preparation of Example 3197 Example 3197

[002732] Example 3197 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002733] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002734] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.7 mg, and its purity estimated by LCMS analysis was 95%.

[002735] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 981.3 (M+2H).

[002736] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 981.4 (M+2H). Preparation of Example 3198 Example 3198

[002737] Example 3198 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002738] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002739] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.4 mg, and its purity estimated by LCMS analysis was 99%.

[002740] LCMS Analysis Condition D: Retention time = 1.81 min; ESI-MS(+) m/z 965.6 (M+2H).

[002741] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 965.5 (M+2H). Preparation of Example 3199 Example 3199

[002742] Example 3199 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002743] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002744] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-75% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.3 mg, and its purity estimated by LCMS analysis was 92%.

[002745] LCMS Analysis Condition D: Retention time = 1.82 min; ESI-MS(+) m/z 951.8 (M+2H).

[002746] LCMS Analysis Condition E: Retention time = 1.79 min; ESI-MS( +) m/z 951.7 (M+2H). Preparation of Example 3200 Example 3200

[002747] Example 3200 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002748] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002749] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 94%.

[002750] LCMS Analysis Condition D: Retention time = 1.82 min; ESI-MS(+) m/z 944.7 (M+2H).

[002751] LCMS Analysis Condition E: Retention time = 1.57 min; ESI-MS(+) m/z 944.6 (M+2H). Preparation of Example 3201 Example 3201

[002752] Example 3201 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002753] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002754] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-70% B over 25 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.1 mg, and its purity estimated by LCMS analysis was 100%.

[002755] LCMS Analysis Condition D: Retention time = 1.90 min; ESI-MS(+) m/z 958.6 (M+2H).

[002756] LCMS Analysis Condition E: Retention time = 1.63 min; ESI-MS(+) m/z 958.5 (M+2H). Preparation of Example 3202 Example 3202

[002757] Example 3202 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002758] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002759] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.1 mg, and its purity estimated by LCMS analysis was 97%.

[002760] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 966.8 (M+2H).

[002761] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 966.1 (M+2H). Preparation of Example 3203 Example 3203

[002762] Example 3203 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002763] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002764] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.6 mg, and its purity estimated by LCMS analysis was 99%.

[002765] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 959.3 (M+2H).

[002766] LCMS Analysis Condition E: Retention time = 1.50 min; ESI-MS(+) m/z 959.3 (M+2H). Preparation of Example 3204 Example 3204

[002767] Example 3204 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002768] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002769] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.1 mg, and its purity estimated by LCMS analysis was 95%.

[002770] LCMS Analysis Condition D: Retention time 1.64 min; ESI-MS(+) m/z 918.4 (M+2H).

[002771] LCMS Analysis Condition E: Retention time 1.76 min; ESI-MS(+) m/z 918.1 (M+2H). Preparation of Example 3205 Example 3205

[002772] Example 3205 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002773] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002774] The crude material was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.7 mg, and its purity was estimated to be 99% by LCMS analysis.

[002775] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 918.4 (M+2H).

[002776] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS( +) m/z 918.5 (M+2H).

[002777] ESI-HRMS(+) m/z: Calculated: 917.9173 (M+2H); Found: 917.9147 (M+2H). Preparation of Example 3206 Example 3206

[002778] Example 3206 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002779] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". The eighth coupling of Fmoc-N-Me-Phe(3-F)-OH was performed using the "N-Methylation Methylation on Resin Method A" procedure.

[002780] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 20-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.6 mg, and its purity estimated by LCMS analysis was 96%.

[002781] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 907.6 (M+2H).

[002782] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 908.0 (M+2H).

[002783] ESI-HRMS(+) m/z: Calculated: 907.4266 (M+2H); Found: 907.4237 (M+2H). Preparation of Example 3207 Example 3207

[002784] Example 3207 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002785] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002786] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-65% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 16.3 mg, and its purity estimated by LCMS analysis was 95%.

[002787] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 867.1 (M+2H).

[002788] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 867.2 (M+2H).

[002789] ESI-HRMS(+) m/z: Calculated: 866.4394 (M+2H); Found: 866.4367 (M+2H). Preparation of Example 3208 Example 3208

[002790] Example 3208 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002791] The crude material was purified via preparatory LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 40-95% B over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3208-A and isomer 3208-B) were obtained. The yield of product s isomer 3208-A and isomer 3208-B was 1.68 mg and 1.47 mg respectively, and their estimated purity were 97% and 99%, respectively, by HPLC "Analysis Condition B" using a gradient from 35% to 85% buffer B over 25 min.

[002792] LCMS Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 954.7 (M+2H)for isomer 3208-A and 1.50 min; ESI-MS(+) m/z 954.3 (M+2H)for isomer 3208-B.

[002793] ESI-HRMS(+) m/z for isomer 3208-A: Calculated: 953.9473 (M+2H); Found: 953.9456 (M+2H). Preparation of Example 3209 Example 3209

[002794] Example 3209 was prepared by following the general synthesis sequence described for the preparation of Example 3078, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “Custom Amino Acid Coupling Procedure”, “CEM Method A: Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002795] The crude material was purified via preparative LC/MS with the following conditions: Column: FENOMENEX® Luna 20x250 5μ particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: Acetonitrile with 0.05% TFA; Gradient: 40-95% B over 50 minutes, then a 5-minute hold at 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. Two isomers (isomer 3209-A and isomer 3209-B) were obtained. The yield of isomer 3209-A and isomer 3209-B products was 2.35 mg and 3.2 mg, respectively, and their estimated purity was 96% and 99%, respectively, by HPLC "Analysis Condition B" using a gradient from 35% to 85% buffer B over 25 min.

[002796] LCMS Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 981.7 (M+2H)for isomer 3209-A and 1.54 min; ESI-MS(+) m/z 981.4 (M+2H)for isomer 3209-B.

[002797] ESI-HRMS(+) m/z for isomer 3209-A: Calculated: 980.9332 (M+2H); Found: 980.9318 (M+2H). Preparation of Example 3500 Example 3500

[002798] Example 3500 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002799] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002800] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 23.2 mg, and its estimated purity by HPLC analysis was 100% using the general "Analysis Conditions B" 35-95% for 30 minutes.

[002801] LCMS Analysis Condition C: Retention time = 1.64 min; ESI-MS(+) m/z 1855.5 (M+H). Preparation of Example 3501 Example 3501

[002802] Example 3501 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002803] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002804] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 22.3 mg, and its estimated purity by HPLC analysis was 97.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002805] LCMS Analysis Condition C: Retention time = 1.35 min; ESI-MS(+) m/z 1838.7 (M+H). Preparation of Example 3502 Example 3502

[002806] Example 3502 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002807] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002808] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 33.4 mg, and its estimated purity by HPLC analysis was 96.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002809] LCMS Analysis Condition C: Retention time = 1.67 min; ESI-MS(+) m/z 1811.7 (M+H). Preparation of Example 3503 Example 3503

[002810] Example 3503 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002811] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002812] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 19.4 mg, and its estimated purity by HPLC analysis was 96.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002813] LCMS Analysis Condition C: Retention time = 1.62 min; ESI-MS(+) m/z 1861.9 (M+H). Preparation of Example 3504 Example 3504

[002814] Example 3504 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002815] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002816] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 13.6 mg, and its estimated purity by HPLC analysis was 98.9% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 300A 150x4.6mm (575289-17); Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 30-95% B over 30 minutes.; Flow rate: 1 mL/min. UV detection: 217 nM.

[002817] LCMS Analysis Condition C: Retention time = 1.53 min; ESI-MS(+) m/z 1798.6 (M+H). Preparation of Example 3505 Example 3505

[002818] Example 3505 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002819] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002820] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-55% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 18.4 mg, and its estimated purity by HPLC analysis was 97.2% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002821] LCMS Analysis Condition C: Retention time = 1.77 min; ESI-MS(+) m/z 1748.0 (M+H). Preparation of Example 3506 Example 3506

[002822] Example 3506 was prepared following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002823] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002824] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 3.4 mg, and its estimated purity by HPLC analysis was 99.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002825] LCMS Analysis Condition C: Retention time = 1.38 min; ESI-MS(+) m/z 1790.9 (M+H). Preparation of Example 3507 Example 3507

[002826] Example 3507 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002827] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002828] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 45 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 14.3 mg, and its estimated purity by HPLC analysis was 100% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002829] LCMS Analysis Condition C: Retention time = 1.38 min; ESI-MS(+) m/z 1764.0 (M+H). Preparation of Example 3508 Example 3508

[002830] Example 3508 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002831] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002832] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 8.7 mg, and its estimated purity by HPLC analysis was 93% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002833] LCMS Analysis Condition C: Retention time = 1.36 min; ESI-MS(+) m/z 1841.1 (M+H). Preparation of Example 3509 Example 3509

[002834] Example 3509 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002835] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002836] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 45 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 9.5 mg, and its estimated purity by HPLC analysis was 98.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002837] LCMS Analysis Condition C: Retention time = 1.61 min; ESI-MS(+) m/z 1813.8 (M+H). Preparation of Example 3510 Example 3510

[002838] Example 3510 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002839] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002840] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 7.1 mg, and its estimated purity by HPLC analysis was 99.6% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002841] Analysis Condition A: Retention time = 1.29 min; ESI-MS(+) m/z 941.9 (M+2H). Preparation of Example 3511 Example 3511

[002842] Example 3511 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002843] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002844] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 5.0 mg, and its estimated purity by HPLC analysis was 83% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002845] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 952.4 (M+2H). Preparation of Example 3512 Example 3512

[002846] Example 3512 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002847] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002848] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 45 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 29.7 mg, and its estimated purity by HPLC analysis was 99.2% using general “Analysis Conditions B” 35-80% for 30 minutes.

[002849] LCMS Analysis Condition C: Retention time = 1.72 min; ESI-MS(+) m/z 1869.9 (M+H).

[002850] LCMS Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 935.3 (M+2H). Preparation of Example 3513 Example 3513

[002851] Example 3513 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002852] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002853] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 7.1 mg, and its estimated purity by HPLC analysis was 87% using general “Analysis Conditions B” 35-80% for 30 minutes.

[002854] Analysis Condition A: Retention time = 1.27 min; ESI-MS(+) m/z 894.2 (M+2H). Preparation of Example 3514 Example 3514

[002855] Example 3514 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002856] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002857] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 5.0 mg, and its estimated purity by HPLC analysis was 90% using general “Analysis Conditions B” 35-80% for 30 minutes.

[002858] Analysis Condition A: Retention time = 1.34 min; ESI-MS(+) m/z 905.8 (M+2H). Preparation of Example 3515 Example 3515

[002859] Example 3515 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002860] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002861] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 5.6 mg, and its estimated purity by HPLC analysis was 99% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002862] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 904.8 (M+2H). Preparation of Example 3516 Example 3516

[002863] Example 3516 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002864] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002865] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 1.8 mg, and its estimated purity by HPLC analysis was 89% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1); Gradient: 30-95% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[002866] LCMS Analysis Condition C: Retention time = 1.87 min; ESI-MS(+) m/z 1812.1 (M+H). Preparation of Example 3517 Example 3517

[002867] Example 3517 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002868] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C". Prefilled Fmoc-Gly-Trityl resin was used in place of Seiber resin.

[002869] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 5.6 mg, and its estimated purity by HPLC analysis was 95% using general “Analysis Conditions B” 30-80% for 30 minutes.

[002870] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 899.8 (M+2H). Preparation of Example 3518 Example 3518

[002871] Example 3518 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002872] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002873] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 2.8 mg, and its estimated purity by HPLC analysis was 82% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002874] LCMS Analysis Condition C: Retention time = 1.53 min; ESI-MS(+) m/z 1772.7 (M+H). Preparation of Example 3519 Example 3519

[002875] Example 3519 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002876] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002877] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 15.7 mg, and its estimated purity by HPLC analysis was 96% using general “Analysis Conditions B” 35-95% for 30 minutes.

[002878] LCMS Analysis Condition C: Retention time = 1.68 min; ESI-MS(+) m/z 1847.4 (M+H). Preparation of Example 3520 Example 3520

[002879] Example 3520 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002880] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002881] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.9 mg, and its purity estimated by LCMS analysis was 100%.

[002882] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 907.9 (M+2H). Preparation of Example 3522 Example 3522

[002883] Example 3522 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002884] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002885] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 13.2 mg, and its purity estimated by LCMS analysis was 93.5%.

[002886] LCMS Analysis Condition E: Retention time = 1.61 min; ESI-MS(+) m/z 937.8 (M+2H). Preparation of Example 3523 Example 3523

[002887] Example 3523 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002888] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002889] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 14.4 mg, and its purity estimated by LCMS analysis was 99.5%.

[002890] LCMS Analysis Condition E: Retention time = 1.58 min; ESI-MS(+) m/z 906.4 (M+2H). Preparation of Example 3524 Example 3524

[002891] Example 3524 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002892] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002893] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 12.7 mg, and its purity estimated by LCMS analysis was 100.0%.

[002894] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 905.4 (M+2H). Preparation of Example 3525 Example 3525

[002895] Example 3525 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002896] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002897] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.3 mg, and its purity estimated by LCMS analysis was 96.4%.

[002898] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 899.0 (M+2H). Preparation of Example 3526 Example 3526

[002899] Example 3526 was prepared following the general synthesis sequence described below.

[002900] To a 50 mL polypropylene tube was added Sieber resin (140 mg, 0.100 mmol), and the tube was placed on the CEM Liberty microwave peptide synthesizer. The following procedures were then performed in sequence: “CEM Method A: Resin swelling procedure” was followed; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Gly-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Cys(Trt)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Leu-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Tyr(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Tyr(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Sar-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Tyr(tBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-[N-Me]Phe-OH; “CEM Method A: Custom amino acid coupling procedure” was followed with Fmoc-Val-OH using 10 eq. for 2 h at 75 °C; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Asp(OtBu)-OH; “CEM Method A: Standard coupling procedure” was followed with Fmoc-Sar-OH; “CEM Method A: Custom Amino Acid Coupling Procedure” was followed with Fmoc-[N-Me]Nle-OH using 5 eq. for 10 min; “CEM Method A: Custom Amino Acid Coupling Procedure” was followed with Fmoc-[N-Me]Phe-OH using 5 eq. for 10 min; “CEM Method A: Standard Coupling Procedure” was followed with Fmoc-Phe-OH using 5 eq. for 10 min; “Prelude Method A: Chloroacetyl Chloride Coupling Procedure A” was followed, “Global Deprotection Method B” was followed, and “Cyclization Method C” was followed.

[002901] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 12.9 mg, and its purity estimated by LCMS analysis was 97.8%.

[002902] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 887.5 (M+2H). Preparation of Example 3527 Example 3527

[002903] Example 3527 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002904] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002905] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.8 mg, and its estimated purity by LCMS analysis was 95.0%.

[002906] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 928.0 (M+2H).

[002907] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 928.2 (M+2H). Preparation of Example 3528 Example 3528

[002908] Example 3528 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002909] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002910] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.3 mg, and its purity estimated by LCMS analysis was 100.0%.

[002911] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 906.3 (M+2H).

[002912] LCMS Analysis Condition E: Retention time = 1.95 min; ESI-MS(+) m/z 906.0 (M+2H). Preparation of Example 3529 Example 3529

[002913] Example 3529 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002914] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002915] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.7 mg, and its purity estimated by LCMS analysis was 100.0%.

[002916] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 906.5 (M+2H).

[002917] LCMS Analysis Condition E: Retention time = 1.96 min; ESI-MS(+) m/z 906.0 (M+2H). Preparation of Example 3531 Example 3531

[002918] Example 3531 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002919] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002920] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.6 mg, and its purity estimated by LCMS analysis was 95.7%.

[002921] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 911.6 (M+2H).

[002922] LCMS Analysis Condition E: Retention time = 1.68 min; ESI-MS(+) m/z 911.4 (M+2H). Preparation of Example 3532 Example 3532

[002923] Example 3532 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[002924] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002925] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.9 mg, and its purity estimated by LCMS analysis was 95.7%.

[002926] LCMS Analysis Condition D: Retention time = 1.47 min; ESI-MS(+) m/z 921.3 (M+2H).

[002927] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 920.9 (M+2H). Preparation of Example 3533 Example 3533

[002928] Example 3533 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002929] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.41 mg, and its purity estimated by LCMS analysis was 100.0%.

[002930] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 920.7 (M+2H).

[002931] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 920.7 (M+2H). Preparation of Example 3534 Example 3534

[002932] Example 3534 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002933] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.72 mg, and its purity estimated by LCMS analysis was 100.0%.

[002934] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 890.7 (M+2H).

[002935] LCMS Analysis Condition E: Retention time = 1.94 min; ESI-MS(+) m/z 890.5 (M+2H). Preparation of Example 3535 Example 3535

[002936] Example 3535 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002937] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.81 mg, and its purity estimated by LCMS analysis was 99.3%.

[002938] LCMS Analysis Condition E: Retention time = 2.03 min; ESI-MS(+) m/z 916.1 (M+2H). Preparation of Example 3536 Example 3536

[002939] Example 3536 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002940] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.61 mg, and its purity estimated by LCMS analysis was 94.2%.

[002941] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 930.1 (M+2H).

[002942] LCMS Analysis Condition E: Retention time = 1.71 min; ESI-MS(+) m/z 930.2 (M+2H). Preparation of Example 3537 Example 3537

[002943] Example 3537 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002944] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.81 mg, and its estimated purity by LCMS analysis was 91.1%.

[002945] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 915.7 (M+2H).

[002946] LCMS Analysis Condition E: Retention time = 1.84 min; ESI-MS(+) m/z 915.8 (M+2H). Preparation of Example 3538 Example 3538

[002947] Example 3538 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002948] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.91 mg, and its purity estimated by LCMS analysis was 95.8%.

[002949] LCMS Analysis Condition D: Retention time = 1.82 min; ESI-MS(+) m/z 916.0 (M+2H).

[002950] LCMS Analysis Condition E: Retention time = 2.05 min; ESI-MS(+) m/z 915.9 (M+2H). Preparation of Example 3539 Example 3539

[002951] Example 3539 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002952] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.52 mg, and its purity estimated by LCMS analysis was 91.2%.

[002953] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 910.5 (M+2H).

[002954] LCMS Analysis Condition E: Retention time = 1.90 min; ESI-MS(+) m/z 910.4 (M+2H). Preparation of Example 3540 Example 3540

[002955] Example 3540 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002956] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.52 mg, and its purity estimated by LCMS analysis was 93.2%.

[002957] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 890.7 (M+2H).

[002958] LCMS Analysis Condition E: Retention time = 1.95 min; ESI-MS(+) m/z 890.8 (M+2H). Preparation of Example 3541 Example 3541

[002959] Example 3541 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002960] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.41 mg, and its estimated purity by LCMS analysis was 91.7%.

[002961] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 921.2 (M+2H).

[002962] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 921.2 (M+2H). Preparation of Example 3542 Example 3542

[002963] Example 3542 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002964] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 93.2%.

[002965] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 903.2 (M+2H).

[002966] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 903.1 (M+2H). Preparation of Example 3543 Example 3543

[002967] Example 3543 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002968] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.71 mg, and its purity estimated by LCMS analysis was 100.0%.

[002969] LCMS Analysis Condition D: Retention time = 1.71 min; ESI-MS(+) m/z 923.3 (M+2H).

[002970] LCMS Analysis Condition E: Retention time = 1.95 min; ESI-MS(+) m/z 923.0 (M+2H). Preparation of Example 3544 Example 3544

[002971] Example 3544 was prepared following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[002972] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 2.3 mg, and its purity estimated by LCMS analysis was 98.9%.

[002973] LCMS Analysis Condition D: Retention time = 1.51 min; ESI-MS(+) m/z 896.4 (M+2H).

[002974] LCMS Analysis Condition E: Retention time = 1.64 min; ESI-MS(+) m/z 896.3 (M+2H). Preparation of Example 3545 Example 3545

[002975] Example 3545 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002976] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002977] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.4 mg, and its purity estimated by LCMS analysis was 96.5%.

[002978] LCMS Analysis Condition D: Retention time = 1.80 min; ESI-MS(+) m/z 917.4 (M+2H).

[002979] LCMS Analysis Condition E: Retention time = 2.01 min; ESI-MS(+) m/z 917.4 (M+2H). Preparation of Example 3546 Example 3546

[002980] Example 3546 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002981] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002982] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 12.5 mg, and its purity estimated by LCMS analysis was 98.4%.

[002983] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 896.7 (M+2H).

[002984] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 897.2 (M+2H). Preparation of Example 3547 Example 3547

[002985] Example 3547 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002986] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002987] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 12.5 mg, and its purity estimated by LCMS analysis was 95.5%.

[002988] LCMS Analysis Condition D: Retention time = 1.88 min; ESI-MS(+) m/z 928.9 (M+2H).

[002989] LCMS Analysis Condition E: Retention time = 2.12 min; ESI-MS(+) m/z 928.9 (M+2H). Preparation of Example 3548 Example 3548

[002990] Example 3548 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002991] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002992] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.7 mg, and its purity estimated by LCMS analysis was 99.1%.

[002993] LCMS Analysis Condition D: Retention time = 1.62 min; ESI-MS(+) m/z 894.2 (M+2H).

[002994] LCMS Analysis Condition E: Retention time = 1.85 min; ESI-MS(+) m/z 894.2 (M+2H). Preparation of Example 3549 Example 3549

[002995] Example 3549 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[002996] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[002997] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 8.41 mg, and its estimated purity by LCMS analysis was 99.2%.

[002998] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 913.5 (M+2H).

[002999] LCMS Analysis Condition E: Retention time = 1.99 min; ESI-MS(+) m/z 913.6 (M+2H). Preparation of Example 3550 Example 3550

[003000] Example 3550 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[003001] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003002] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 13.72 mg, and its estimated purity by LCMS analysis was 97.6%.

[003003] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 913.3 (M+2H).

[003004] LCMS Analysis Condition E: Retention time = 1.95 min; ESI-MS(+) m/z 913.5 (M+2H). Preparation of Example 3551 Example 3551

[003005] Example 3551 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003006] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.82 mg, and its purity estimated by LCMS analysis was 93.7%.

[003007] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 905.6 (M+2H).

[003008] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 905.9 (M+2H). Preparation of Example 3552 Example 3552

[003009] Example 3552 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003010] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.61 mg, and its purity estimated by LCMS analysis was 95.2%.

[003011] LCMS Analysis Condition D: Retention time = 1.40 min; ESI-MS(+) m/z 920.7 (M+2H).

[003012] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 920.8 (M+2H). Preparation of Example 3553 Example 3553

[003013] Example 3553 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003014] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.22 mg, and its purity estimated by LCMS analysis was 97.7%.

[003015] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 906.3 (M+2H).

[003016] LCMS Analysis Condition E: Retention time = 1.89 min; ESI-MS(+) m/z 905.7 (M+2H). Preparation of Example 3555 Example 3555

[003017] Example 3555 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[003018] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003019] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.82 mg, and its purity estimated by LCMS analysis was 93.2%.

[003020] LCMS Analysis Condition D: Retention time = 1.38 min; ESI-MS(+) m/z 892.4 (M+2H).

[003021] LCMS Analysis Condition E: Retention time = 1.51 min; ESI-MS(+) m/z 892.6 (M+2H). Preparation of Example 3556 Example 3556

[003022] Example 3556 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[003023] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003024] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.02 mg, and its estimated purity by LCMS analysis was 91.0%.

[003025] LCMS Analysis Condition D: Retention time = 1.41 min; ESI-MS(+) m/z 892.3 (M+2H).

[003026] LCMS Analysis Condition E: Retention time = 1.50 min; ESI-MS(+) m/z 892.1 (M+2H). Preparation of Example 3557 Example 3557

[003027] Example 3557 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003028] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003029] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 5.3 mg, and its estimated purity by HPLC analysis was 83% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1); Gradient: 25–75% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003030] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 907.9 (M+2H).

[003031] LCMS Analysis Condition C: Retention time = 1.73 min; ESI-MS(+) m/z 1815.0 (M+H). Preparation of Example 3558 Example 3558

[003032] Example 3558 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003033] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003034] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 1.8 mg, and its estimated purity by HPLC analysis was 96% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1); Gradient: 25–75% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003035] Analysis Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 919.5 (M+2H) LCMS Analysis Condition C: Retention time = 1.88 min; ESI-MS(+) m/z 1837.1 (M+H). Preparation of Example 3559 Example 3559

[003036] Example 3559 was prepared by following the general synthetic sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Double Pair Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003037] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 3.5 mg, and its estimated purity by HPLC analysis was 89% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 25-55% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003038] LCMS Analysis Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 919.5 (M+2H).

[003039] LCMS Analysis Condition C: Retention time = 1.88 min; ESI-MS(+) m/z 1837.1 (M+H). Preparation of Example 3560 Example 3560

[003040] Example 3560 was prepared following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003041] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 20.72 mg, and its estimated purity by LCMS analysis was 99.0%.

[003042] LCMS Analysis Condition D: Retention time = 1.78 min; ESI-MS(+) m/z 912.2 (M+2H).

[003043] LCMS Analysis Condition E: Retention time = 2.01 min; ESI-MS(+) m/z 912.2 (M+2H). Preparation of Example 3561 Example 3561

[003044] Example 3561 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003045] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 16.3 mg, and its purity estimated by LCMS analysis was 94%.

[003046] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 890.8 (M+2H).

[003047] LCMS Analysis Condition E: Retention time = 1.72 min; ESI-MS( +) m/z 890.7 (M+2H). Preparation of Example 3562 Example 3562

[003048] Example 3562 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003049] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.6 mg, and its purity estimated by LCMS analysis was 94.9%.

[003050] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 911.8 (M+2H).

[003051] LCMS Analysis Condition E: Retention time = 1.81 min; ESI-MS(+) m/z 912.0 (M+2H). Preparation of Example 3563 Example 3563

[003052] Example 3563 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003053] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 11.6 mg, and its purity estimated by LCMS analysis was 95.9%.

[003054] LCMS Analysis Condition D: Retention time = 1.54 min; ESI-MS(+) m/z 899.1 (M+2H).

[003055] LCMS Analysis Condition E: Retention time = 1.76 min; ESI-MS(+) m/z 898.8 (M+2H). Preparation of Example 3564 Example 3564

[003056] Example 3564 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003057] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 95.4%.

[003058] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS(+) m/z 898.9 (M+2H).

[003059] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 898.8 (M+2H). Preparation of Example 3565 Example 3565

[003060] Example 3565 was prepared following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003061] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 15.2 mg, and its purity estimated by LCMS analysis was 95.8%.

[003062] LCMS Analysis Condition D: Retention time = 1.50 min; ESI-MS(+) m/z 890.8 (M+2H).

[003063] LCMS Analysis Condition E: Retention time = 1.73 min; ESI-MS(+) m/z 891.2 (M+2H). Preparation of Example 3566 Example 3566

[003064] Example 3566 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003065] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.56 mg, and its purity estimated by LCMS analysis was 100.0%.

[003066] LCMS Analysis Condition D: Retention time = 1.70 min; ESI-MS(+) m/z 906.2 (M+2H).

[003067] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 906.2 (M+2H). Preparation of Example 3567 Example 3567

[003068] Example 3567 was prepared following the general synthetic sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-chloro-4-fluorophenyl)propanoic acid was used.

[003069] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 40-85% B over 35 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 9.82 mg, and its estimated purity by HPLC analysis was 98.8% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 25-55% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003070] LCMS Analysis Condition C: Retention time = 1.88 min; ESI-MS(+) m/z 1849.9 (M+H). Preparation of Example 3568 Example 3568

[003071] Example 3568 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin swelling procedure”, “CEM Method A: Standard coupling procedure”, “CEM Method A: Custom amino acid coupling procedure”, “Chloroacetyl chloride coupling procedure A”, “Global deprotection method B”, and “Cyclization method C”.

[003072] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 40-85% B over 35 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 8.08 mg, and its estimated purity by HPLC analysis was 98.8% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 25-55% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003073] LCMS Analysis Condition C: Retention time = 1.81 min; ESI-MS(+) m/z 1815.0 (M+H). Preparation of Example 3569 Example 3569

[003074] Example 3569 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003075] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003076] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 16.3 mg, and its purity estimated by LCMS analysis was 96%.

[003077] LCMS Analysis Condition D: Retention time = 1.83 min; ESI-MS(+) m/z 916.9 (M+2H).

[003078] LCMS Analysis Condition E: Retention time = 1.86 min; ESI-MS(+) m/z 917.3 (M+2H). Preparation of Example 3570 Example 3570

[003079] Example 3570 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003080] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003081] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 27.0 mg, and its estimated purity by LCMS analysis was 97%.

[003082] LCMS Analysis Condition D: Retention time = 1.60 min; ESI-MS(+) m/z 900.8 (M+2H).

[003083] LCMS Analysis Condition E: Retention time = 1.78 min; ESI-MS(+) m/z 900.8 (M+2H). Preparation of Example 3571 Example 3571

[003084] Example 3571 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003085] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003086] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 25.0 mg, and its purity estimated by LCMS analysis was 95%.

[003087] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 900.7 (M+2H).

[003088] LCMS Analysis Condition E: Retention time = 1.76 min; ESI-MS(+) m/z 900.9 (M+2H). Preparation of Example 3572 Example 3572

[003089] Example 3572 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003090] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003091] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 16.01 mg, and its estimated purity by LCMS analysis was 90.8%.

[003092] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 919.4 (M+2H).

[003093] LCMS Analysis Condition E: Retention time = 1.90 min; ESI-MS(+) m/z 918.9 (M+2H). Preparation of Example 3573 Example 3573

[003094] Example 3573 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003095] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003096] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 9.71 mg, and its purity estimated by LCMS analysis was 92.4%.

[003097] LCMS Analysis Condition D: Retention time = 1.76 min; ESI-MS(+) m/z 919.0 (M+2H).

[003098] LCMS Analysis Condition E: Retention time = 1.96 min; ESI-MS(+) m/z 919.3 (M+2H). Preparation of Example 3574 Example 3574

[003099] Example 3574 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003100] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003101] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 16.8 mg, and its estimated purity by HPLC analysis was 94.1% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1); Gradient: 2555% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003102] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 925.0 (M+2H). LCMS Analysis Condition C: Retention time = 1.89 min; ESI-MS(+) m/z 1848.5 (M+H). Preparation of Example 3575 Example 3575

[003103] Example 3575 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003104] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003105] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The yield of the product was 19.7 mg, and its estimated purity by HPLC analysis was 94.1% using "Analysis Condition B"; Gradient: 30-75% B over 30 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003106] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 920.0 (M+2H). LCMS Analysis Condition C: Retention time = 1.76 min; ESI-MS(+) m/z 1839.3 (M+H). Preparation of Example 3576 Example 3576

[003107] Example 3576 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003108] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003109] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.70 mg, and its purity estimated by LCMS analysis was 97.0%.

[003110] LCMS Analysis Condition D: Retention time = 1.61 min; ESI-MS(+) m/z 919.8 (M+2H).

[003111] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 919.8 (M+2H).Preparation of Example 3577 Example 3577

[003112] Example 3577 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003113] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003114] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.92 mg, and its purity estimated by LCMS analysis was 91.3%.

[003115] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 905.2 (M+2H).

[003116] LCMS Analysis Condition E: Retention time = 1.84 min; ESI-MS(+) m/z 904.8 (M+2H).Preparation of Example 3578 Example 3578

[003117] Example 3578 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003118] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003119] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.21 mg, and its purity estimated by LCMS analysis was 100.0%.

[003120] LCMS Analysis Condition D: Retention time = 1.65 min; ESI-MS(+) m/z 919.1 (M+2H).

[003121] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 919.0 (M+2H).Preparation of Example 3579 Example 3579

[003122] Example 3579 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003123] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.52 mg, and its purity estimated by LCMS analysis was 99.1%.

[003124] LCMS Analysis Condition D: Retention time = 1.64 min; ESI-MS(+) m/z 906.8 (M+2H).

[003125] LCMS Analysis Condition E: Retention time = 1.82 min; ESI-MS(+) m/z 907.3 (M+2H).Preparation of Example 3580 Example 3580

[003126] Example 3580 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[003127] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003128] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.81 mg, and its purity estimated by LCMS analysis was 96.1%.

[003129] LCMS Analysis Condition D: Retention time = 1.84 min; ESI-MS(+) m/z 919.2 (M+2H).

[003130] LCMS Analysis Condition E: Retention time = 2.06 min; ESI-MS(+) m/z 919.4 (M+2H).Preparation of Example 3581 Example 3581

[003131] Example 3581 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003132] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003133] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 28.22 mg, and its purity estimated by LCMS analysis was 94.4%.

[003134] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 901.2 (M+2H).

[003135] LCMS Analysis Condition E: Retention time = 1.85 min; ESI-MS(+) m/z 901.3 (M+2H).Preparation of Example 3582 Example 3582

[003136] Example 3582 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetyl Chloride Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003137] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 26.6 mg, and its purity estimated by LCMS analysis was 96.8%.

[003138] LCMS Analysis Condition D: Retention time = 1.58 min; ESI-MS(+) m/z 904.7 (M+2H).

[003139] LCMS Analysis Condition E: Retention time = 1.80 min; ESI-MS(+) m/z 904.8 (M+2H).Preparation of Example 3583 Example 3583

[003140] Example 3583 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003141] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 14.60 mg, and its purity estimated by LCMS analysis was 98.8%.

[003142] LCMS Analysis Condition D: Retention time = 1.57 min; ESI-MS(+) m/z 919.8 (M+2H).Preparation of Example 3584 Example 3584

[003143] Example 3584 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003144] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 50 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 3.06 mg, and its estimated purity by HPLC analysis was 95.4% using the following conditions: Column: FENOMENEX® Kinetex 2.6μ C18(2) 2.1 x 50mm Ser. #515561-57; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1); Gradient: 2555% B over 20 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 60 °C.

[003145] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 919.0 (M+2H).

[003146] LCMS Analysis Condition C: Retention time = 1.71 min; ESI-MS(+) m/z 1837.1 (M+H).Preparation of Example 3585 Example 3585

[003147] Example 3585 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003148] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003149] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. Two isomeric products were isolated: Isomer A and B.

[003150] The yield of isomer A was 1.70 mg, and its estimated purity by HPLC analysis was 100.0% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile: 30-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003151] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 923.0 (M+2H). LCMS Analysis Condition C: Retention time = 1.75 min; ESI-MS(+) m/z 1845.1 (M+H).

[003152] The yield of isomer B was 2.18 mg, and its estimated purity by HPLC analysis was 92.8% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile: 35-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003153] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 923.9 (M+2H).

[003154] LCMS Analysis Condition C: Retention time = 1.77 min; ESI-MS(+) m/z 1847.9 (M+H). Preparation of Example 3586 Example 3586

[003155] Example 3586 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003156] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003157] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 4.79 mg, and its estimated purity by HPLC analysis was 96.6% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile: 35-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003158] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 916.9 (M+2H). LCMS Analysis Condition C: Retention time = 1.71 min; ESI-MS(+) m/z 1832.9 (M+H). Preparation of Example 3588 Example 3588

[003159] Example 3588 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003160] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003161] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 95% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 3.19 mg, and its estimated purity by HPLC analysis was 91.9% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.025% ammonium acetate in 5% methanol/water; Mobile phase B: Acetonitrile/water (4:1): 30-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003162] Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 920.0 (M+2H).

[003163] LCMS Analysis Condition C: Retention time = 1.65 min; ESI-MS(+) m/z 1838.3 (M+H). Preparation of Example 3589 Example 3589

[003164] Example 3589 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003165] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003166] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.31 mg, and its purity estimated by LCMS analysis was 98.3%.

[003167] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 91 A (M+2H).

[003168] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 973.7 (M+2H). Preparation of Example 3590 Example 3590

[003169] Example 3590 was prepared by following the general synthesis sequence described for the preparation of Example 72, consisting of the following general procedures:

[003170] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003171] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.60 mg, and its purity estimated by LCMS analysis was 95.7%.

[003172] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 967.3 (M+2H).

[003173] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 966 (M+2H). Preparation of Example 3591 Example 3591

[003174] Example 3591 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003175] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003176] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 10.21 mg, and its purity estimated by LCMS analysis was 100.0%.

[003177] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 973.8 (M+2H).

[003178] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 973.9 (M+2H). Preparation of Example 3592 Example 3592

[003179] Example 3592 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003180] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003181] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.40 mg, and its purity estimated by LCMS analysis was 93.2%.

[003182] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 966.8 (M+2H).

[003183] LCMS Analysis Condition E: Retention time = 1.92 min; ESI-MS(+) m/z 966.9 (M+2H). Preparation of Example 3593 Example 3593

[003184] Example 3593 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003185] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 7.80 mg, and its purity estimated by LCMS analysis was 98.0%.

[003186] LCMS Analysis Condition D: Retention time = 1.49 min; ESI-MS(+) m/z 962.2 (M+2H).

[003187] LCMS Analysis Condition E: Retention time = 1.59 min; ESI-MS(+) m/z 962.2 (M+2H). Preparation of Example 3594 Example 3594

[003188] Example 3594 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003189] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 2.08 mg, and its estimated purity by HPLC analysis was 89.3% using “Analysis Conditions B"; 30-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003190] Analysis Condition A: Retention time = 1.29 min; ESI-MS(+) m/z 1925.6 (M+H) LCMS Analysis Condition C: Retention time = 1.32 min; ESI-MS(+) m/z 1924.4 (M+H).

[003191] ESI-HRMS(+) m/z: Calculated: 962.4605 (M+2H); Found: 962.45821 (M+2H). Preparation of Example 3595 Example 3595

[003192] Example 3595 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003193] The crude material was purified via preparative HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The yield of the product was 3.39 mg, and its estimated purity by HPLC analysis was 100% using "Analysis Conditions B"; 35-75% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM, Oven: 40 °C.

[003194] Analysis Condition A: Retention time = 1.67 min; ESI-MS(+) m/z 1925.4 (M(-Trt)+H).

[003195] LCMS Analysis Condition C: Retention time = 1.69 min; ESI-MS(+) m/z 1927.6 (M(-Trt)+H).

[003196] ESI-HRMS(+) m/z: Calculated: 1083.5153 (M+2H); Found: 1083.51169 (M+2H). Preparation of Example 3596 Example 3596

[003197] Example 3596 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003198] The crude material was purified via preparatory HPLC under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 2.52 mg, and its purity estimated by HPLC analysis was 90.6% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile: 35-60% B for 25 min.; Flow rate: 1 mL/min. UV detection: 217 nM.

[003199] Analysis Condition A: Retention time = 1.35 min; ESI-MS(+) m/z 1978.3 (M+H). LCMS Analysis Condition C: Retention time = 1.39 min; ESI-MS(+) m/z 1979.4 (M+H). Preparation of Example 3597 Example 3597

[003200] Example 3597 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003201] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. Two isomeric products were isolated.

[003202] The yield of isomer A was 3.40 mg, and its purity estimated by LCMS analysis was 98.9%.

[003203] LCMS Analysis Condition D: Retention time = 1.53 min; ESI-MS(+) m/z 920.0 (M+2H).

[003204] LCMS Analysis Condition E: Retention time = 1.54 min; ESI-MS(+) m/z 920.4 (M+2H).

[003205] The yield of isomer B was 4.50 mg, and its purity estimated by LCMS analysis was 98.4%.

[003206] LCMS Analysis Condition D: Retention time = 1.72 min; ESI-MS(+) m/z 920.5 (M+2H).

[003207] LCMS Analysis Condition E: Retention time = 1.74 min; ESI-MS(+) m/z 920.2 (M+2H). Preparation of Example 3598 Example 3598

[003208] Example 3598 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003209] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.45 mg, and its purity estimated by LCMS analysis was 95.7%.

[003210] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 944.0 (M+2H).

[003211] LCMS Analysis Condition E: Retention time = 1.65 min; ESI-MS(+) m/z 943 (M+2H). Preparation of Example 3599 Example 3599

[003212] Example 3599 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003213] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.01 mg, and its estimated purity by LCMS analysis was 92.7%.

[003214] LCMS Analysis Condition D: Retention time = 1.63 min; ESI-MS(+) m/z 951.7 (M+2H).

[003215] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 951.7 (M+2H). Preparation of Example 3600 Example 3600

[003216] Example 3600 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003217] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.40 mg, and its purity estimated by LCMS analysis was 95.4%.

[003218] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 921.2 (M+2H).

[003219] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 920.6 (M+2H). Preparation of Example 3601 Example 3601

[003220] Example 3601 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003221] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 5.30 mg, and its purity estimated by LCMS analysis was 96.0%.

[003222] LCMS Analysis Condition D: Retention time = 1.66 min; ESI-MS(+) m/z 920.8 (M+2H).

[003223] LCMS Analysis Condition E: Retention time = 1.87 min; ESI-MS(+) m/z 920.9 (M+2H). Preparation of Example 3602 Example 3602

[003224] Example 3602 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003225] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003226] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 35 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 0.99 mg, and its estimated purity by HPLC analysis was 96% using the following conditions: Column: YMC Pack ODS-AQ 3 μm 150 x; Mobile phase A: 0.025 ammonium acetate/acetonitrile (8:2); Mobile phase B: 0.025% ammonium acetate/acetonitrile (2:8): 30-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM. Oven 40 °C.

[003227] LCMS Analysis Condition C: Retention time = 1.35 min; ESI-MS(+) m/z 1783.0 (M+H).

[003228] Analysis Condition A: Retention time = 1.27 min; ESI-MS(+) m/z 1783.8 (M+H). Preparation of Example 3603 Example 3603

[003229] Example 3603 was prepared by following the general synthetic sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “On-Resin N-Methylation Procedure” for the N-methylation of Fmoc-2-Nal-OH, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003230] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 0.89 mg, and its purity estimated by HPLC analysis was 100% using “Analysis Conditions C": 30-60% B for 15 min.; Flow rate: 1 mL/min. UV detection: 217 nM. Oven 40 °C.

[003231] LCMS Analysis Condition C: Retention time = 1.36 min; ESI-MS(+) m/z 1845.8 (M+H).

[003232] Analysis Condition A: Retention time = 1.33 min; ESI-MS(+) m/z 1847.5 (M+H). Preparation of Example 3604 Example 3604

[003233] Example 3604 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003234] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003235] The crude material was purified via preparative LC/MS under the following conditions: Column: FENOMENEX® Luna 5μ C18(2) 250 x 21.2 Axia, 100A Ser. #520221-1 ; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Gradient: 35-75% B over 40 min, then a 5 min gradient to 85% B; Flow rate: 15 mL/min. Fractions containing the desired product were combined and dried. The product was dissolved in a minimum of acetonitrile and water, frozen, and lyophilized to give a white amorphous solid. The product yield was 1.10 mg, and its purity estimated by HPLC analysis was 96% using the following conditions: Column: FENOMENEX® Jupiter 5μ C18 150 x 4.6mm 300A.; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile: 35-60% B for 25 min.; Flow rate: 1 mL/min. UV detection: 217 nM. Oven 40 °C.

[003236] LCMS Analysis Condition C: Retention time = 1.51 min; ESI-MS(+) m/z 1839.9 (M+H). Preparation of Example 3605 Example 3605

[003237] Example 3605 was prepared following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003238] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003239] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 6.50 mg, and its purity estimated by LCMS analysis was 93.8%.

[003240] LCMS Analysis Condition D: Retention time = 1.75 min; ESI-MS(+) m/z 950.5 (M+2H).

[003241] LCMS Analysis Condition E: Retention time = 1.77 min; ESI-MS(+) m/z 950.5 (M+2H). Preparation of Example 3606 Example 3606

[003242] Example 3606 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003243] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003244] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.07 mg, and its purity estimated by LCMS analysis was 92.5%.

[003245] LCMS Analysis Condition D: Retention time = 1.73 min; ESI-MS(+) m/z 967.4 (M+2H).

[003246] LCMS Analysis Condition E: Retention time = 1.75 min; ESI-MS(+) m/z 967.5 (M+2H). Preparation of Example 3607 Example 3607

[003247] Example 3607 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003248] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003249] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 3.8 mg, and its purity estimated by LCMS analysis was 96.2%.

[003250] LCMS Analysis Condition D: Retention time = 1.56 min; ESI-MS(+) m/z 943.3 (M+2H).

[003251] LCMS Analysis Condition E: Retention time = 1.61 min; ESI-MS(+) m/z 943.2 (M+2H). Preparation of Example 3608 Example 3608

[003252] Example 3608 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003253] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003254] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 1.49 mg, and its estimated purity by LCMS analysis was 91.1%.

[003255] LCMS Analysis Condition D: Retention time = 1.69 min; ESI-MS(+) m/z 950.6 (M+2H).

[003256] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 950.7 (M+2H).

[003257] ESI-HRMS(+) m/z: Calculated: 950.4230 (M+2H); Found: 950.4200 (M+2H). Preparation of Example 3609 Example 3609

[003258] Example 3609 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003259] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003260] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 0.39 mg, and its purity estimated by LCMS analysis was 91.5%.

[003261] LCMS Analysis Condition D: Retention time = 1.67 min; ESI-MS(+) m/z 934.1 (M+2H).

[003262] LCMS Analysis Condition E: Retention time = 1.86 min; ESI-MS(+) m/z 934.0 (M+2H).

[003263] ESI-HRMS(+) m/z: Calculated: 933.4146 (M+2H); Found: 933.4126 (M+2H). Preparation of Example 3610 Example 3610

[003264] Example 3610 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003265] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 14.79 mg, and its estimated purity by LCMS analysis was 96.0%.

[003266] LCMS Analysis Condition D: Retention time = 1.46 min; ESI-MS(+) m/z 892.0 (M+2H).

[003267] LCMS Analysis Condition E: Retention time = 1.40 min; ESI-MS(+) m/z 892.0 (M+2H).

[003268] ESI-HRMS(+) m/z: Calculated: 891.9267 (M+2H); Found: 891.9229 (M+2H). Preparation of Example 3611 Example 3611

[003269] Example 3611 was prepared by following the general synthesis sequence described for the preparation of Example 3026, consisting of the following general procedures: “CEM Method A: Resin Swelling Procedure”, “CEM Method A: Standard Coupling Procedure”, “CEM Method A: Custom Amino Acid Coupling Procedure”, “Chloroacetic Acid Coupling Procedure A”, “Global Deprotection Method B”, and “Cyclization Method C”.

[003270] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 25.53 mg, and its purity estimated by LCMS analysis was 100.0%.

[003271] LCMS Analysis Condition D: Retention time = 1.68 min; ESI-MS(+) m/z 929.7 (M+2H).

[003272] LCMS Analysis Condition E: Retention time = 1.70 min; ESI-MS(+) m/z 929.7 (M+2H).

[003273] ESI-HRMS(+) m/z: Calculated: 929.4447 (M+2H); Found: 929.4428 (M+2H). Preparation of Example 3613 Example 3613

[003274] Example 3613 was prepared by following the general synthetic sequence described for the preparation of Example 72, consisting of the following general procedures:

[003275] "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Simple Coupling Procedure", "Prelude Method A: Secondary Amine Coupling Procedure", "Prelude Method A: Chloroacetic Acid Coupling Procedure A", "Global Deprotection Method B", and "Cyclization Method C".

[003276] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18 300, 19 x 250 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 25 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried. The yield of the product was 4.93 mg, and its purity estimated by LCMS analysis was 95.5%.

[003277] LCMS Analysis Condition D: Retention time = 1.74 min; ESI-MS(+) m/z 966.9 (M+2H).

[003278] LCMS Analysis Condition E: Retention time = 1.76 min; ESI-MS(+) m/z 966.8 (M+2H). Analytical Data:

[003279] Mass Spectrometry: "ESI-MS(+)" means electrospray ionization mass spectrometry performed in positive ion mode; "ESI-MS(-)" means electrospray ionization mass spectrometry performed in negative ion mode; "ESI-HRMS(+)" means electrospray ionization high-resolution mass spectrometry performed in positive ion mode; "ESI-HRMS(-)" means electrospray ionization high-resolution mass spectrometry performed in negative ion mode. Detected masses are reported using the “m/z” unit designation. Compounds with exact masses greater than 1000 were frequently detected as doubly or triply charged ions. Analysis Condition A:

[003280] Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B, 0-100% B over 3 min, then a 0.5 min hold at 100% B; Flow rate: 1 mL/min; Detection: UV at 220 nm. Assay Condition B:

[003281] Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B, 0-100% B over 3 min, then a 0.5 min hold at 100% B; Flow rate: 0.5 mL/min; Detection: UV at 220 nm. Assay Condition C:

[003282] Column: Waters AQUITY® BEH C18 2.1 x 50 mm 1.7 μm particles; Mobile phase A: water with 0.05% TFA; Mobile phase B: acetonitrile with 0.05% TFA; Temperature: 40 °C; Gradient: 0% B, 0-100% B over 1.5 minutes, then a 0.5 minute hold at 100% B; Flow rate: 0.8 mL/min; Detection: UV at 220 nm. General Procedures: Prelude Method A:

[003283] All manipulations were performed with automation on a Prelude peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 mL polypropylene tube equipped with a bottom frit; where the reaction scale exceeded 0.100 mmol, a 40 mL polypropylene tube equipped with a bottom frit was used. The tube is connected to the Prelude peptide synthesizer through both the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly coats the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube. “Periodic agitation” describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds.

[003284] Chloroacetyl chloride solutions in DMF were used within 24 hours of preparation. Amino acid solutions were generally not used beyond three weeks of preparation. HATU solutions were used within 5 days of preparation. DMF = dimethylformamide; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Rink = (2,4-dimethoxyphenyl)(4-alkoxyphenyl)methanamine, where "4-alkoxy” describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Rink linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.56 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)-OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[003285] The “Prelude Method A” procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink ligand bound to the resin. This scale corresponds to approximately 178 mg of the Rink-Merrifield resin described above. All procedures can be scaled above the 0.100 mmol scale by adjusting the described volumes by the scale multiple. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as the “Resin Swelling Procedure”. Coupling of amino acids to the N-terminus of a primary amine used the “Single Coupling Procedure” described below. Coupling of amino acids to the N-terminus of a secondary amine used the “Double Coupling Procedure” described below. Coupling of chloroacetyl chloride to the N-terminus of the peptide is described by the “Chloroacetyl Chloride Coupling Procedure” detailed below. Resin swelling procedure:

[003286] To a 10 mL polypropylene solid phase reaction vessel was added Merrifield:Rink resin (178 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel was added DMF (2.0 mL), after which the mixture was stirred periodically for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[003287] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.8 M in DMF, 0.5 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. Acetic anhydride (2.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Double coupling procedure:

[003288] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.8 M in DMF, 0.5 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.8 M in DMF, 0.5 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. Acetic anhydride (2.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel, and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetyl chloride coupling procedure:

[003289] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 min and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.0 mL) was added through the top of the vessel and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added DIPEA (0.8M in DMF, 3.0 mL, 24 eq.), followed by chloroacetyl chloride (0.8M in DMF, 1.65 mL, 13.2 eq.). The mixture was stirred periodically for 30 min, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the top of the vessel and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was placed in a stream of N2 for 15 min. Simphony A method:

[003290] This collection of procedures is identical to that of "Prelude Method A" with the exceptions noted. For all procedures a Symphony X peptide synthesizer (Protein Technologies) was used in place of a Prelude peptide synthesizer and all reagents were added through the top of the reaction vessel. Resin Swelling Procedure:

[003291] This procedure is identical to "Prelude Method A: Resin Swelling Procedure". Simple coupling procedure:

[003292] This procedure is identical to "Prelude Method A: Single Coupling Procedure" except that the concentration of the DIPEA solution was 0.4M and 1.0 mL of this solution was distributed to the reaction. Double Coupling Procedure:

[003293] This procedure is identical to "Prelude Method A: Double Coupling Procedure" except that the concentration of the DIPEA solution was 0.4M and 1.0 mL of this solution was distributed to the reaction. Chloroacetyl Chloride Coupling Procedure:

[003294] This procedure is identical to "Prelude Method A: Chloroacetyl Chloride Coupling Procedure". Global Deprotection Method A:

[003295] All manipulations were done manually unless indicated. The procedure "Global Deprotection Method A" describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink ligand bound to the resin. The procedure can be scaled up above the 0.100 mmol scale by adjusting the described volumes by the multiple of the scale. A "deprotection solution" was prepared by combining trifluoroacetic acid (22 mL), phenol (1.325 g), water (1.25 mL), and triisopropylsilane (0.5 mL) in a 40 mL glass vial. The resin was removed from the reaction vessel and transferred to a 40 mL glass vial. To the vial was added the “deprotection solution” (2.0 mL). The mixture was mixed vigorously on a shaker (1000 rpm for 1 min, then 500 rpm for 1-2 h). The mixture was filtered through a 0.2 μ syringe filter, and the solids were extracted with either the “deprotection solution” (1.0 mL) or TFA (1.0 mL). To a 24 mL test tube filled with the combined filtrates was added Et2O (15 mL). The mixture was mixed vigorously, and a significant amount of a white solid precipitated. The mixture was centrifuged for 5 min, and then the solution was decanted from the solids and discarded. The solids were suspended in Et2O (20 mL); then the mixture was centrifuged for 5 min; and the solution was decanted from the solids and discarded. For a final period, the solids were suspended in Et2O (20 mL); the mixture was centrifuged for 5 min; and the solution was decanted from the solids and discarded to give the crude peptide as a white to off-white solid. Cyclization Method A:

[003296] All manipulations were done manually unless indicated. The "Cyclization Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the multiple of the scale. The crude peptide solids were dissolved in 0.1 M aqueous MeCN:NH4OAc (30 mL:30 mL), and the solution was then cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then allowed to stand without stirring for 12-18 h. The reaction solution was concentrated, and the residue was then dissolved in DMSO:MeOH. This solution was subjected to purification by reversed-phase HPLC to give the desired cyclic peptide. Cyclization method B:

[003297] All manipulations were done manually unless indicated. The "Cyclization Method B" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink linker bound to the resin that was used to generate the peptide. This scale is not based on a direct determination of the amount of peptide used in the procedure. The procedure can be scaled above the 0.100 mmol scale by adjusting the volumes described by the scale multiple. The crude peptide solids were dissolved in 0.1 M aqueous MeCN:NH4OAc (1:1) to a total volume of 18-22 mL, and the solution was then cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then allowed to stand without stirring for 12-18 h. The reaction solution was concentrated and the residue was then dissolved in DMSO:MeOH. This solution was subjected to reversed-phase HPLC purification to give the desired cyclic peptide. General synthesis sequence A:

[003298] "General synthetic sequence A" describes a general sequence of procedures that were used to give the cyclic peptides described in this invention. For the purposes of this general procedure, the procedures of “Simphony Method A” are interchangeable with those of “Prelude Method A.” To a 10 mL polypropylene solid-phase reaction vessel was added Rink-Merrifield resin (178 mg, 0.100 mmol), and the reaction vessel was placed in the Prelude peptide synthesizer. “Prelude Method A: Resin Swelling Procedure” was followed. Then a series of amino acid couplings were performed in sequence on the Prelude following either “Prelude Method A: Single Coupling Procedure” if the N-terminus of the resin-bound peptide was a primary amine or “Prelude Method A: Double Coupling Procedure” if the N-terminus of the resin-bound peptide was a secondary amine. “Prelude Method A: Chloroacetyl Chloride Coupling Procedure” was followed; and then “Prelude Method A: "global deprotection A" was followed; and then "Cyclization Method A" was followed. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)([13C]methyl)amino)hexanoic acid Scheme: Step 1:

[003299] A mixture containing paraformaldehyde (13C-labeled) (500 mg, 16.65 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)hexanoic acid (4527 mg, 12.81 mmol), and p-toluenesulfonic acid (221 mg, 1.281 mmol) was refluxed in toluene (100 mL) for 2 h. The reaction was then cooled to room temperature, washed with saturated sodium bicarbonate solution followed by brine, dried over MgSO4, filtered, and evaporated to give the product from Step 1 (4.694 g, 12.81 mmol) as a yellow oil. The yield was assumed to be 100%. ESI-MS(+) m/z = 389.2 (M+Na). Step 2:

[003300] All of the product from Step 1 (4.694 g, 12.83 mmol) was dissolved in CHCl3 (40 mL) and to the solution was added triethylsilane (10.24 mL, 64.1 mmol) followed by TFA (10 mL, 130 mmol). The solution was stirred at room temperature under positive N2 pressure for 18 h. The volatiles were removed in vacuo to give a thick oil. The oil was dissolved in EtOAc and then extracted with saturated sodium bicarbonate (2 x 100 mL). Solids at the interface of the phases were collected with the aqueous phase. The aqueous phase was adjusted with aqueous HCl to pH 4-5. A white solid precipitated near the end of the pH adjustment. The mixture was extracted with EtOAc (200 mL) and the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to give the pure product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(([13C]methyl)amino)hexanoic acid (3 g, 8.14 mmol, 63.5% yield) as a white solid. 1H NMR (400 MHz, CDCl3) DDD 7.78 (d, J=7.1 Hz, 2H), 7.66 - 7.52 (m, 2H), 7.41 (d, J=6.8 Hz, 2H), 7.33 (d, J=6.1 Hz, 2H), 4.84 -4.59 (m, 1H), 4.55 - 4.40 (m, 2H), 4.34 - 4.17 (m, 1H), 3.16 - 2.98 (m, 1H), 2.71 (br. s., 1H), 1.77 (br. s., 1H), 1.44 - 1.14 (m, 5H), 0.91 (d, J=7.3 Hz, 3H). ESI-MS(+) m/z = 369.4 (M+H).

[003301] Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)([13C]methyl)amino)propanoic acid Scheme: Step 1:

[003302] A mixture containing paraformaldehyde (C13-labeled) (250 mg, 8.33 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (1994 mg, 6.40 mmol), and p-toluenesulfonic acid (110 mg, 0.640 mmol) was refluxed in toluene (50 mL) for 2 h. The reaction was then cooled to room temperature, washed with saturated sodium bicarbonate solution followed by brine, dried over MgSO4, filtered, and evaporated to give the product from Step 1 (2.08 g, 6.41 mmol) as a yellow oil. The yield was assumed to be 100%. ESI-MS(+) m/z = 348.1 (M+Na). Step 2:

[003303] All of the product from Step 1 (2.08 g, 6.41 mmol) was dissolved in CHCl3 (20 mL) and to the solution was added triethylsilane (5.12 mL, 32.1 mmol) followed by TFA (4.94 mL, 64.1 mmol). The solution was stirred at room temperature under positive N2 pressure for 18 h. Volatiles were removed to give a thick oil. The oil was dissolved in EtOAc and then extracted with saturated sodium bicarbonate (2 x 100 mL). The solids at the interface of the phases were collected with the aqueous phase. The aqueous phase was adjusted to pH 4-5 using aqueous HCl. A white solid precipitated near the end of the pH adjustment. The mixture was extracted with EtOAc (200 mL) and the organic phase was washed with brine, dried over MgSO4, filtered, and concentrated to give the pure product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)([13C]methyl)amino)propanoic acid (1 g, 3.06 mmol, 47.8% yield) as a white solid. 1H NMR (400MHz, chloroform-d)DDD7.79 (d, J=7.3 Hz, 2H), 7.62 (br. s., 2H), 7.43 (t, J=7.2 Hz, 2H), 7.34 (t, J=7.3 Hz, 2H), 4.88 (br. s., 1H), 4.52 - 4. 37 (m, 2H), 4.29 (d, J=6.1 Hz, 1H), 3.11 (s, 1H), 2.76 (s, 2H), 1.49 (d, J=6.8 Hz, 2H), 1.39 (br. s., 1H). ESI-MS(+) m/z = 349.2 (M+H). Preparation of (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-hydroxypiperidine-2-carboxylic acid Scheme: Step 1:

[003304] TFA (5 mL, 64.9 mmol) was added to a solution of (2S,5S)-di-tert-butyl 5-hydroxypiperidine-1,2-dicarboxylate (1 g, 3.32 mmol) in DCM (5 mL) at room temperature, and the solution was stirred for 1 h after which LCMS analysis indicated complete conversion (removal of Boc). The solution was concentrated in vacuo and the residue was then treated with 3 mL of concentrated aqueous HCl. The solution was stirred for 5 min after which LCMS analysis indicated complete conversion (removal of tBu). The solution was concentrated in vacuo to give (2S,5S)-5-hydroxypiperidine-2-carboxylic acid, HCl (0.6 g) as an oil. The yield was assumed to be 100%. ESI-MS(+) m/z = 146.2 (M+H). Step 2:

[003305] To a solution of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid, HCl (.603 g, 3.32 mmol) in 1,4-dioxane (4 mL) and water (16 mL) was added potassium carbonate (1.835 g, 13.28 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (0.859 g, 3.32 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and then treated with water (10 mL). The resulting mixture was extracted with diethyl ether (2 × 15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO4 and concentrated to give the crude product (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-hydroxypiperidine-2-carboxylic acid (800 mg, 65.6% yield) as a white solid. 1H NMR (500MHz, methanol-d4)DDD7.86 - 7.78 (m, 2H), 7.69 - 7.57 (m, 2H), 7.48 - 7.37 (m, 2H), 7.37 - 7.20 (m, 2H), 4.81 - 4.77 (m, 1H), 4.59 - 4.36 (m, 2H), 4.32 - 4.20 (m, 1H), 4.18 - 4.08 (m, 1H), 3.75 - 3.64 (m, 2H), 3.58 - 3.43 (m, 1H), 2.01 - 1.89 (m, 1H), 1.81 - 1.57 (m, 1H), 1.30 - 1.17 (m, 1H). ESI-MS(+) m/z = 368.2 (M+Na). Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid Scheme: Step 1:

[003306] To a 250 mL round bottom flask equipped with a stir bar was added acetic acid (50 mL) and hydrobromic acid in AcOH (27 mL, 149 mmol), followed by (S)-2-amino-3-(4-hydroxyphenyl)propanoic acid (13.47 g, 74.3 mmol). To the stirred solution was added dropwise over 3 h via an addition funnel bromine (4.14 mL, 80 mmol) in AcOH (20 mL). The solution was stirred at room temperature. After 9 days, stirring was stopped and the mixture was filtered (reaction time not optimized). The filter cake was washed with AcOH (100 mL) and then Et2O (150 mL). The isolated off-white solids were dried in vacuo to give the product (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoic acid hydrobromide (23.9 g, 85% yield) as a pale yellow powder. 1H NMR (500 MHz, methanol-d4) DDD 7.47 - 7.41 (m, 1H), 7.12 (dd, J=8.2, 2.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.22 (dd, J=7.6, 5.4 Hz, 1H), 3.23 (dd, J=14.8, 5.4 Hz, 1H), 3.08 (dd, J=14.7, 7.7 Hz, 1H). Step 2:

[003307] To a solution of (S)-2-amino-3-(3-bromo-4-hydroxyphenyl)propanoic acid hydrobromide (3 g, 8.80 mmol) in 1,4-dioxane (12 mL) and water (48 mL) was added potassium carbonate (4.86 g, 35.2 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (2.276 g, 8.80 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and then treated with water (50 mL). The resulting mixture was extracted with diethyl ether (2x15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3x20 mL). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The product was purified via silica gel chromatography (120 g column, 30-90% EtOAc:Hexanes, 20 column volumes) to give the product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid (3.42 g, 55.2% yield) as a light yellow solid. 1H NMR (400MHz, chloroform-d)DDD7.80 (t, J=7.9 Hz, 4H), 7.68 (d, J=7.6 Hz, 2H), 7.60 (d, J=7.3 Hz, 2H), 7.49 - 7.32 (m, 9H), 7.16 (br. s., 2H), 5.32 (s, 1H), 4.73 (br. s., 1H), 4.58 (d, J=7.3 Hz, 2H), 4.54 - 4.34 (m, 2H), 4.24 (t, J=6.6 Hz, 1H), 3.31 -3.03 (m, 2H). ESI- MS(+) m/z = 721 (M+H20). Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)propanoic acid Scheme: Step 1:

[003308] To a 0 °C solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate (4 g, 12.56 mmol) and cesium carbonate (4.50 g, 13.82 mmol) in DMF (40 mL) was added tert-butyl 2-bromoacetate (2.015 mL, 13.82 mmol) and allowed to warm to room temperature by removing the ice bath and stirring for 18 h. The reaction was poured into 1:1 ice-water:1 N HCl and extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSO4, filtered, and evaporated to give the crude product. The product was purified via silica gel chromatography (80 g column, 0-50% EtOAc:Hexanes for 20 CV) to give the product (S)-methyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 86% yield). 1H NMR (400MHz, chloroform-d)DDD7.56 (d, J=7.8 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.17 -7.12 (m, 1H), 6.92 (s, 1H), 5.09 (d, J=7.6 Hz, 1H), 4.71 (s, 2H), 3 - 3.59 (m, 3H), 3.30 (d, J=5.1 Hz, 2H), 1.45 (s, 18H). ESI- MS(+) m/z = 433 (M+H). Step 2:

[003309] Lithium hydroxide monohydrate (0.455 g, 10.84 mmol) was added to a solution of (S)-methyl 3-( 1 -(2-(tert-butoxy)-2-oxoethyl)- 1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (4.69 g, 10.84 mmol) in dioxane (50 mL) and water (16.67 mL) and stirred at room temperature for 1 h. The reaction was quenched with 1 M HCl and extracted with EtOAc. The organic layer was washed with brine, collected, dried over MgSO4, filtered, and evaporated to give the crude material. The crude material was purified via silica gel chromatography (120 g column, 0-50% EtOAc:Hex for 20 CV) to give the product (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.54 g, 78% yield). 1H NMR (400MHz, chloroform-d)DDD7.62 (d, J=7.8 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.15 (ddd, J=7.9, 5.6, 2.3 Hz, 1H), 6.99 (s, 1H), 5.08 (d, J=7.8 Hz, 1H), 4 .71 (s, 2H), 4.65 (br. s., 1H), 3.42 - 3.31 (m, 2H), 1.46 (s, 18H). ESI-MS(+) m/z = 441 (M+Na). Step 3:

[003310] HCl (4M in dioxane, 10 mL, 40.0 mmol) was cooled in an ice bath under a N2 atmosphere. (S)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 g, 2.390 mmol) was added to the HCl solution. The ice bath was removed and the reaction was stirred for 30 min. The solution was concentrated (bath temperature = room temperature) to give the product (S)-2-amino-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)propanoic acid, HCl (848 mg, 100% yield) as a sticky oil. ESI-MS(+) m/z = 319.2 (M+Na).Step 4:

[003311] To a solution of (S)-2-amino-3-( 1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)propanoic acid, HCl (848 mg, 2390 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1321 mg, 9.56 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (618 mg, 2390 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and treated with water (10 mL). The resulting mixture was extracted with diethyl ether (2 × 15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The product was purified via prep HPLC (10-100% CH3CN:water with 0.1% TFA buffer) to give the product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)propanoic acid (405 mg, 0.749 mmol, 31.3% yield) as a white solid. 1H NMR (500MHz, methanol- cU)DDD7.80 (d, J=7.6 Hz, 2H), 7.67 - 7.60 (m, 2H), 7.39 (t, J=7.5 Hz, 2H), 7.32 - 7.22 (m, 3H), 7.18 (td, J=7.6, 0.9 Hz, 1H), .08 (td, J=7.5, 0.9 Hz, 1H), 7.04 (s, 1H), 4.54 (dd, J=8.4, 4.9 Hz, 1H), 4.36 - 4.23 (m, 2H), 4.23 - 4.14 (m, 1H), 3.43 - 3.35 (m, 2H), 3.25 - 3.09 (m, 1H), 1.55 - 1.38 (m, 9H). ESI-MS(+) m/z = 541.3 (M+H). Preparation of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((6-methoxy-isoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid Scheme: Step 1:

[003312] To a solution of (2S,4R)-4-((6-methoxy-isoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid, HCl (750 mg, 2.309 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1277 mg, 9.24 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (597 mg, 2.309 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and treated with water (10 mL). The resulting mixture was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3x20 mL). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The product was purified via silica gel chromatography (40 g column, 0-10% MeOH in DCM for 20 CV) to give the product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((6-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid as a white solid. 1H NMR (400MHz, chloroform- d)DDD8.09 (d, J=9.3 Hz, 1H), 8.00 - 7.88 (m, 1H), 7.80 - 7.65 (m, 2H), 7.65 - 7.47 (m, 2H), 7.37 (t, J=7.2 Hz, 2H), 7.34 - 7. 29 (m, 2H), 7.25 - 7.12 (m, 2H), 7.09 - 7.04 (m, 1H), 5.83 (br. s., 1H), 4.76 (t, J=7.9 Hz, 1H), 4.61 - 4.39 (m, 3H), 4.30 -4.19 (m, 2H), 4.06 - 3.94 (m, 3H), 2.70 (dd, J=7.9, 3.3 Hz, 2H). ESI-MS(+) m/z = 511 (M+H). Preparation of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid Scheme: Step 1:

[003313] TFA (5.0 mL, 65 mmol) was added to a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (300 mg, 0.686 mmol) in DCM (5 mL) and stirred at room temperature until LCMS analysis indicated complete conversion. The solution was concentrated to give the product (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg) as a thick oil. The yield was assumed to be 100%. ESI-MS(+) m/z = 337 (M+H). Step 2:

[003314] To a solution of (2S,4R)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid, TFA (310 mg, 0.687 mmol) in 1,4-dioxane (3 mL) and water (12 mL) was added potassium carbonate (380 mg, 2.75 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (178 mg, 0.687 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and treated with water (10 mL). The resulting mixture was extracted with diethyl ether (2 x 15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3 x 20 mL). The combined organic layers were dried over MgSO 4 and concentrated to give the crude product. The product was purified via prep HPLC (10100% CH3CN:water, 0.1% TFA buffer) to give the product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid (250 mg, 65% yield) as a white solid. 1H NMR (500MHz, methanol-d4)DDD7.90 - 7.75 (m, 2H), 7.73 - 7.63 (m, 2H), 7.58 - 7.49 (m, 2H), 7.49 - 7.39 (m, 2H), 7.37 - 7.31 (m, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.20 - 7.14 (m, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.04 (td, J=7.4, 1.0 Hz, 1H), 4.68 - 4.56 (m, 2H), 4.51 (t, J=8.3 Hz, 1H), 4.44 - 4.33 (m, 2H), 4.27 - 4.16 (m, 2H), 3.99 - 3.92 (m, 1H), 3.81 - 3.73 (m, 1H), 3.73 - 3.64 (m, IH). ESI-MS(+) m/z = 337 (M+ H). Preparation of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)-pyrrolidine-2-carboxylic acid Scheme: Step 1:

[003315] TFA (5 mL, 64.9 mmol) was added to a solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (500 mg, 1.556 mmol) in DCM (5 mL) and stirred at room temperature until LCMS analysis indicated complete conversion. The solution was concentrated to give the product. The yield was assumed to be 100%. ESI-MS(+) m/z = 222 (M+H). Step 2:

[003316] To a solution of (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid, TFA (522 mg, 1.557 mmol) in 1,4-dioxane (4 mL) and water (16 mL) was added potassium carbonate (861 mg, 6.23 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (403 mg, 1.557 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and treated with water (10 mL). The resulting mixture was extracted with diethyl ether (2x15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3x20 mL). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The product was purified via prep HPLC (10-100%CH3CN:water 0.1% TFA buffer) to give the pure product (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (430mg, 62.3% yield) as a white solid. 1H NMR (500MHz, methanol-d4)DDD7.86 - 7.76 (m, 2H), 7.71 - 7.57 (m, 2H), 7.44 - 7.27 (m, 9H), 4.58 - 4.50 (m, 2H), 4.49 - 4.33 (m, 3H), 4.29 -4.19 (m, 2H), 3.72 - 3.49 (m, 2H), 2.49 (br. s., 1H), 2.10 (ddd, J=13.4, 8.2, 4.8 Hz, 1H). ESI-MS(+) m/z = 444 (M+H). Preparation of (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid Scheme: Step 1:

[003317] To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 m 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9H-fluoren-9-yl)methylcarbonohydrochloride (562 mg 2.171 mmol) at 0 °C. The mixture was stirred at room temperature for 18 h and then treated with water (10 mL). The resulting mixture was extracted with diethyl ether (2 × 15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO 4 and concentrated to give the crude product. The product was purified via prep HPLC (10-100% CH3CN: Water with 0.1% TFA buffer) to give the product (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294mg, 30% yield) as a white solid. 1H NMR (500MHz, methanol-d4)DDD7.83 (t, J=6.6 Hz, 2H), 7.68 -7.58 (m, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55 - 4.39 (m, 3H), 4.33 - 4.18 (m, 1H), 2.91 - 2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z = 475 (M+Na). Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid Scheme: Step 1:

[003318] To a round bottom flask equipped with a stir bar was added (S)-methyl 3-hydroxy-2-(tritylamino)propanoate (10.0 g, 27.7 mmol), triphenylphosphine (7.98 g, 30.4 mmol), and toluene (100 mL). The solution was stirred at room temperature for 30 min, and then to the solution were added m-cresol (3.78 mL, 36.0 mmol) and diisopropylazodicarboxylate ("DIAD", 5.92 mL, 30.4 mmol). The solution was heated to 80 °C with stirring for 18 h. The solution was cooled to room temperature and concentrated and the resulting residue was chromatographed on silica gel (hexanes:EtOAc) to give (S)-methyl 3-(m-tolyloxy)-2-(tritylamino)propanoate, 8.28 g (66%). 1H-NMR (400MHz, CDCl3)DDD7.53 (d, J=7.6 Hz, 6H), 7.29 - 7.23 (m, 5H), 7.21 -7.11 (m, 4H), 6.77 (d, J=7.3 Hz, 1H), 6.73 - 6.64 (m, 2H), 5.30 (s, 2H), 4.25 (dd, J=9.3, 4.9 Hz, 1H), 4.01 (dd, J=9.2, 6.7 Hz, 1H), 3.76 - 3.68 (m, 1H), 3.22 (s, 3H), 2.88 (d, J=10.5 Hz, 1H), 2.32 (s, 3H). Step 2:

[003319] To a round bottom flask equipped with a stir bar and charged with (S)-methyl 3-(m-tolyloxy)-2-(tritylamino)propanoate (8.28 g, 18.34 mmol) in MeOH (30 mL) and THF (30 mL) was added lithium hydroxide in water (55.0 mmol, 27.5 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N aqueous HCl. The mixture was diluted with EtOAc and the organic phase was isolated and washed with brine; dried over MgSO4, filtered, and then concentrated in vacuo. The resulting residue was purified via silica gel chromatography to give (S)-3-(m-tolyloxy)-2-(tritylamino)propanoic acid, 1.47 g (18%). 1H NMR (400MHz, CDCl3)DDD7.44 (d, J =7.1 Hz, 6H), 7.35 - 7.24 (m, 8H), 7.09 (t, J =7.8 Hz, 1H), 6.76 (d, J =7.6 Hz, 1H), 6.52 (s, 1H), 6.46 (d, J =8.1 Hz, 1H), 4.07 (dd, J=9.2, 2.3 Hz, 1H), 3.71 (t, J =3.2 Hz, 1H), 2.79 (dd, J=9.2, 4.0 Hz, 1H), 2.28 (s, 3H). Step 3:

[003320] To a round bottom flask equipped with a stir bar and charged with (S)-3-(m-tolyloxy)-2-(tritylamino)propanoic acid (1.47 g, 3.36 mmol) cooled to 0 °C was added trifluoroacetic acid (6.0 mL, 78 mmol). The solution was stirred for 1 h. The volatiles were removed in vacuo and the residue was then dissolved in MeOH (5 mL) and concentrated again in vacuo. The resulting crude (S)-2-amino-3-(m-tolyloxy)propanoic acid TFA salt was taken directly to Step 4. Step 4:

[003321] To a round bottom flask equipped with a stir bar and charged with all of the (S)-2-amino-3-(m-tolyloxy)propanoic acid TFA salt given in Step 3 (assumed 3.36 mmol) was added 1,4-Dioxane (4 mL) and water (16 mL), followed by K2CO3 (1.17 g, 8.49 mmol). The mixture was cooled to 0 °C, and then to the mixture was added (9H-fluoren-9-yl)methylcarbonohydrochloride (549 mg, 2.12 mmol). The mixture was allowed to warm to room temperature with stirring for 18 h. The mixture was diluted with water (10 mL) and then washed with diethyl ether (2 × 15 mL). The aqueous phase was acidified with aqueous HCl (1 M) to pH 2-3, and then extracted with CH2Cl2 (3 x 20 mL). The combined CH2Cl2 solutions were dried over MgSO4, filtered, and then concentrated in vacuo to give (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid as a white solid, 430 mg (31% over two steps). Step 5:

[003322] Using a Dean-Stark setup, a mixture containing paraformaldehyde (340 mg, 11.34 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid (789 mg, 1.890 mmol), and p-toluenesulfonic acid (32.5 mg, 0.189 mmol) was refluxed in toluene (15 mL) for 2 h. The reaction was then cooled to room temperature, washed with saturated sodium bicarbonate solution followed by brine, dried over MgSO4, filtered, and concentrated to give the product (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-((m-tolyloxy)methyl)oxazolidine-3-carboxylate (812 mg, 1.891 mmol, 100% yield) as a yellow oil. ESI-MS(+) m/z = 430 (M+H). Step 6:

[003323] (S)-(9H-Fluoren-9-yl)methyl 5-oxo-4-((m-tolyloxy)methyl)oxazolidine-3-carboxylate (825 mg, 1.921 mmol) was dissolved in CHCl3 (10 mL) and triethylsilane (1.534 mL, 9.60 mmol) was added followed by TFA (10 mL, 130 mmol) and the mixture was stirred at room temperature under positive N2 pressure for 18 h. The reaction was then rotovaporated to a thick oil. The oil was dissolved in EtOAc and then extracted with saturated sodium bicarbonate (10 mL x2). There was an intermediate layer between the aqueous layer and the organic layer which appeared to be the deprotonated product. The aqueous layer and the intermediate layer were separated and collected and then acidified to pH 4-5. The solution formed a precipitate once acidic. EtOAc (200 ml) was used to extract the precipitate. The organic layer was washed with brine, collected, dried over MgSO4, filtered, and evaporated to give the pure product (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid (506 mg, 1.173 mmol, 61.0% yield) as a white solid. ESI-MS(+) m/z = 454 (M+Na). Preparation of Example 5001 Example 5001

[003324] Example 5001 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003325] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.2 mg, and its purity estimated by LCMS analysis was 100%.

[003326] Analysis Condition A: Retention time = 1.81 min; ESI-MS(+) m/z 933.0 (M+2H).

[003327] Analysis Condition B: Retention time = 2.93 min; ESI-MS(+) m/z 933.8 (M+2H). Preparation of Example 5002 Example 5002

[003328] Example 5002 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003329] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, followed by a 4 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 11.0 mg, and its purity was estimated to be 97% by LCMS analysis.

[003330] Assay Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 926.0 (M+2H). Assay Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 617.6 (M+2H). Preparation of Example 5003 Example 5003

[003331] Example 5003 was prepared by following “General Synthetic Sequence A” with “Cyclization Method B” replacing “Cyclization Method A”. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 40 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.3 mg, and its purity was estimated by analysis by LCMS was 100%.

[003332] Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 942 (M+2H).

[003333] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 942.7 (M+2H). Preparation of Example 5004 Example 5004

[003334] Example 5004 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003335] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 40.8 mg, and its purity estimated by LCMS analysis was 99%.

[003336] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 940.8 (M+2H).

[003337] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 941.0 (M+2H).

[003338] ESI-HRMS(+) m/z: Calculated: 940.9398 (M+2H); Found: 940.9378 (M+2H). Preparation of Example 5005 Example 5005

[003339] Example 5005 was prepared following “General Synthetic Sequence A”. (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid was used in the fourth amino acid coupling step. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 21.3 mg, and its purity estimated by LCMS analysis was 100%.

[003340] Analysis Condition A: Retention time = 1.78 min; ESI-MS(+) m/z 971.2 (M+2H).

[003341] Analysis Condition B: Retention time = 2.94 min; ESI-MS(+) m/z 971.2 (M+2H). Preparation of Example 5006 Example 5006

[003342] Example 5006 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003343] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 42.3 mg, and its purity estimated by LCMS analysis was 99%.

[003344] Analysis Condition A: Retention time = 1.88 min; ESI-MS(+) m/z 898.4 (M+2H).

[003345] Analysis Condition B: Retention time = 2.97 min; ESI-MS(+) m/z 898.9 (M+2H). Preparation of Example 5007 Example 5007

[003346] Example 5007 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003347] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 44.0 mg, and its purity estimated by LCMS analysis was 100%.

[003348] Analysis Condition A: Retention time = 1.97 min; ESI-MS(+) m/z 892.1 (M+2H).

[003349] Analysis Condition B: Retention time = 3.02 min; ESI-MS(+) m/z 892.0 (M+2H). Preparation of Example 5008 Example 5008

[003350] Example 5008 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003351] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 70-100% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 30.6 mg, and its purity was estimated to be 100% by LCMS analysis.

[003352] Analysis Condition A: Retention time = 1.78 min; ESI-MS(+) m/z 933.8 (M+2H).

[003353] Analysis Condition B: T Example 5009

[003354] Example 5009 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003355] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.5 mg, and its purity estimated by LCMS analysis was 100%.

[003356] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 911.5 (M+2H).

[003357] Analysis Condition B: Retention time = 2.69 min; ESI-MS(+) m/z 911.9 (M+2H). Preparation of Example 5010 Example 5010

[003358] Example 5010 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003359] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.2 mg, and its purity estimated by LCMS analysis was 100%.

[003360] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 920.1 (M+2H).

[003361] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 919.8 (M+2H). Preparation of Example 5011 Example 5001

[003362] Example 5011 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003363] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.0 mg, and its purity estimated by LCMS analysis was 99%.

[003364] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 911.5 (M+2H).

[003365] Analysis Condition B: Retention time = 2.45 min; ESI-MS(+) m/z 911.4 (M+2H). Preparation of Example 5012 Example 5012

[003366] Example 5012 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003367] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 40-80% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.0 mg, and its purity was estimated to be 99% by LCMS analysis.

[003368] Analysis Condition A: Retention time = 1.77 min; ESI-MS(+) m/z 935.8 (M+2H). Preparation of Example 5013 Example 5013

[003369] Example 5013 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003370] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.4 mg, and its purity estimated by LCMS analysis was 100%.

[003371] Analysis Condition A: Retention time = 1.79 min; ESI-MS(+) m/z 916.9 (M+2H).

[003372] Analysis Condition B: Retention time = 2.94 min; ESI-MS(+) m/z 917.5 (M+2H). Preparation of Example 5014 Example 5014

[003373] Example 5014 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003374] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.3 mg, and its purity estimated by LCMS analysis was 100%.

[003375] Analysis Condition A: Retention time = 1.77 min; ESI-MS(+) m/z 905.5 (M+2H).

[003376] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 905.5 (M+2H). Preparation of Example 5015 Example 5015

[003377] Example 5015 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003378] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.3 mg, and its purity estimated by LCMS analysis was 99%.

[003379] Analysis Condition A: Retention time = 1.89 min; ESI-MS(+) m/z 876.7 (M+2H).

[003380] Analysis Condition B: Retention time = 2.99 min; ESI-MS(+) m/z 877.0 (M+2H). Preparation of Example 5016 Example 5016

[003381] Example 5016 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003382] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.0 mg, and its purity estimated by LCMS analysis was 97%.

[003383] Analysis Condition A: Retention time = 1.91 min; ESI-MS(+) m/z 898.0 (M+2H).

[003384] Analysis Condition B: Retention time = 2.98 min; ESI-MS(+) m/z 898.5 (M+2H). Preparation of Example 5017 Example 5017

[003385] Example 5017 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003386] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.8 mg, and its purity estimated by LCMS analysis was 98%.

[003387] Analysis Condition A: Retention time = 1.97 min; ESI-MS(+) m/z 905.0 (M+2H).

[003388] Analysis Condition B: Retention time = 3.01 min; ESI-MS(+) m/z 905.3 (M+2H). Preparation of Example 5018 Example 5018

[003389] Example 5018 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003390] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its purity estimated by LCMS analysis was 97%.

[003391] Analysis Condition A: Retention time = 1.95 min; ESI-MS(+) m/z 904.9 (M+2H).

[003392] Analysis Condition B: Retention time = 3.00 min; ESI-MS(+) m/z 905.0 (M+2H). Preparation of Example 5019 Example 5019

[003393] Example 5019 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003394] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.1 mg, and its purity estimated by LCMS analysis was 99%.

[003395] Analysis Condition A: Retention time = 1.88 min; ESI-MS(+) m/z 912.8 (M+2H).

[003396] Analysis Condition B: Retention time = 2.92 min; ESI-MS(+) m/z 913.0 (M+2H). Preparation of Example 5020 Example 5020

[003397] Example 5020 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003398] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.1 mg, and its purity estimated by LCMS analysis was 99%.

[003399] Analysis Condition A: Retention time = 1.88 min; ESI-MS(+) m/z 919.4 (M+2H).

[003400] Analysis Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 920.0 (M+2H). Preparation of Example 5021 Example 5021

[003401] Example 5021 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003402] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.3 mg, and its purity estimated by LCMS analysis was 100%.

[003403] Analysis Condition A: Retention time = 2.14 min; ESI-MS(+) m/z 899.6 (M+2H).

[003404] Analysis Condition B: Retention time = 2.93 min; ESI-MS(+) m/z 899.8 (M+2H). Preparation of Example 5022 Example 5022

[003405] Example 5022 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003406] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.0 mg, and its purity estimated by LCMS analysis was 98%.

[003407] Analysis Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 950.0 (M+2H).

[003408] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 950.2 (M+2H). Preparation of Example 5023 Example 5023

[003409] Example 5023 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003410] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.1 mg, and its purity estimated by LCMS analysis was 100%.

[003411] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 957.1 (M+2H).

[003412] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 957.2 (M+2H). Preparation of Example 5024 Example 5024

[003413] Example 5024 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003414] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 27.5 mg, and its purity estimated by LCMS analysis was 100%.

[003415] Analysis Condition A: Retention time = 2.07 min; ESI-MS(+) m/z 963.4 (M+2H).

[003416] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 963.3 (M+2H). Preparation of Example 5025 Example 5025

[003417] Example 5025 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003418] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.8 mg, and its purity estimated by LCMS analysis was 98%.

[003419] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 957.2 (M+2H). Preparation of Example 5026 Example 5026

[003420] Example 5026 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003421] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: water with 20 mM ammonium acetate; Mobile phase B: 95:5 methane:water with 20 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 17.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[003422] Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z 896.0 (M+2H).

[003423] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 895.9 (M+2H). Preparation of Example 5027 Example 5027

[003424] Example 5027 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003425] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.3 mg, and its purity estimated by LCMS analysis was 100%.

[003426] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 898.5 (M+2H).

[003427] Analysis Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 898.5 (M+2H). Preparation of Example 5028 Example 5028

[003428] Example 5028 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003429] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 37.1 mg, and its purity was estimated to be 100% by LCMS analysis.

[003430] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 941.9 (M+2H).

[003431] Analysis Condition B: Retention time = 2.52 min; ESI-MS(+) m/z 941.9 (M+2H). Preparation of Example 5029 Example 5029

[003432] Example 5029 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003433] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 23.5 mg, and its purity estimated by LCMS analysis was 100%.

[003434] Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 935.9 (M+2H).

[003435] Analysis Condition B: Retention time = 2.54 min; ESI-MS(+) m/z 935.9 (M+2H). Preparation of Example 5030 Example 5030

[003436] Example 5030 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003437] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 40 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 6.1 mg, and its purity was estimated to be 100% by LCMS analysis.

[003438] Analysis Condition A: Retention time = 1.72 min; ESI-MS(+) m/z 905.5 (M+2H).

[003439] Analysis Condition B: Retention time = 2.89 min; ESI-MS(+) m/z 905.5 (M+2H). Preparation of Example 5031 Example 5031

[003440] Example 5031 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003441] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 11.7 mg, and its purity was estimated to be 100% by LCMS analysis.

[003442] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 935.4 (M+2H).

[003443] Analysis Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 935.5 (M+2H). Preparation of Example 5032 Example 5032

[003444] Example 5032 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003445] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 27.1 mg, and its purity was estimated to be 98% by LCMS analysis.

[003446] Analysis Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 934.0 (M+2H).

[003447] Analysis Condition B: Retention time = 2.55 min; ESI-MS(-) m/z 932.0 (M-2H). Preparation of Example 5033 Example 5033

[003448] Example 5033 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003449] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.5 mg, and its purity estimated by LCMS analysis was 100%.

[003450] Analysis Condition A: Retention time = 1.93 min; ESI-MS(+) m/z 948.5 (M+2H).

[003451] Analysis Condition B: Retention time = 2.97 min; ESI-MS(+) m/z 949.1 (M+2H). Preparation of Example 5034 Example 5034

[003452] Example 5034 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003453] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.4 mg, and its purity estimated by LCMS analysis was 95%.

[003454] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 943.0 (M+2H).

[003455] Analysis Condition B: Retention time = 2.50 min; ESI-MS(+) m/z 943.1 (M+2H). Preparation of Example 5035 Example 5035

[003456] Example 5035 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003457] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.9 mg, and its purity estimated by LCMS analysis was 100%.

[003458] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 919.6 (M+2H).

[003459] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 919.5 (M+2H). Preparation of Example 5026 Example 5036

[003460] Example 5036 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003461] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 17.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[003462] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 927.6 (M+2H).

[003463] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 927.6 (M+2H). Preparation of Example 5037 Example 5037

[003464] Example 5037 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003465] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 20.8 mg, and its purity was estimated to be 100% by LCMS analysis.

[003466] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 928.0 (M+2H).

[003467] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 927.9 (M+2H). Preparation of Example 5038 Example 5038

[003468] Example 5038 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003469] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 19.2 mg, and its purity was estimated to be 99% by LCMS analysis.

[003470] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 927.2 (M+2H).

[003471] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 927.0 (M+2H). Preparation of Example 5039 Example 5039

[003472] Example 5039 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003473] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.8 mg, and its purity estimated by LCMS analysis was 99%.

[003474] Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 928.0 (M+2H).

[003475] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 928.0 (M+2H). Preparation of Example 5040 Example 5040

[003476] Example 5040 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003477] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity estimated by LCMS analysis was 99%.

[003478] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 901.6 (M+2H).

[003479] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 901.7 (M+2H). Preparation of Example 5041 Example 5041

[003480] Example 5041 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003481] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-50% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 100%.

[003482] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 935.8 (M+2H).

[003483] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 935.5 (M+2H). Preparation of Example 5042 Example 5042

[003484] Example 5042 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003485] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.8 mg, and its purity estimated by LCMS analysis was 99%.

[003486] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 910.2 (M+2H).

[003487] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 910.1 (M+2H). Preparation of Example 5043 Example 5043

[003488] Example 5043 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003489] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-50% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.9 mg, and its purity estimated by LCMS analysis was 99%.

[003490] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 942.3 (M+2H).

[003491] Analysis Condition B: Retention time = 2.50 min; ESI-MS(+) m/z 942.1 (M+2H). Preparation of Example 5044 Example 5044

[003492] Example 5044 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.1 mg, and its purity estimated by LCMS analysis was 98%.

[003493] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 916.7 (M+2H).

[003494] Analysis Condition B: Retention time = 2.52 min; ESI-MS(+) m/z 916.4 (M+2H). Preparation of Example 5045 Example 5045

[003495] Example 5045 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003496] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 18.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[003497] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 936.5 (M+2H).

[003498] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 936.4 (M+2H). Preparation of Example 5046 Example 5046

[003499] Example 5046 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003500] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-50% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 19.9 mg, and its purity was estimated to be 98% by LCMS analysis.

[003501] Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 942.9 (M+2H).

[003502] Analysis Condition B: Retention time = 2.50 min; ESI-MS(+) m/z 942.9 (M+2H). Preparation of Example 5047 Example 5047

[003503] Example 5047 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003504] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-50% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 6.3 mg, and its purity was estimated to be 98% by LCMS analysis.

[003505] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 921.2 (M+2H).

[003506] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 921.4 (M+2H). Preparation of Example 5048 Example 5048

[003507] Example 5048 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003508] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.5 mg, and its purity estimated by LCMS analysis was 99%.

[003509] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 895.6 (M+2H).

[003510] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 895.7 (M+2H). Preparation of Example 5049 Example 5049

[003511] Example 5049 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003512] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity estimated by LCMS analysis was 97%.

[003513] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 895.9 (M+2H).

[003514] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 896.2 (M+2H). Preparation of Example 5050 Example 5050

[003515] Example 5050 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003516] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-50% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 10-50% B over 40 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 5.2 mg, and its purity was estimated to be 100% by LCMS analysis.

[003517] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 921.7 (M+2H).

[003518] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 921.8 (M+2H). Preparation of Example 5051 Example 5051

[003519] Example 5051 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.0 mg, and its purity estimated by LCMS analysis was 97%.

[003520] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 957.3 (M+2H).

[003521] Analysis Condition B: Retention time = 2.93 min; ESI-MS(+) m/z 957.5 (M+2H). Preparation of Example 5052 Example 5052

[003522] Example 5052 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.4 mg, and its purity estimated by LCMS analysis was 100%.

[003523] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 978.9 (M+2H).

[003524] Analysis Condition B: Retention time = 2.68 min; ESI-MS(-) m/z 977.3 (M-2H). Preparation of Example 5053 Example 5053

[003525] Example 5053 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.8 mg, and its purity estimated by LCMS analysis was 99%.

[003526] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 936.1 (M+2H).

[003527] Analysis Condition B: Retention time = 2.73 min; ESI-MS(+) m/z 936.5 (M+2H). Preparation of Example 5054 Example 5054

[003528] Example 5054 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.7 mg, and its purity estimated by LCMS analysis was 100%.

[003529] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 944.2 (M+2H).

[003530] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 944.4 (M+2H). Preparation of Example 5055 Example 5055

[003531] Example 5055 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.8 mg, and its purity estimated by LCMS analysis was 99%.

[003532] Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 950.6 (M+2H).

[003533] Analysis Condition B: Retention time = 2.69 min; ESI-MS(-) m/z 949.2 (M-2H). Preparation of Example 5056 Example 5056

[003534] Example 5056 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.4 mg, and its purity estimated by LCMS analysis was 98%.

[003535] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 950.4 (M+2H).

[003536] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 950.9 (M+2H). Preparation of Example 5057 Example 5057

[003537] Example 5057 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 18.1 mg, and its purity estimated by LCMS analysis was 100%.

[003538] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 944 (M+2H). Assay Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 944.8 (M+2H). Preparation of Example 5058 Example 5058

[003539] Example 5058 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.7 mg, and its purity estimated by LCMS analysis was 98%.

[003540] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 951.7 (M+2H).

[003541] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 951.7 (M+2H). Preparation of Example 5059 Example 5059

[003542] Example 5059 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.5 mg, and its purity was estimated by analysis by LCMS was 99%.

[003543] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 902.2 (M+2H).

[003544] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 902.3 (M+2H). Preparation of Example 5060 Example 5060

[003545] Example 5060 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.4 mg, and its purity estimated by LCMS analysis was 98%.

[003546] Analysis Condition A: Retention time = 1.40 min; ESI-MS(+) m/z 910.2 (M+2H).

[003547] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 910.2 (M+2H). Preparation of Example 5061 Example 5061

[003548] Example 5061 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.5 mg, and its purity was estimated by analysis by LCMS was 100%.

[003549] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 903.4 (M+2H).

[003550] Analysis Condition B: Retention time = 2.62 min; ESI-MS(-) m/z 901.6 (M-2H). Preparation of Example 5062 Example 5062

[003551] Example 5062 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.6 mg, and its purity estimated by LCMS analysis was 98%.

[003552] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 929.2 (M+2H).

[003553] Analysis Condition B: Retention time = 2.59 min; ESI-MS(-) m/z 926.8 (M-2H). Preparation of Example 5063 Example 5063

[003554] Example 5063 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.2 mg, and its purity estimated by LCMS analysis was 99%.

[003555] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 895.7 (M+2H).

[003556] Analysis Condition B: Retention time = 2.65 min; ESI-MS(-) m/z 893.8 (M-2H). Preparation of Example 5064 Example 5064

[003557] Example 5064 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.1 mg, and its purity was estimated by analysis by LCMS was 96%.

[003558] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 935.8 (M+2H).

[003559] Analysis Condition B: Retention time = 2.57 min; ESI-MS(-) m/z 933.2 (M-2H). Preparation of Example 5065 Example 5065

[003560] Example 5065 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity was estimated by analysis by LCMS was 95%.

[003561] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 949.3 (M+2H).

[003562] Analysis Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 949.3 (M+2H). Preparation of Example 5066 Example 5066

[003563] Example 5066 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.4 mg, and its purity was estimated by analysis by LCMS was 100%.

[003564] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 949 (M+2H).

[003565] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 949.8 (M+2H). Preparation of Example 5067 Example 5067

[003566] Example 5067 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.5 mg, and its purity was estimated by analysis by LCMS was 96%.

[003567] Analysis Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 923.7 (M+2H).

[003568] Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z 923.7 (M+2H). Preparation of Example 5068 Example 5068

[003569] Example 5068 was prepared following “General Synthetic Sequence A” but with the following modification: “Cyclization Method B” was used in place of “Cyclization Method A”, the scale was 0.600 mmol and all reagent portions were adjusted accordingly, and the resin was 2-chlorotrityl resin with Fmoc-Gly preloaded on the resin. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 8.7 mg, and its purity estimated by LCMS analysis was 100%.

[003570] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 956.8 (M+2H).

[003571] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 956.8 (M+2H). Preparation of Example 5069 Example 5069

[003572] Example 5069 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A" and operated on a 0.300 mmol scale and all reagent portions were adjusted accordingly. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 40 min, followed by a 5-min retention at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 112.8 mg, and its purity estimated by LCMS analysis was 93%.

[003573] Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 971.2 (M+2H). Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 971.3 (M+2H). ESI-HRMS(+) m/z: Calculated: 970.4798 (M+2H); Found: 970.4764 (M+2H). Preparation of Example 5070 Example 5070

[003574] Example 5070 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.0 mg, and its purity was estimated by analysis by LCMS was 100%.

[003575] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 909.6 (M+2H).

[003576] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 909.1 (M+2H). Preparation of Example 5071 Example 5071

[003577] Example 5071 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity was estimated by analysis by LCMS was 95%.

[003578] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 917.1 (M+2H).

[003579] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 917.2 (M+2H). Preparation of Example 5072 Example 5072

[003580] Example 5072 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.2 mg, and its purity was estimated by analysis by LCMS was 100%.

[003581] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 915.1 (M+2H).

[003582] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 915.1 (M+2H). Preparation of Example 5073 Example 5073

[003583] Example 5073 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.8 mg, and its purity estimated by LCMS analysis was 98%.

[003584] Assay Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 915.9 (M+2H). Assay Condition B: Retention time = 2.73 min; ESI-MS(+) m/z 915.9 (M+2H). Preparation of Example 5074 Example 5074

[003585] Example 5074 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.9 mg, and its purity estimated by LCMS analysis was 98%.

[003586] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 924.3 (M+2H).

[003587] Analysis Condition B: Retention time = 2.76 min; ESI-MS(+) m/z 923.8 (M+2H). Preparation of Example 5075 Example 5075

[003588] Example 5075 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.4 mg, and its purity estimated by LCMS analysis was 97%.

[003589] Analysis Condition A: Retention time = 1.60 min.

[003590] Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z 941.8 (M+2H); ESI-MS(-) m/z 940.3 (M-2H).

[003591] ESI-HRMS(+) m/z: Calculated: 941.4589 (M+2H); Found: 941.4568 (M+2H). Preparation of Example 5076 Example 5076

[003592] Example 5076 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.4 mg, and its purity was estimated by analysis by LCMS was 100%.

[003593] Analysis Condition A: Retention time = 1.65 min.

[003594] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 949.1 (M+2H); ESI-MS(-) m/z 947.7 (M-2H). Preparation of Example 5077 Example 5077

[003595] Example 5077 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.6 mg, and its purity estimated by LCMS analysis was 98%.

[003596] Analysis Condition A: Retention time = 1.76 min.

[003597] Analysis Condition B: Retention time = 2.90 min; ESI-MS(-) m/z 960.3 (M-2H). ESI-HRMS(+) m/z: Calculated: 961.4745 (M+2H); Found: 961.4715 (M+2H). Preparation of Example 5078 Example 5078

[003598] Example 5078 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.0 mg, and its purity estimated by LCMS analysis was 96%.

[003599] Analysis Condition A: Retention time = 1.51 min.

[003600] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 927.7 (M+2H). ESI-HRMS(+) m/z: Calculated: 927.4432 (M+2H); Found: 927.4402 (M+2H). Preparation of Example 5079 Example 5079

[003601] Example 5079 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.6 mg, and its purity was estimated by analysis by LCMS was 100%.

[003602] Analysis Condition A: Retention time = 1.63 min.

[003603] Analysis Condition B: Retention time = 2.77 min.

[003604] Analysis Condition C: Retention time = 1.024 min; ESI-MS(+) m/z 935.35 (M+2H).

[003605] ESI-HRMS(+) m/z: Calculated: 933.4614 (M+2H); Found: 933.4583 (M+2H). Preparation of Example 5080 Example 5080

[003606] Example 5080 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.7 mg, and its purity estimated by LCMS analysis was 100%.

[003607] Analysis Condition A: Retention time = 1.64 min.

[003608] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 941.2 (M+2H). ESI-HRMS(+) m/z: Calculated: 940.4692 (M+2H); Found: 940.4675 (M+2H). Preparation of Example 5081 Example 5081

[003609] Example 5081 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.1 mg, and its purity estimated by LCMS analysis was 100%.

[003610] Analysis Condition A: Retention time = 1.56 min.

[003611] Analysis Condition B: Retention time = 2.71 min.

[003612] Analysis Condition C: Retention time = 0.997 min; ESI-MS(+) m/z 941.5 (M+2H).

[003613] ESI-HRMS(+) m/z: Calculated: 940.4511 (M+2H); Found: 940.4484 (M+2H). Preparation of Example 5082 Example 5082

[003614] Example 5082 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 21.7 mg, and its purity estimated by LCMS analysis was 99%.

[003615] Analysis Condition A: Retention time = 1.71 min.

[003616] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 928.9 (M+2H). ESI-HRMS(+) m/z: Calculated: 928.4818 (M+2H); Found: 928.4794 (M+2H). Preparation of Example 5083 Example 5083

[003617] Example 5083 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.0 mg, and its purity estimated by LCMS analysis was 97%.

[003618] Analysis Condition A: Retention time = 1.68 min.

[003619] Analysis Condition B: Retention time = 2.74 min.

[003620] ESI-HRMS(+) m/z: Calculated: 915.4740 (M+2H) Found: 915.4709 (M+2H). Preparation of Example 5084 Example 5084

[003621] Example 5084 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A".

[003622] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.4 mg, and its purity was estimated to be 99% by LCMS analysis.

[003623] Analysis Condition B: Retention time = 2.71 min; ESI-MS(-) m/z 1855.3 (M-H).

[003624] ESI-HRMS(+) m/z: Calculated: 928.4511 (M+2H); Found: 928.4483 (M+2H). Preparation of Example 5085 Example 5085

[003625] Example 5085 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 30.4 mg, and its purity estimated by LCMS analysis was 96%.

[003626] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 939.2 (M+2H).

[003627] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 939.3 (M+2H).

[003628] ESI-HRMS(+) m/z: Calculated: 938.4585 (M+2H); Found: 938.4562 (M+2H). Preparation of Example 5086 Example 5086

[003629] Example 5086 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 44.2 mg, and its purity estimated by LCMS analysis was 95%.

[003630] Analysis Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 963.7 (M+2H).

[003631] Analysis Condition B: Retention time = 2.53 min; ESI-MS(-) m/z 961.8 (M-2H).

[003632] ESI-HRMS(+) m/z: Calculated: 962.9856 (M+2H); Found: 962.9827 (M+2H). Preparation of Example 5087 Example 5087

[003633] Example 5087 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.8 mg, and its purity estimated by LCMS analysis was 99%.

[003634] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 914.7 (M+2H).

[003635] Analysis Condition B: Retention time = 2.68 min; ESI-MS(-) m/z 912.7 (M-2H).

[003636] ESI-HRMS(+) m/z: Calculated: 913.9378 (M+2H); Found: 913.9353 (M+2H). Preparation of Example 5088 Example 5088

[003637] Example 5088 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 30.4 mg, and its purity estimated by LCMS analysis was 96%.

[003638] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 939.2 (M+2H).

[003639] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 939.3 (M+2H).

[003640] ESI-HRMS(+) m/z: Calculated: 938.4585 (M+2H); Found: 938.4562 (M+2H). Preparation of Example 5089 Example 5089

[003641] Example 5089 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.2 mg, and its purity was estimated by analysis by LCMS was 97%.

[003642] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 962 A (M+2H).

[003643] Analysis Condition B: Retention time = 2.70 min; ESI-MS(+) m/z 962.7 (M+2H).

[003644] ESI-HRMS(+) m/z: Calculated: 962.0085 (M+2H); Found: 962.0052 (M+2H). Preparation of Example 5090 Example 5090

[003645] Example 5090 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.6 mg, and its purity estimated by LCMS analysis was 99%.

[003646] Analysis Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 942.4 (M+2H). Analysis Condition B: Retention time = 2.80 min; ESI-MS(+) m/z 942.3 (M+2H). ESI-HRMS(+) m/z: Calculated: 941.4771 (M+2H); Found: 941.4739 (M+2H). Preparation of Example 5091 Example 5091

[003647] Example 5091 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.4 mg, and its purity estimated by LCMS analysis was 97%.

[003648] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 934.9 (M+2H).

[003649] Analysis Condition B: Retention time = 2.64 min.

[003650] ESI-HRMS(+) m/z: Calculated: 934.4692 (M+2H); Found: 934.4662 (M+2H). Preparation of Example 5092 Example 5092

[003651] Example 5092 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.3 mg, and its purity estimated by LCMS analysis was 100%.

[003652] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 957.0 (M+2H).

[003653] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 956.9 (M+2H).

[003654] ESI-HRMS(+) m/z: Calculated: 955.9778 (M+2H); Found: 955.9749 (M+2H). Preparation of Example 5093 Example 5093

[003655] Example 5093 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.3 mg, and its purity estimated by LCMS analysis was 98%.

[003656] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 929.0 (M+2H).

[003657] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 929.3 (M+2H).

[003658] ESI-HRMS(+) m/z: Calculated: 928.9494 (M+2H); Found: 928.4476 (M+2H). Preparation of Example 5094 Example 5094

[003659] Example 5094 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.1 mg, and its purity estimated by LCMS analysis was 96%.

[003660] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 949.3 (M+2H).

[003661] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 949.3 (M+2H).

[003662] ESI-HRMS(+) m/z: Calculated: 948.4905 (M+2H); Found: 948.4872 (M+2H). Preparation of Example 5095 Example 5095

[003663] Example 5095 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.9 mg, and its purity estimated by LCMS analysis was 97%.

[003664] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 963.4 (M+2H).

[003665] Analysis Condition B: Retention time = 2.73 min; ESI-MS(+) m/z 963.4 (M+2H).

[003666] ESI-HRMS(+) m/z: Calculated: 962.5005 (M+2H); Found: 962.4969 (M+2H). Preparation of Example 5096 Example 5096

[003667] Example 5096 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 48.4 mg, and its purity estimated by LCMS analysis was 97%.

[003668] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 964.3 (M+2H).

[003669] Analysis Condition B: Retention time = 2.67 min; ESI-MS(+) m/z 964.4 (M+2H).

[003670] ESI-HRMS(+) m/z: Calculated: 963.4720 (M+2H); Found: 963.4685 (M+2H). Preparation of Example 5097 Example 5097

[003671] Example 5097 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.9 mg, and its purity estimated by LCMS analysis was 98%.

[003672] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 928.8 (M+2H).

[003673] Analysis Condition B: Retention time = 2.70 min; ESI-MS(+) m/z 928.8 (M+2H).

[003674] ESI-HRMS(+) m/z: Calculated: 927.9534 (M+2H); Found: 927.9498 (M+2H). Preparation of Example 5098 Example 5098

[003675] Example 5098 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.0 mg, and its purity estimated by LCMS analysis was 97%.

[003676] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 950.3 (M+2H).

[003677] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 950.9 (M+2H).

[003678] ESI-HRMS(+) m/z: Calculated: 949.9483 (M+2H); Found: 949.9460 (M+2H). Preparation of Example 5099 Example 5099

[003679] Example 5099 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.4 mg, and its purity estimated by LCMS analysis was 100%.

[003680] Analysis Condition A: Retention time = 1.424 min; ESI-MS(+) m/z 971.00 (M+2H).

[003681] ESI-HRMS(+) m/z: Calculated: 970.4616 (M+2H); Found: 970.4595 (M+2H). Preparation of Example 5100 Example 5100

[003682] Example 5100 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 25.4 mg, and its purity estimated by LCMS analysis was 100%.

[003683] Analysis Condition A: Retention time = 1.44 min.

[003684] Analysis Condition B: Retention time = 2.67 min; ESI-MS(+) m/z 971.1 (M+2H). ESI-HRMS(+) m/z: Calculated: 969.9878 (M+2H); Found: 969.9850 (M+2H). Preparation of Example 5101 Example 5101

[003685] Example 5101 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.4 mg, and its purity estimated by LCMS analysis was 98%.

[003686] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 929.2 (M+2H). Analysis Condition B: Retention time = 2.67 min; ESI-MS(+) m/z 929.3 (M+2H).

[003687] ESI-HRMS(+) m/z: Calculated: 928.4329 (M+2H); Found: 928.4301 (M+2H). Preparation of Example 5102 Example 5102

[003688] Example 5102 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.6 mg, and its purity estimated by LCMS analysis was 100%.

[003689] Analysis Condition A: Retention time = 1.35 min; ESI-MS(+) m/z 964.2 (M+2H).

[003690] Analysis Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 964.3 (M+2H).

[003691] ESI-HRMS(+) m/z: Calculated: 963.4776 (M+2H); Found: 963.4740 (M+2H). Preparation of Example 5103 Example 5103

[003692] Example 5103 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.4 mg, and its purity estimated by LCMS analysis was 100%.

[003693] Analysis Condition A: Retention time = 1.35 min; ESI-MS(+) m/z 942.8 (M+2H).

[003694] Analysis Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 943.2 (M+2H). Preparation of Example 5104 Example 5104

[003695] Example 5104 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.5 mg, and its purity estimated by LCMS analysis was 100%.

[003696] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 935.7 (M+2H).

[003697] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 935.7 (M+2H).

[003698] ESI-HRMS(+) m/z: Calculated: 934.9669 (M+2H); Found: 934.9637 (M+2H). Preparation of Example 5105 Example 5105

[003699] Example 5105 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.2 mg, and its purity estimated by LCMS analysis was 99%.

[003700] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 956.6 (M+2H).

[003701] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 957.0 (M+2H).

[003702] ESI-HRMS(+) m/z: Calculated: 956.4698 (M+2H); Found: 956.4670 (M+2H). Preparation of Example 5106 Example 5106

[003703] Example 5106 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.3 mg, and its purity estimated by LCMS analysis was 100%.

[003704] Analysis Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 970.4 (M+2H).

[003705] Analysis Condition B: Retention time = 2.99 min; ESI-MS(+) m/z 970.3 (M+2H).

[003706] ESI-HRMS(+) m/z: Calculated: 969.9696 (M+2H); Found: 969.9662 (M+2H). Preparation of Example 5107 Example 5107

[003707] Example 5107 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.7 mg, and its purity estimated by LCMS analysis was 100%.

[003708] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 941.8 (M+2H). Analysis Condition B: Retention time = 2.86 min; ESI-MS(+) m/z 941.4 (M+2H). ESI-HRMS(+) m/z: Calculated: 940.9794 (M+2H); Found: 940.9762 (M+2H). Preparation of Example 5108 Example 5108

[003709] Example 5108 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.5 mg, and its purity estimated by LCMS analysis was 100%.

[003710] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 922.5 (M+2H).

[003711] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 922.7 (M+2H).

[003712] ESI-HRMS(+) m/z: Calculated: 921.9352 (M+2H); Found: 921.9318 (M+2H). Preparation of Example 5109 Example 5109

[003713] Example 5109 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity estimated by LCMS analysis was 100%.

[003714] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 927.3 (M+2H). Analysis Condition B: Retention time = 2.80 min; ESI-MS(+) m/z 927.0 (M+2H). ESI-HRMS(+) m/z: Calculated: 926.4536 (M+2H); Found: 926.4504 (M+2H). Preparation of Example 5110 Example 5110

[003715] Example 5110 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.2 mg, and its purity estimated by LCMS analysis was 100%.

[003716] Analysis Condition A: Retention time = 1.40 min; ESI-MS(+) m/z 984.8 (M+2H).

[003717] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 984.9 (M+2H).

[003718] ESI-HRMS(+) m/z: Calculated: 984.0091 (M+2H); Found: 984.0061 (M+2H). Preparation of Example 5111 Example 5111

[003719] Example 5111 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.7 mg, and its purity estimated by LCMS analysis was 100%.

[003720] Analysis Condition A: Retention time = 1.28 min; ESI-MS(+) m/z 943.8 (M+2H). Analysis Condition B: Retention time = 2.49 min; ESI-MS(+) m/z 943.8 (M+2H). ESI-HRMS(+) m/z: Calculated: 942.9405 (M+2H); Found: 942.9380 (M+2H). Preparation of Example 5112 Example 5112

[003721] Example 5112 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.1 mg, and its purity estimated by LCMS analysis was 100%.

[003722] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 964.3 (M+2H).

[003723] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 964.2 (M+2H).

[003724] ESI-HRMS(+) m/z: Calculated: 963.4720 (M+2H); Found: 963.4688 (M+2H). Preparation of Example 5113 Example 5113

[003725] Example 5113 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.0 mg, and its purity estimated by LCMS analysis was 100%.

[003726] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 964.3 (M+2H).

[003727] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 964.3 (M+2H).

[003728] ESI-HRMS(+) m/z: Calculated: 963.4476 (M+2H); Found: 963.4742 (M+2H). Preparation of Example 5114 Example 5114

[003729] Example 5114 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.1 mg, and its purity estimated by LCMS analysis was 100%.

[003730] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 943.3 (M+2H).

[003731] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 943.3 (M+2H).

[003732] ESI-HRMS(+) m/z: Calculated: 942.4461 (M+2H); Found: 942.4485 (M+2H). Preparation of Example 5115 Example 5115

[003733] Example 5115 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-95% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.3 mg, and its purity estimated by LCMS analysis was 100%.

[003734] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 916.6 (M+2H).

[003735] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 917.1 (M+2H).

[003736] ESI-HRMS(+) m/z: Calculated: 916.4454 (M+2H); Found: 916.4431 (M+2H). Preparation of Example 5116 Example 5116

[003737] Example 5116 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.2 mg, and its purity estimated by LCMS analysis was 100%.

[003738] Analysis Condition A: Retention time = 1.67 min; ESI-MS(+) m/z 881.9 (M+2H).

[003739] Analysis Condition B: Retention time = 2.66 min; ESI-MS(-) m/z 880.5 (M-2H).

[003740] ESI-HRMS(+) m/z: Calculated: 882.4267 (M+2H); Found: 882.4241 (M+2H). Preparation of Example 5117 Example 5117

[003741] Example 5117 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.6 mg, and its purity estimated by LCMS analysis was 100%.

[003742] Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 883.5 (M+2H).

[003743] Analysis Condition B: Retention time = 2.55 min; ESI-MS(-) m/z 881.8 (M-2H).

[003744] ESI-HRMS(+) m/z: Calculated: 883.3982 (M+2H); Found: 883.3956 (M+2H). Preparation of Example 5118 Example 5118

[003745] Example 5118 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.3 mg, and its purity was estimated to be 99% by LCMS analysis.

[003746] Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z 896.3 (M+2H).

[003747] Analysis Condition B: Retention time = 2.67 min; ESI-MS(-) m/z 894.2 (M-2H).

[003748] ESI-HRMS(+) m/z: Calculated: 895.9322 (M+2H); Found: 895.9297 (M+2H). Preparation of Example 5119 Example 5119

[003749] Example 5119 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.1 mg, and its purity was estimated by LCMS analysis to be 99%.

[003750] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 897.4 (M+2H).

[003751] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 897.6 (M+2H).

[003752] ESI-HRMS(+) m/z: Calculated: 896.9193 (M+2H); Found: 896.9218 (M+2H). Preparation of Example 5120 Example 5120

[003753] Example 5120 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.7 mg, and its purity estimated by LCMS analysis was 98%.

[003754] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 950.2 (M+2H).

[003755] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 950.2 (M+2H).

[003756] ESI-HRMS(+) m/z: Calculated: 949.4563 (M+2H); Found: 949.4537 (M+2H). Preparation of Example 5121 Example 5121

[003757] Example 5121 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.3 mg, and its purity estimated by LCMS analysis was 100%.

[003758] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 929.2 (M+2H).

[003759] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 928.8 (M+2H).

[003760] ESI-HRMS(+) m/z: Calculated: 928.4329 (M+2H); Found: 928.4301 (M+2H). Preparation of Example 5122 Example 5122

[003761] Example 5122 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.6 mg, and its purity estimated by LCMS analysis was 100%.

[003762] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 906.6 (M+2H).

[003763] Analysis Condition B: Retention time = 2.85 min; ESI-MS(+) m/z 906.3 (M+2H).

[003764] ESI-HRMS(+) m/z: Calculated: 905.9403 (M+2H); Found: 905.9375 (M+2H). Preparation of Example 5123 Example 5123

[003765] Example 5123 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.2 mg, and its purity estimated by LCMS analysis was 99%.

[003766] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 950.1 (M+2H).

[003767] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 950.2 (M+2H).

[003768] ESI-HRMS(+) m/z: Calculated: 949.4620 (M+2H); Found: 949.4589 (M+2H). Preparation of Example 5124 Example 5124

[003769] Example 5124 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.0 mg, and its purity estimated by LCMS analysis was 99%.

[003770] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 970.9 (M+2H).

[003771] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 971.2 (M+2H).

[003772] ESI-HRMS(+) m/z: Calculated: 970.4854 (M+2H); Found: 970.4820 (M+2H). Preparation of Example 5125 Example 5125

[003773] Example 5125 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 40.6 mg, and its purity estimated by LCMS analysis was 100%.

[003774] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 914.0 (M+2H).

[003775] Analysis Condition B: Retention time = 2.69 min; ESI-MS(+) m/z 914.1 (M+2H).

[003776] ESI-HRMS(+) m/z: Calculated: 913.4276 (M+2H); Found: 913.4242 (M+2H). Preparation of Example 5126 Example 5126

[003777] Example 5126 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.7 mg, and its purity estimated by LCMS analysis was 100%.

[003778] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 950.2 (M+2H).

[003779] Analysis Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 950.2 (M+2H).

[003780] ESI-HRMS(+) m/z: Calculated: 949.4381 (M+2H); Found: 949.4355 (M+2H). Preparation of Example 5127 Example 5127

[003781] Example 5127 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.2 mg, and its purity estimated by LCMS analysis was 100%.

[003782] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 902.0 (M+2H). Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 902.2 (M+2H). ESI-HRMS(+) m/z: Calculated: 901.4402 (M+2H); Found: 901.4375 (M+2H). Preparation of Example 5128 Example 5128

[003783] Example 5128 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.1 mg, and its purity estimated by LCMS analysis was 99%.

[003784] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 904.0 (M+2H).

[003785] Analysis Condition B: Retention time = 2.73 min; ESI-MS(+) m/z 904.1 (M+2H).

[003786] ESI-HRMS(+) m/z: Calculated: 903.4194 (M+2H); Found: 903.4167 (M+2H). Preparation of Example 5129 Example 5129

[003787] Example 5129 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.3 mg, and its purity estimated by LCMS analysis was 99%.

[003788] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 917.1 (M+2H).

[003789] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 917.2 (M+2H).

[003790] ESI-HRMS(+) m/z: Calculated: 916.4511 (M+2H); Found: 916.4482 (M+2H). Preparation of Example 5130 Example 5130

[003791] Example 5130 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.6 mg, and its purity estimated by LCMS analysis was 97%.

[003792] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 932 A (M+2H).

[003793] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 932.2 (M+2H).

[003794] ESI-HRMS(+) m/z: Calculated: 931.4563 (M+2H); Found: 931.4534 (M+2H). Preparation of Example 5131 Example 5131

[003795] Example 5131 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.3 mg, and its purity estimated by LCMS analysis was 100%.

[003796] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 931.8 (M+2H).

[003797] Analysis Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 931.6 (M+2H).

[003798] ESI-HRMS(+) m/z: Calculated: 930.9643 (M+2H); Found: 930.9617 (M+2H). Preparation of Example 5132 Example 5132

[003799] Example 5132 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 44.8 mg, and its purity estimated by LCMS analysis was 100%.

[003800] Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 950.2 (M+2H).

[003801] Analysis Condition B: Retention time = 2.52 min; ESI-MS(+) m/z 950.4 (M+2H).

[003802] ESI-HRMS(+) m/z: Calculated: 949.4620 (M+2H); Found: 949.4587 (M+2H). Preparation of Example 5133 Example 5133

[003803] Example 5133 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.5 mg, and its purity estimated by LCMS analysis was 100%.

[003804] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 922.5 (M+2H).

[003805] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 922.7 (M+2H).

[003806] ESI-HRMS(+) m/z: Calculated: 921.9352 (M+2H); Found: 921.9318 (M+2H). Preparation of Example 5134 Example 5134

[003807] Example 5134 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.8 mg, and its purity estimated by LCMS analysis was 100%.

[003808] Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 943.2 (M+2H). Analysis Condition B: Retention time = 2.54 min; ESI-MS(+) m/z 943.1 (M+2H). ESI-HRMS(+) m/z: Calculated: 942.4541 (M+2H); Found: 942.4513 (M+2H). Preparation of Example 5135 Example 5135

[003809] Example 5135 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.8 mg, and its purity estimated by LCMS analysis was 100%.

[003810] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 869.4 (M+2H).

[003811] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 870.0 (M+2H).

[003812] ESI-HRMS(+) m/z: Calculated: 869.4007 (M+2H); Found: 869.3986 (M+2H). Preparation of Example 5137 Example 5137

[003813] Example 5137 was prepared following “General Synthetic Sequence A” but using “Cyclization Method B” in place of “Cyclization Method A”, and was prepared on a 0.300 mmol scale where the reagent amounts were adjusted appropriately. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 102.2 mg, and its estimated purity by LCMS analysis was 98%.

[003814] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 964.3 (M+2H). Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 964.1 (M+2H). ESI-HRMS(+) m/z: Calculated: 963.4720 (M+2H); Found: 963.4687 (M+2H). Preparation of Example 5138 Example 5138

[003815] Example 5138 was prepared following “General Synthetic Sequence A” but using “Cyclization Method B” in place of “Cyclization Method A”, and was prepared on a 0.300 mmol scale where reagent amounts were adjusted accordingly. The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 57.8 mg, and its purity estimated by LCMS analysis was 100%.

[003816] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 971.2 (M+2H).

[003817] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 971.2 (M+2H). Preparation of Example 5139 Example 5139

[003818] Example 5139 was prepared following “General Synthetic Sequence A” but using “Cyclization Method B” in place of “Cyclization Method A”, and was prepared on a 0.300 mmol scale where the reagent amounts were adjusted appropriately. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 27.7 mg, and its purity estimated by LCMS analysis was 100%.

[003819] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 950.1 (M+2H).

[003820] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 950.1 (M+2H).

[003821] ESI-HRMS(+) m/z: Calculated: 949.4563 (M+2H); Found: 949.4541 (M+2H). Preparation of Example 5140 Example 5140

[003822] Example 5140 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.5 mg, and its purity estimated by LCMS analysis was 98%.

[003823] Analysis Condition A: Retention time = 1.34 min; ESI-MS(+) m/z 901.8 (M+2H).

[003824] Analysis Condition B: Retention time = 2.51 min; ESI-MS(+) m/z 902.1 (M+2H).

[003825] ESI-HRMS(+) m/z: Calculated: 901.4822 (M+2H); Found: 901.4800 (M+2H). Preparation of Example 5141 Example 5141

[003826] Example 5141 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.0 mg, and its purity estimated by LCMS analysis was 100%.

[003827] Analysis Condition A: Retention time = 1.40 min; ESI-MS(+) m/z 935.8 (M+2H).

[003828] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 935.5 (M+2H).

[003829] ESI-HRMS(+) m/z: Calculated: 934.9487 (M+2H); Found: 934.9471 (M+2H). Preparation of Example 5142 Example 5142

[003830] Example 5142 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity estimated by LCMS analysis was 100%.

[003831] Analysis Condition A: Retention time = 1.31 min; ESI-MS(+) m/z 935.1 (M+2H).

[003832] Analysis Condition B: Retention time = 2.49 min; ESI-MS(+) m/z 935.6 (M+2H).

[003833] ESI-HRMS(+) m/z: Calculated: 934.9487 (M+2H); Found: 934.9467 (M+2H). Preparation of Example 5143 Example 5143

[003834] Example 5143 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.4 mg, and its purity was estimated by analysis by LCMS was 100%.

[003835] Analysis Condition A: Retention time = 1.34 min; ESI-MS(+) m/z 935.3 (M+2H).

[003836] Analysis Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 935.4 (M+2H).

[003837] ESI-HRMS(+) m/z: Calculated: 934.9487 (M+2H); Found: 934.9464 (M+2H). Preparation of Example 5144 Example 5144

[003838] Example 5144 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.1 mg, and its purity estimated by LCMS analysis was 100%.

[003839] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 952 (M+2H).

[003840] Analysis Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 952.7 (M+2H).

[003841] ESI-HRMS(+) m/z: Calculated: 951.9409 (M+2H); Found: 951.9385 (M+2H). Preparation of Example 5145 Example 5145

[003842] Example 5145 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.0 mg, and its purity estimated by LCMS analysis was 100%.

[003843] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 935.9 (M+2H).

[003844] Analysis Condition B: Retention time = 2.60 min; ESI-MS(-) m/z 934.2 (M-2H).

[003845] ESI-HRMS(+) m/z: Calculated: 935.4407 (M+2H); Found: 935.4385 (M+2H). Preparation of Example 5146 Example 5146

[003846] Example 5146 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 0.5 mg, and its purity estimated by LCMS analysis was 100%.

[003847] Analysis Condition A: Retention time = 1.33 min; ESI-MS(+) m/z 935.5 (M+2H).

[003848] Analysis Condition B: Retention time = 2.53 min; ESI-MS(-) m/z 933.2 (M-2H).

[003849] ESI-HRMS(+) m/z: Calculated: 934.9487 (M+2H); Found: 934.9464 (M+2H). Preparation of Example 5147 Example 5147

[003850] Example 5147 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.9 mg, and its purity estimated by LCMS analysis was 100%.

[003851] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 952.6 (M+2H).

[003852] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 952.7 (M+2H).

[003853] ESI-HRMS(+) m/z: Calculated: 951.9409 (M+2H); Found: 951.9377 (M+2H). Preparation of Example 6001 Example 6001

[003854] Example 6001 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003855] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.2 mg, and its purity estimated by LCMS analysis was 99%.

[003856] Analysis Condition A: Retention time = 1.778 min; ESI-MS(+) m/z 955.25 (M+2H). Preparation of Example 6002 Example 6002

[003857] Example 6002 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003858] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.4 mg, and its purity estimated by LCMS analysis was 100%.

[003859] Analysis Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 978.2 (M+2H).

[003860] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 977.8 (M+2H). Preparation of Example 6003 Example 6003

[003861] Example 6003 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003862] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 40-80% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.2 mg, and its purity estimated by LCMS analysis was 100%.

[003863] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 948.1 (M+2H).

[003864] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 948.1 (M+2H). Preparation of Example 6004 Example 6004

[003865] Example 6004 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003866] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.7 mg, and its purity estimated by LCMS analysis was 100%.

[003867] Analysis Condition A: Retention time = 1.69 min; ESI-MS(+) m/z 934.3 (M+2H).

[003868] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 934.0 (M+2H). Preparation of Example 6005 Example 6005

[003869] Example 6005 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003870] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.1 mg, and its purity estimated by LCMS analysis was 98%.

[003871] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 920.4 (M+2H).

[003872] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 920.5 (M+2H). Preparation of Example 6006 Example 6006

[003873] Example 6006 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003874] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 11.4 mg, and its purity estimated by LCMS analysis was 100%.

[003875] Analysis Condition A: Retention time = 1.71 min; ESI-MS(+) m/z 934.8 (M+2H). Preparation of Example 6007 Example 6007

[003876] Example 6007 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003877] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.6 mg, and its purity estimated by LCMS analysis was 98%.

[003878] ESI-MS Analysis Condition (+) m/z 919.2 (M+2H).

[003879] ESI-MS(+) Analysis Condition m/z 919.4 (M+2H). Preparation of Example 6008 Example 6008

[003880] Example 6008 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003881] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.8 mg, and its purity estimated by LCMS analysis was 100%.

[003882] Analysis Condition A: Retention time = 1.93 min; ESI-MS(+) m/z 938.5 (M+2H).

[003883] Analysis Condition B: Retention time = 2.99 min; ESI-MS(+) m/z 938.6 (M+2H). Preparation of Example 6009 Example 6009

[003884] Example 6009 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003885] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.0 mg, and its purity estimated by LCMS analysis was 100%.

[003886] Analysis Condition A: Retention time = 1.87 min; ESI-MS(+) m/z 963.2 (M+2H).

[003887] Analysis Condition B: Retention time = 2.97 min; ESI-MS(+) m/z 963.0 (M+2H). Preparation of Example 6010 Example 6010

[003888] Example 6010 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003889] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.0 mg, and its purity estimated by LCMS analysis was 98%.

[003890] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 913.5 (M+2H).

[003891] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 913.4 (M+2H). Preparation of Example 6011 Example 6011

[003892] Example 6011 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003893] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.0 mg, and its purity estimated by LCMS analysis was 100%.

[003894] Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z 926.4 (M+2H).

[003895] Analysis Condition B: Retention time = 2.87 min; ESI-MS(+) m/z 926.5 (M+2H). Preparation of Example 6012 Example 6012

[003896] Example 6012 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003897] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its purity estimated by LCMS analysis was 99%.

[003898] Analysis Condition A: Retention time = 1.71 min; ESI-MS(+) m/z 937.6 (M+2H).

[003899] Analysis Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 937.4 (M+2H). Preparation of Example 6013 Example 6013

[003900] Example 6013 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003901] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.2 mg, and its purity estimated by LCMS analysis was 100%.

[003902] Analysis Condition A: Retention time = 1.96 min; ESI-MS(+) m/z 258.6 (M+2H).

[003903] Analysis Condition B: Retention time = 3.08 min; ESI-MS(-) m/z 956.5 (M-2H). Preparation of Example 6014 Example 6014

[003904] Example 6014 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003905] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 7.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[003906] Analysis Condition A: Retention time = 1.83 min; ESI-MS(+) m/z 951.5 (M+2H).

[003907] Analysis Condition B: Retention time = 2.85 min; ESI-MS(+) m/z 951.4 (M+2H). Preparation of Example 6015 Example 6015

[003908] Example 6015 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003909] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;

[003910] Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.5 mg, and its purity estimated by LCMS analysis was 98%.

[003911] Analysis Condition A: Retention time = 1.73 min; ESI-MS(+) m/z 937.5 (M+2H).

[003912] Analysis Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 937.5 (M+2H). Preparation of Example 6016 Example 6016

[003913] Example 6016 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003914] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.4 mg, and its purity estimated by LCMS analysis was 98%.

[003915] Analysis Condition A: Retention time = 1.97 min; ESI-MS(+) m/z 958.5 (M+2H).

[003916] Analysis Condition B: Retention time = 3.03 min; ESI-MS(+) m/z 958.4 (M+2H). Preparation of Example 6017 Example 6017

[003917] Example 6017 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003918] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity estimated by LCMS analysis was 100%.

[003919] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 984.4 (M+2H).

[003920] Analysis Condition B: Retention time = 2.56 min; ESI-MS(-) m/z 983.1 (M-2H). Preparation of Example 6018 Example 6018

[003921] Example 6018 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003922] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 14.6 mg, and its purity was estimated to be 99% by LCMS analysis.

[003923] Analysis Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 976.0 (M+2H).

[003924] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 976.7 (M+2H). Preparation of Example 6019 Example 6019

[003925] Example 6019 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS with the following conditions:

[003926] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 60-100% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.4 mg, and its purity estimated by LCMS analysis was 100%.

[003927] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 990.9 (M+2H).

[003928] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 991.2 (M+2H). Preparation of Example 6020 Example 6020

[003929] Example 6020 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003930] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.3 mg, and its purity estimated by LCMS analysis was 99%.

[003931] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 1004.6 (M+2H).

[003932] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 1004.6 (M+2H). Preparation of Example 6021 Example 6021

[003933] Example 6021 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003934] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-50% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.2 mg, and its purity estimated by LCMS analysis was 100%.

[003935] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 929.8 (M+2H).

[003936] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 930.4 (M+2H). Preparation of Example 6022 Example 6022

[003937] Example 6022 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003938] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 19.5 mg, and its purity estimated by LCMS analysis was 100%.

[003939] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 960.9 (M+2H).

[003940] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 960.9 (M+2H). Preparation of Example 6023 Example 6023

[003941] Example 6023 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003942] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.2 mg, and its purity estimated by LCMS analysis was 96%.

[003943] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 946.8 (M+2H). Preparation of Example 6024 Example 6024

[003944] Example 6024 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003945] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its purity estimated by LCMS analysis was 100%.

[003946] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 913.8 (M+2H).

[003947] Analysis Condition B: Retention time = 2.61 min; ESI-MS(-) m/z 911.9 (M-2H). Preparation of Example 6025 Example 6025

[003948] Example 6025 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003949] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.7 mg, and its purity estimated by LCMS analysis was 94%.

[003950] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 934.7 (M+2H).

[003951] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 934.4 (M+2H). Preparation of Example 6026 Example 6026

[003952] Example 6026 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.9 mg, and its purity was estimated to be 99% by LCMS analysis.

[003953] Analysis Condition A: Retention time = 1.48 min; ESI-MS(-) m/z 940.9 (M-2H).

[003954] Analysis Condition B: Retention time = 2.62 min; ESI-MS(-) m/z 940.7 (M-2H). Preparation of Example 6027 Example 6027

[003955] Example 6027 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003956] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.2 mg, and its purity estimated by LCMS analysis was 100%.

[003957] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 941.3 (M+2H).

[003958] Analysis Condition B: Retention time = 2.72 min; ESI-MS(+) m/z 941.3 (M+2H). Preparation of Example 6028 Example 6028

[003959] Example 6028 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003960] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.0 mg, and its purity estimated by LCMS analysis was 99%.

[003961] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 939.6 (M+2H).

[003962] Analysis Condition B: Retention time = 2.73 min; ESI-MS(-) m/z 937.8 (M-2H). Preparation of Example 6029 Example 6029

[003963] Example 6029 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 16.9 mg, and its estimated purity by LCMS analysis was 96%.

[003964] Analysis Condition A: Retention time = 1.72 min; ESI-MS(+) m/z 947.8 (M+2H).

[003965] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 947.8 (M+2H). Preparation of Example 6030 Example 6030

[003966] Example 6030 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 25.5 mg, and its purity estimated by LCMS analysis was 98%.

[003967] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 942.7 (M+2H).

[003968] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 942.7 (M+2H). Preparation of Example 6031 Example 6031

[003969] Example 6031 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(m-tolyloxy)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B for 30 min, followed by a 5-min retention at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 16.6 mg, and its purity estimated by LCMS analysis was 98%.

[003970] Assay Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 942.6 (M+2H). Assay Condition B: Retention time = 2.70 min; ESI-MS(+) m/z 943.2 (M+2H). Preparation of Example 6032 Example 6032

[003971] Example 6032 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003972] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 21.9 mg, and its purity was estimated to be 96% by LCMS analysis.

[003973] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 937.0 (M+2H).

[003974] Analysis Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 936.9 (M+2H). Preparation of Example 6033 Example 6033

[003975] Example 6033 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003976] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 13.2 mg, and its purity was estimated to be 97% by LCMS analysis.

[003977] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 944.1 (M+2H).

[003978] Analysis Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 944.4 (M+2H). Preparation of Example 6034 Example 6034

[003979] Example 6034 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[003980] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 30-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;

[003981] Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.5 mg, and its purity estimated by LCMS analysis was 97%.

[003982] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 943.5 (M+2H).

[003983] Analysis Condition B: Retention time = 2.63 min; ESI-MS(-) m/z 941.8 (M-2H). Preparation of Example 6035 Example 6035

[003984] Example 6035 was prepared following “General Synthetic Sequence A”. The amino acids (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)([13C]methyl)amino)propanoic acid and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(([13C]methyl)amino)hexanoic acid were used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a retention of 5 minutes at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 26.1 mg, and its purity estimated by LCMS analysis was 96%.

[003985] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 958.2 (M+2H).

[003986] Analysis Condition B: Retention time = 2.83 min; ESI-MS(-) m/z 955.7 (M-2H). Preparation of Example 6036 Example 6036

[003987] Example 6036 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.4 mg, and its purity estimated by LCMS analysis was 95%.

[003988] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 91 A (M+2H).

[003989] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 973.6 (M+2H). Preparation of Example 6037 Example 6037

[003990] Example 6037 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(([13C]methyl)amino)hexanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 26.5 mg, and its purity estimated by LCMS analysis was 99%.

[003991] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 957.3 (M+2H).

[003992] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 957.4 (M+2H). Preparation of Example 6038 Example 6038

[003993] Example 6038 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(([13C]methyl)amino)hexanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 23.0 mg, and its purity estimated by LCMS analysis was 99%.

[003994] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 957.3 (M+2H).

[003995] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 957.4 (M+2H). Preparation of Example 6039 Example 6039

[003996] Example 6039 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)([13C]methyl)amino)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 18.8 mg, and its purity estimated by LCMS analysis was 95%.

[003997] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 957.3 (M+2H).

[003998] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 957.3 (M+2H). Preparation of Example 6040 Example 6040

[003999] Example 6040 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004000] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.8 mg, and its purity estimated by LCMS analysis was 100%.

[004001] Analysis Condition A: Retention time = 1.64 min.

[004002] Analysis Condition B: Retention time = 2.75 min. Preparation of Example 6041 Example 6041

[004003] Example 6041 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004004] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.5 mg, and its purity estimated by LCMS analysis was 95%.

[004005] Analysis Condition A: Retention time = 1.80 min; ESI-MS(+) m/z 922.8 (M+2H).

[004006] Analysis Condition B: Retention time = 2.96 min; ESI-MS(+) m/z 922.9 (M+2H). Preparation of Example 6042 Example 6042

[004007] Example 6042 was prepared following “General Synthetic Sequence A”. The amino acid (2S,5S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-5-hydroxypiperidine-2-carboxylic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 17.3 mg, and its purity estimated by LCMS analysis was 100%.

[004008] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 922.8 (M+2H).

[004009] Analysis Condition B: Retention time = 2.78 min; ESI-MS(+) m/z 922.8 (M+2H). Preparation of Example 6043 Example 6043

[004010] Example 6043 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 15.2 mg, and its purity estimated by LCMS analysis was 97%.

[004011] Analysis Condition A: Retention time = 1.40 min; ESI-MS(+) m/z 953.0 (M+2H).

[004012] Analysis Condition B: Retention time = 2.71 min; ESI-MS(-) m/z 950.6 (M-2H). Preparation of Example 6044 Example 6044

[004013] Example 6044 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.9 mg, and its purity estimated by LCMS analysis was 97%.

[004014] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 958.5 (M+2H).

[004015] Analysis Condition B: Retention time = 2.50 min; ESI-MS(-) m/z 957.7 (M-2H). Preparation of Example 6045 Example 6045

[004016] Example 6045 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-((((9H-fluoren-9-yl)methoxy)carbonyl)oxy)-3-bromophenyl)propanoic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 0 min hold at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 96%.

[004017] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 938.7 (M+2H).

[004018] Analysis Condition B: Retention time = 2.50 min; ESI-MS(-) m/z 935.5 (M-2H). Preparation of Example 6046 Example 6046

[004019] Example 6046 was prepared following “General Synthetic Sequence A”. The amino acid (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-3-yl)propanoic acid was used. The crude material was purified via preparatory LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 30-70% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions:

[004020] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.1 mg, and its purity estimated by LCMS analysis was 97%.

[004021] Assay Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 944 (M+2H). Assay Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 944.3 (M+2H). Preparation of Example 6047 Example 6047

[004022] Example 6047 was prepared following “General Synthetic Sequence A”. The amino acid (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyloxy)pyrrolidine-2-carboxylic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The material was further purified via preparatory LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, followed by a 5-min retention at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 29.7 mg, and its purity estimated by LCMS analysis was 100%.

[004023] Assay Condition A: Retention time = 1.80 min; ESI-MS(+) m/z 960.7 (M+2H). Assay Condition B: Retention time = 2.94 min; ESI-MS(+) m/z 960.3 (M+2H). Preparation of Example 6048 Example 6048

[004024] Example 6048 was prepared following “General Synthetic Sequence A”. The amino acid (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((6-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.1 mg, and its purity estimated by LCMS analysis was 100%.

[004025] Analysis Condition A: Retention time = 1.87 min; ESI-MS(+) m/z 993.8 (M+2H).

[004026] Analysis Condition B: Retention time = 2.98 min; ESI-MS(+) m/z 994.2 (M+2H). Preparation of Example 6049 Example 6049

[004027] Example 6049 was prepared following “General Synthetic Sequence A”. The amino acid (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-((3-bromoquinolin-2-yl)oxy)pyrrolidine-2-carboxylic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions:

[004028] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-70% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity estimated by LCMS analysis was 100%.

[004029] Analysis Condition A: Retention time = 1.96 min; ESI-MS(+) m/z 1018.1 (M+2H).

[004030] Analysis Condition B: Retention time = 3.07 min; ESI-MS(+) m/z 1018.1 (M+2H). Preparation of Example 6050 Example 6050

[004031] Example 6050 was prepared following “General Synthetic Sequence A”. The amino acid (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid was used. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-95% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via evaporation centrifuge. The product yield was 14.9 mg, and its purity estimated by LCMS analysis was 97%.

[004032] Analysis Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 914.8 (M+2H).

[004033] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 915.0 (M+2H). Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-phenyl-1H-indol-3-yl)propanoic acid

[004034] To a mixture of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid (500 mg, 1.172 mmol) and silver(I) tetrafluoroborate (456 mg, 2.345 mmol) in a sealed, reusable 150 mL round bottom flask at room temperature in a N2 atmosphere was added a mixture of iodobenzene (478 mg, 2.345 mmol) in DMF (3 mL), followed by a mixture of trifluoroacetic acid (0.090 mL, 1.172 mmol) in DMF (3 mL) and then a mixture of diacetoxypalladium (13.16 mg, 0.059 mmol) in DMF (4 mL). The flask was tightly capped and stirred at 95 °C in an oil bath for 17 h. The mixture was diluted with EtOAc (150 mL), and filtered. The filtrate was evaporated, and the residue was dissolved in MeOH and purified by Shimadzu-VP preparative reversed-phase HPLC using the separation method: Solvent A = 10% MeOH-90% H2O-0.1% TFA, Solvent B = 90% MeOH-10% H2O-0.1% TFA, Initial % B = 50, Final % B = 100, Gradient time = 10 min, Stop time = 12 min, Flow rate = 30 mL/min, Column: SunFire Prep C18 19 x 100 5μm, (UV detection at 220 nm). The desired fractions combined at retention time = 8.513 min were evaporated to give an off-white solid of the product (247 mg).

[004035] 1H NMR (400 MHz, DMSO-d6)DDDl2.70 (br s, 1H), 11.23 (s, 1H), 7.88 (d, J= 7.3, 2H), 7.80 (d, J= 8.1, 1H ), 7.73 (d, J= 7.8, 1H), 7.70 - 7.62 (m, 4H), 7.49 (t, J= 7.6, 2H), 7.43 - 7.34 (m, 4H), 7.30 (m, 1H), 7.25 (m, 1H), 7.10 (t, J= 7.5, 1H), 7.00 (m, 1H), 4.35 -4.30 (m, 1H), 4.16 - 4.09 (m, 3H), 3.41 (m, 1H), 3.20 (dd, J= 14.4, 8.6, 1H). The position of the phenyl ring in the indole C2 was indicated by observation of the long band correlation of CH between the phenyl protons H11/H15 and the C2 carbon of indole. Optical rotation [a]2% -9.83° (1.75 mg/mL, MeOH). LCMS (ES+) m/z = 503.1 (M+H), time retention time = 2,250 min. LCMS were performed using the Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC Method: Solvent A = 10% MeOH90% H2O0.1% TFA, Solvent B = 90% MeOH10% H2O0.1% TFA, Initial % B = 0, Final % B = 100, Efficiency Time gradient = 2 min, Dwell time at 3 min, Flow rate = 1 ml/min, Column: FENOMENEX®-Luna, 2.0 x 30mm, 3μm. Preparation of (S)-2-((((9H-fluoren -9-yl)methoxy)carbonyl)amino)-3-(2-(4-fluorophenyl)-1H-indol-3-yl)propanoic acid

[004036] To (1-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid (1 g, 2.345 mmol) and silver(I) tetrafluoroborate (0.913 g, 4.69 mmol) in a sealed and reusable 150 mL round bottom flask at room temperature in a N2 atmosphere was added a mixture of 1-fluoro-4-iodobenzene (1.041 g, 4.69 mmol) in DMF (5 mL), followed by a mixture of trifluoroacetic acid (0.181 mL, 2.345 mmol) in DMF (5 mL) and then a mixture of diacetoxypalladium (0.026 g, 0.117 mmol) in DMF (5 mL). An additional 5 mL of DMF was added to the reaction mixture. The flask was tightly capped and stirred at 95 °C in an oil bath for 18 h. The mixture was diluted with 300 mL EtOAc, filtered, and the filtrate was washed with brine (2 × 100 mL). The organic solution was evaporated. The residue was dissolved in MeOH and purified by Shimadzu-VP preparative reversed-phase HPLC using the separation method: Solvent A = 10% MeOH-90% H2O-0.1% TFA, Solvent B = 90% MeOH-10% H2O-0.1% TFA, Initial %B = 50, Final %B = 100, Gradient time = 10 min, Stop time = 12 min, Flow rate = 30 mL/min, Column: SunFire Prep C18 19 x 100 5μm, (UV detection at 220 nm). The combined desired fractions at retention time = 8.679 min were evaporated to give an off-white solid of the product (586.8mg).

[004037] 1H NMR (400 MHz, DMSO-d6)DDDl2.68 (br s, 1H), 11.24 (s, 1H), 7.88 (d, J= 7.6, 2H), 7.79 (d, J= 8.3, 1H ), 7.72 - 7.63 (m, 5H), 7.43 - 7.38 (m, 2H), 7.35 - 7.23 (m, 5H), 7.10 (t, J= 7.6, 1H), 7.00 (m, 1H), 4.33 - 4.28 (m, 1H), 4.15 - 4.09 (m, 3H), 3.36 (m, 1H), 3.18 (dd, J= 14.4, 8.8, 1H). [a]20D -10.07° (1.35 mg/mL, solvent). LCMS (ES+) m/z = 521.0 (M+H), retention time = 2.262 min. LCMS were performed using the instrument of Shimadzu-VP with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A = 10% MeOH/90% H2O/0.1% TFA, Solvent B = 90% MeOH/10% H2O/0.1% TFA, Initial %B = 0, Final %B = 100, Gradient time = 2 min, Dwell time = 3 min, Flow rate = 1 ml/min, Column: FENOMENEX®-Luna, 2.0 x 30mm, 3μm. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid

[004038] To a sealed 150 mL round bottom flask were added (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid (1 g, 2.345 mmol), silver(I) tetrafluoroborate (0.913 g, 4.69 mmol), DMF (20 mL), 3-iodoanisole (1.098 g, 4.69 mmol), 2,2,2-trifluoroacetic acid (0.181 mL, 2.345 mmol), and diacetoxypalladium (0.026 g, 0.117 mmol). The mixture was purged/degassed with nitrogen for 5 min. The flask was capped tightly, and the mixture was stirred at 95 °C for 18 h. The reaction mixture was diluted with EtOAc (300mL), filtered, and the filtrate was washed with brine (2x100mL). The organic solution was evaporated. The residue was purified by column chromatography (BIOTA GE® silica gel column 25m, EtO-Ac/Hexane = 0 to 100%) to give the product (560mg, 42%) as a light brown solid. 1H NMR (400MHz, chloroform-d)DDD8.19 (s, 1H), 7.81 - 7.68 (m, 3H), 7.53 - 7.04 (m, 13H), 6.92 (dd, J=8.3, 2.0 Hz, 1H), 5.20 (d, J=8.0 Hz, 1H), 4.72 - 4. 62 (m, 1H), 4.26 - 4.19 (m, 2H), 3.80 (s, 3H), 3.65 - 3.45 (m, 2H); [a]20D -10.35° (2.88 mg/mL, MeOH). LCMS retention time = 1,862 min., m/z = 533 (M+H), 95.0% purity. LCMS data were obtained on a Shimadzu LC/MICROMASS® Analytical LC Platform (ESI+) at 220 nm using the following condition setting: FENOMENEX® Luna 3μm C18, 2 x 50 mm column, with a 0-100% B gradient (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water/ 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid

[004039] (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid ( 1.12g, 85%) was obtained from (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-methoxybenzene using the procedure described for (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino acid)-3-(2-(3-methoxyphenyl)-1H -indol-3-yl)propanoic acid. 1H NMR (400MHz, DMSO- dβ)DDDl2.89 - 12.48 (m, 1H), 11.14 (s, 1H), 7.93 - 7.77 (m, 2H), 7.72 - 7.58 (m, 5H), 7.46 - 7.22 (m , 6H), 7.11 - 6.94 (m, 4H), 4.30 (dd, J=8.5, β.0 Hz, 1H), 4.18 - 4.07 (m, 3H), 3.84 - 3.77 (s, 3H), 3.35 (m , 1H), 3.23 - 3.14 (m, 1H); [a]20D -9.44° (3.05 mg/mL, MeOH). LCMS retention time = 1.810 min., m/z = 533 (M+H), 97.3% purity. LCMS data were obtained on a Shimadzu LC/MICROMASS® Analytical LC Platform (ESI+) at 220 nm using the following setting conditions: FENOMENEX® Luna 3μm C18, 2 x 50 mm column, with a 0-100% B gradient (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), ( A = 90% HPLC grade water/ 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid

[004040] (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid ( 1.11 g, ββ%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and l-iodo-4-ethoxybenzene using the procedure described for (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino acid)-3-(2-(3-methoxyphenyl)-1H -indol-3-yl)propanoic acid. 1H NMR (400MHz, chloroform- d)DDD8.12 (s, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.69 (d, J=7.8 Hz, 1H), 7.54 - 7.34 (m, 8H) , 7.33 - 7.12 (m, 4H), β.97 - β.90 (m, 2H), 5.1β (d, J=7.8 Hz, 1H), 4.64 (d, J=6.3 Hz, 1H), 4.28 - 4.06 (m, 4H), 3.62 - 3.42 (m, 2H), 1.44 - 1.36 (t, J=8.0Hz, 3H); [a]20D -10.68° (4.01 mg/mL, MeOH). LCMS retention time = 1.898 min., m/z 547 = (M+H), 98.2% purity. LCMS data were obtained on a Shimadzu LC/MICROMASS® Analytical LC Platform (ESI+) at 220nm using the following conditions setting: FENOMENEX® Luna 3μm C18, 2 x 50 mm column, with a 0-100% gradient. of B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water/ 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile ), in 2 minutes with a 1-minute hold at a flow rate of 1 mL/minute. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4- -1H-indol-3-yl)propanoic acid Step 1: 1-iodo-4-propoxybenzene

[004041] A suspension of 4-iodophenol (3 g, 13.64 mmol), 1-bromopropane (1.845 g, 15.00 mmol), and sodium carbonate (7.54 g, 54.5 mmol) in DMF (30 mL) was stirred at 80 °C for 4 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (3x75 mL). The combined organic extracts were washed with 0.5 M NaOH (2x50 mL), and water (2x50 mL), and then dried over MgSO4. The solvent was removed. The crude product (3.11 g) was obtained, which was used directly in the next reaction without further purification. 1H NMR (400MHz, chloroform-d)DDD7.61 - 7.53 (m, 2H), 6.74 - 6.67 (m, 2H), 3.90 (t, J=6.5 Hz, 2H), 1.88 - 1.76 (m, 2H), 1.05 (t, J=7.4 Hz, 3H). Step 2:

[004042] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-propoxyphenyl)-1H-indol-3-yl)propanoic acid ( 830mg, 57%) was obtained from (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1 -iodo-4-propoxybenzene using the procedure described for (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino acid)-3- (2-(3-methoxyphenyl)-1H- indole-3-yl)propanoic acid. 1H NMR (400MHz, chloroform-d)DDD8.14 (s, 1H), 7.83 - 7.59 (m, 3H), 7.54 - 7.12 (m, 11H), 6.93 (d, J=8.5 Hz, 2H), 5.43 - 5.12 (m, 1H), 4.71 - 4.53 (m, 1H), 4.29 - 4.05 (m, 3H), 3.88 (t, J=6.4 Hz, 2H), 3.63 - 3.41 (m, 2H), 1.79 ( sxt, J=7.0 Hz, 2H), 1.09 - 0.98 (m, 3H); [a]20D -7.54° (3.05 mg/mL, MeOH). LCMS retention time = 1.952 min., m/z = 561 (M+H), 99.1% purity. LCMS data were obtained on a Shimadzu analytical LC/MICROMASS® LC Platform (ESI+) at 220nm using the following conditions setting: FENOMENEX® Luna 3μm C18, 2 x 50 mm column, with a 0-100% B gradient. (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water/ 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile), in 2 minutes with a 1-minute hold at a flow rate of 1 mL/minute. Preparation of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-propoxyphenyl)-1H-indol-3-yl)propanoic acid Step 1:

[004043] Iodo-3-propoxybenzene (3.53 g, 98%) was obtained from 3-iodophenol and 1-bromopropane using the procedure described for l-iodo-4-propoxybenzene. 1H NMR (400MHz, chloroform-d) DDD 7.33 - 7.25 (m, 2H), 7.05 - 6.97 (m, 1H), 6.92 - 6.85 (m, 1H), 3.91 (t, J=6.5 Hz, 2H), 1.82 (sxt, J=7.0 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H). Step 2:

[004044] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-propoxyphenyl)-1H-indol-3-yl)propanoic acid ( 1.25g, 83%) was obtained from (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-3-propoxybenzene using the procedure described for (5)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino acid)-3-(2-(3-methoxyphenyl)-1H -indol-3-yl)propanoic acid. 1H NMR (400MHz, chloroform-d)DDD8.28 (s, 1H), 7.80 - 7.70 (m, 3H), 7.53 - 7.09 (m, 13H), 6.94 -6.87 (m, 1H), 5.23 (d , J=8.0 Hz, 1H), 4.68 (d, J=6.0 Hz, 1H), 4.22 - 4.15 (m, 2H), 3.93 (t, J=6.7 Hz, 2H), 3.60 (d, J=5.3 Hz , 1H), 3.52 (d, J=7.0 Hz, 1H), 1.85 - 1.72 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); [a]20D - 11.34° (4.25 mg/mL, MeOH). LCMS retention time = 1.972 min., m/z = 561 (M+H), 99.0% purity. LCMS data were obtained on a Shimadzu LC/MICROMASS® Analytical LC Platform (ESI+) at 220nm using the following conditions setting: FENOMENEX® Luna 3 μm C 18, 2 x 50 mm column, with a 0-100% gradient of B (B = 90% HPLC grade acetonitrile/ 0.1% trifluoroacetic acid/ 10% HPLC grade water), (A = 90% HPLC grade water/ 0.1% trifluoroacetic acid/ 10% HPLC grade acetonitrile ), in 2 minutes with a 1-minute hold at a rate of 1 mL/minute. Preparation of Example 7001 Example 7001

[004045] Example 7001 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-phenyl-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004046] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.1 mg, and its purity estimated by LCMS analysis was 96%.

[004047] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z = 986.4 (M+2H).

[004048] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z = 986.4 (M+2H).

[004049] ESI-HRMS(+) m/z: Calculated: 1969.9894, Found: 1969.9865 (M+H);

[004050] Calculated: 985.4983, Found: 985.4964 (M+2H); Calculated: 657.3347, Found: 657.3327 (M+3H). Preparation of Example 7002 Example 7002

[004051] Example 7002 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-fluorophenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004052] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004053] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.1 mg, and its purity estimated by LCMS analysis was 98%.

[004054] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z = 911 A (M+2H).

[004055] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z = 977.9 (M+2H).

[004056] ESI-HRMS(+) m/z: Calculated: 976.9856, Found: 976.9838 (M+2H). Preparation of Example 7003 Example 7003

[004057] Example 7003 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004058] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004059] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.4 mg, and its purity estimated by LCMS analysis was 98%.

[004060] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z = 983.9 (M+2H).

[004061] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z = 983.1 (M+2H).

[004062] ESI-HRMS(+) m/z: Calculated: 982.9956, Found: 982.9936 (M+2H). Preparation of Example 7004 Example 7004

[004063] Example 7004 was prepared by following the general synthetic sequence described for the preparation of Example 7001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-propoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004064] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004065] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20. lmg, and its purity estimated by LCMS analysis was 97%.

[004066] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z = 996.7 (M+2H).

[004067] Analysis Condition B: Retention time = 2.70 min; ESI-MS(+) m/z = 997.3 (M+2H).

[004068] ESI-HRMS(+) m/z: Calculated: 997.0113, Found: 997.0088 (M+2H). Preparation of Example 7005 Example 7005

[004069] Example 7005 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-propoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004070] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.6 mg, and its purity estimated by LCMS analysis was 98%.

[004071] Analysis Condition A: Retention time = 1.84 min; ESI-MS(+) m/z = 996.7 (M+2H).

[004072] Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z = 997.5 (M+2H).

[004073] ESI-HRMS(+) m/z: Calculated: 997.0113, Found: 997.0086 (M+2H). Preparation of Example 7006 Example 7006

[004074] Example 7006 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004075] The crude material was purified via preparative LC/MS under the following conditions: Column: Waters XBridge c-18, 19 x 200 mm, 5-μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.8 mg, and its purity estimated by LCMS analysis was 100%.

[004076] Analysis Condition A: Retention time = 1.84 min; ESI-MS(+) m/z = 983.6 (M+2H).

[004077] Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z = 983.6 (M+2H).

[004078] ESI-HRMS(+) m/z: Calculated: 982.9956, Found: 982.9930 (M+2H). Preparation of Example 7007 Example 7007

[004079] Example 7007 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004080] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004081] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.7 mg, and its estimated purity by LCMS analysis was 97%.

[004082] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 990.3 (M+2H). Analysis Condition B: Retention time = 2.69 min; ESI-MS(+) m/z 990.6 (M+2H). ESI-HRMS(+) m/z: Calculated: 990.0035, Found: 990.0008 (M+2H). Preparation of Example 7008 Example 7008

[004083] Example 7008 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004084] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.5 mg, and its purity estimated by LCMS analysis was 96%.

[004085] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z = 975.6 (M+2H).

[004086] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z = 975.3 (M+2H).

[004087] ESI-HRMS(+) m/z: Calculated: 974.9982, Found: 974.9949 (M+2H). Preparation of Example 7009 Example 7009

[004088] Example 7009 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004089] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.9 mg, and its purity estimated by LCMS analysis was 99%.

[004090] Analysis Condition A: Retention time = 1.69 min; ESI-MS(+) m/z 990.7 (M+2H).

[004091] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 990.7 (M+2H). ESI-HRMS(+) m/z: Calculated: 990.0035, Found: 990.0014 (M+2H). Preparation of Example 7010 Example 7010

[004092] Example 7010 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004093] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.9 mg, its purity estimated by LCMS analysis was 92%.

[004094] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z = 991 A (M+2H).

[004095] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z = 991 A (M+2H). Preparation of Example 7011 Example 7011

[004096] Example 7011 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A". (5)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-ethoxyphenyl)-1H-indol-3-yl)propanoic acid was used in the sixth amino acid coupling step.

[004097] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity estimated by LCMS analysis was 100%.

[004098] Analysis Condition A: Retention time = 1.73 min; ESI-MS(+) m/z 982.7 (M+2H).

[004099] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 982.6 (M+2H). ESI-HRMS(+) m/z: Calculated: 982.0060, Found: 982.0035 (M+2H). Preparation of Example 7012 Example 7012

[004100] Example 7012 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure". The "Prelude Method A: Single Coupling Procedure" was used to cap the amino terminus of Tyr1 with acrylic acid as the last amino acid coupling step. The obtained resin-bound peptide was then subjected to a "ring-closing olefin metathesis (RCM) reaction" as described below and then followed by the "Global Deprotection Method A".

[004101] “Ring closure olefin metathesis (RCM) reaction: The resin-bound peptide (0.044mmol) was added to a 20 mL conical flask for microwave reactor. The 2nd generation Hoveyda-Grubb catalyst ((1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (27.5mg, 0.033mmol) and 1,2-dichloroethane (10mL) were added, the mixture was degassed, and heated in a microwave reactor at 120° for 1 hour. After the reaction was done, the resin was filtered, and washed with DMF (2X5mL), followed by DCM (3X5mL) and then dried. The crude material was deprotected using "Global Deprotection Method A".

[004102] The product was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.9 mg, and its purity estimated by LCMS analysis was 98%.

[004103] Analysis Condition A: Retention time = 1.52min; ESI-MS(+) m/z = 938.5 (M+2H).

[004104] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z = 938.3 (M+2H). Preparation of Example 7013 Example 7013

[004105] Example 7013 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure". The "Prelude Method A: Single Coupling Procedure" was used to cap the amino terminus of Tyr1 with acrylic acid as the last amino acid coupling step. The obtained resin-bound peptide was then subjected to a "ring-closing olefin metathesis (RCM) reaction" as described below and then followed by the "Global Deprotection Method A".

[004106] “Ring-closure olefin metathesis (RCM) reaction: The resin-bound peptide (0.262mmol) was divided into six batches. Each batch (0.044mmol) was added to a 20mL conical flask for microwave reactor. Hoveyda-Grubb 2nd generation catalyst (27.5mg, 0.033mmol) and 1,2,-dichloroethane (10mL) were added. The mixture was degassed, and heated in a microwave reactor at 120° for 1 hour. After the reaction was done, the resin was filtered, and washed with DMF (2X5mL), followed by DCM (3X5mL) and then dried. The six batches were combined and the crude material was deprotected using "Global deprotection method A".

[004107] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004108] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.1 mg, and its purity estimated by LCMS analysis was 100%.

[004109] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z = 920.5 (M+2H).

[004110] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z = 920.9 (M+2H).

[004111] Examples 7014 through 7064 were prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure". The "Global Deprotection Method A" and "Cyclization Method A" used for the preparation of Examples 7014 through 7064 were modified as follows. Global Deprotection Method A: The "Global Deprotection Method A" procedure describes an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink linker bound to the resin. A "deprotection solution" was prepared by combining in a 40 mL glass jar trifluoroacetic acid (22 mL), phenol (1.325 g), water (1.25 mL), and triisopropylsilane (0.5 mL). The resin was removed from the reaction vessel and transferred to a 40 mL glass jar. To the jar was added the "deprotection solution" (2.0 mL). The mixture was mixed on an orbital shaker (175 rpm for 2 h). The mixture was filtered through a funnel, the solids were washed with more “deprotection solution” (1.0 mL) and collected in a 40 mL screw-cap vial. To the combined filtrates was added Et2O (15 mL). The mixture was mixed vigorously and a significant amount of a white solid precipitated. The mixture was centrifuged for 3 min at 2000 rpm, the solution was decanted from the solids and discarded. The process was repeated x3, and the solids were then allowed to settle on the bench and air-dried for 1-2 h before continuing to give the crude peptide as an off-white solid. Cyclization Method A: The procedure “Cyclization Method A” describes an experiment performed on a 0.100 mmol scale. The crude peptide solids were dissolved in 0.1 M aqueous MeCN:NH4OAc (15 mL: 15 mL), and the solution was then cautiously adjusted to pH = 9.0 using aqueous NaOH (1.0 M). The vials were capped and the solution was then mixed at 175 rpm on an orbital shaker overnight (~18 h). The reaction solution was concentrated and the peptide was then dissolved in MeOH. This solution was subjected to reverse-phase HPLC purification to give the desired cyclic peptide. Preparation of Example 7014

[004112] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.2 mg, and its purity estimated by LCMS analysis was 96%.

[004113] Analysis Condition A: Retention time = 1.87 min; ESI-MS(+) m/z = 923.6 (M+2H).

[004114] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z = 923.7 (M+2H). Preparation of Example 7015

[004115] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 40.4 mg, and its purity estimated by LCMS analysis was 100%.

[004116] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z = 955.3 (M+2H).

[004117] Analysis Condition B: Retention time = 3.06 min; ESI-MS(+) m/z = 954.4 (M+2H). Preparation of Example 7016

[004118] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 40-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 42.5 mg, and its purity estimated by LCMS analysis was 95%.

[004119] Analysis Condition A: Retention time = 1.81 min; ESI-MS(+) m/z = 949.6 (M+2H).

[004120] Analysis Condition B: Retention time = 2.96 min; ESI-MS(+) m/z = 949.4 (M+2H). Preparation of Example 7017

[004121] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 39.3 mg, and its purity estimated by LCMS analysis was 100%.

[004122] Analysis Condition A: Retention time = 1.75 min; ESI-MS(+) m/z = 955.4 (M+2H).

[004123] Analysis Condition B: Retention time = 2.94 min; ESI-MS(+) m/z = 955.6 (M+2H). Preparation of Example 7018

[004124] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.5 mg, and its purity estimated by LCMS analysis was 100%.

[004125] Analysis Condition A: Retention time = 1.77 min; ESI-MS(+) m/z = 954.5 (M+2H).

[004126] Analysis Condition B: Retention time = 2.94 min; ESI-MS(+) m/z = 954.8 (M+2H). Preparation of Example 7019

[004127] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004128] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.4 mg, and its purity estimated by LCMS analysis was 98.6%.

[004129] Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z = 931.7 (M+2H).

[004130] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z = 931.7 (M+2H). Preparation of Example 7020

[004131] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.0 mg, and its purity estimated by LCMS analysis was 100%.

[004132] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z = 910.8 (M+2H).

[004133] Analysis Condition B: Retention time = 2.78 min; ESI-MS(+) m/z = 910.7 (M+2H). Preparation of Example 7021

[004134] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 44.2 mg, and its purity estimated by LCMS analysis was 100%.

[004135] Analysis Condition A: Retention time = 1.73 min; ESI-MS(+) m/z = 910.8 (M+2H).

[004136] Analysis Condition B: Retention time = 2.78 min; ESI-MS(+) m/z = 910.7 (M+2H). Preparation of Example 7022

[004137] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min.

[004138] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.0 mg, and its estimated purity by LCMS analysis was 98%.

[004139] Analysis Condition A: Retention time = 1.73 min; ESI-MS(+) m/z = 898.2 (M+2H).

[004140] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z = 898.3 (M+2H). Preparation of Example 7023

[004141] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004142] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 20 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 20 mM ammonium acetate; Gradient: 10-50% B over 40 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.1 mg, and its purity estimated by LCMS analysis was 80%.

[004143] Analysis Condition A: Retention time = 1.76 min; ESI-MS(+) m/z = 916.2 (M+2H).

[004144] Analysis Condition B: Retention time = 2.92 min; ESI-MS(+) m/z = 916.7 (M+2H). Preparation of Example 7024

[004145] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.4 mg, and its purity estimated by LCMS analysis was 98%.

[004146] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z = 948.9 (M+2H).

[004147] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z = 948.9 (M+2H). Preparation of Example 7025

[004148] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.2 mg, and its purity estimated by LCMS analysis was 95.4%.

[004149] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z = 948.7 (M+2H).

[004150] Analysis Condition B: Retention time = 2.70 min; ESI-MS(+) m/z = 948.9 (M+2H). Preparation of Example 7026

[004151] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min.

[004152] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.6 mg, and its purity estimated by LCMS analysis was 100%.

[004153] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z = 961.4 (M+2H).

[004154] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z = 961.7 (M+2H), 972.6 (M+H+Na). Preparation of Example 7027

[004155] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.2 mg, and its purity estimated by LCMS analysis was 100%.

[004156] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z = 961.5 (M+2H).

[004157] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z = 961.9 (M+2H). Preparation of Example 7028

[004158] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004159] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.1 mg, and its estimated purity by LCMS analysis was 98%.

[004160] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z = 961.4 (M+2H).

[004161] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z = 961.7 (M+2H). Preparation of Example 7029

[004162] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004163] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 53.2 mg, and its purity estimated by LCMS analysis was 98.7%.

[004164] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z = 948.8 (M+2H).

[004165] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z = 948.7 (M+2H). Preparation of Example 7030

[004166] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.8 mg, and its purity estimated by LCMS analysis was 97.8%.

[004167] Analysis Condition A: Retention time = 2.05 min; ESI-MS(+) m/z = 956.8 (M+2H).

[004168] Analysis Condition B: Retention time = 3.11 min; ESI-MS(+) m/z = 956.8 (M+2H).

[004169] ESI-HRMS(+) m/z: Calculated: 955.9709, Found: 955.9667 (M+2H). Preparation of Example 7031

[004170] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.0 mg, and its purity estimated by LCMS analysis was 91.4%.

[004171] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z = 952.3 (M+2H).

[004172] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z = 952.1 (M+2H), 971.7 (M+MeCN+2H).

[004173] ESI-HRMS(+) m/z: Calculated: 951.4614, Found: 951.4591 (M+2H). Preparation of Example 7032

[004174] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min.

[004175] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 20 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 20 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.2 mg, and its purity estimated by LCMS analysis was 98.8%.

[004176] Analysis Condition A: Retention time = 1.61 min; ESI-MS(+) m/z = 951.6 (M+2H).

[004177] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z = 951.8 (M+2H).

[004178] ESI-HRMS(+) m/z: Calculated: 951.4614, Found: 951.4587 (M+2H). Preparation of Example 7033

[004179] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004180] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 20 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 20 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.7 mg, and its purity estimated by LCMS analysis was 98.5%.

[004181] Analysis Condition A: Retention time = 2.05 min; ESI-MS(+) m/z = 952.3 (M+2H).

[004182] Analysis Condition B: Retention time = 3.11 min; ESI-MS(+) m/z = 951.5 (M+2H), 972.0 (M+MeCN+2H).

[004183] ESI-HRMS(+) m/z: Calculated: 951.4614, Found: 951.4590 (M+2H). Preparation of Example 7034

[004184] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 38.1 mg, and its purity estimated by LCMS analysis was 100%.

[004185] Analysis Condition A: Retention time = 2.55 min; ESI-MS(+) m/z = 955.7 (M+2H).

[004186] Analysis Condition B: Retention time = 3.02 min; ESI-MS(+) m/z = 955.7 (M+2H).

[004187] ESI-HRMS(+) m/z: Calculated: 955.9709, Found: 955.9679 (M+2H). Preparation of Example 7035

[004188] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 37.2 mg, and its purity estimated by LCMS analysis was 100%.

[004189] Analysis Condition A: Retention time = 2.02 min; ESI-MS(+) m/z = 928.9 (M+2H).

[004190] Analysis Condition B: Retention time = 3.04 min; ESI-MS(+) m/z = 928.7 (M+2H), 940.6 (M+H+Na).

[004191] ESI-HRMS(+) m/z: Calculated: 928.9851, Found: 928.9822 (M+2H). Preparation of Example 7036

[004192] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.3 mg, and its purity estimated by LCMS analysis was 100%.

[004193] Analysis Condition A: Retention time = 2.21 min; ESI-MS(+) m/z = 950.4 (M+2H).

[004194] Analysis Condition B: Retention time = 3.17 min; ESI-MS(+) m/z = 950.5 (M+2H).

[004195] ESI-HRMS(+) m/z: Calculated: 950.0085, Found: 950.0054 (M+2H). Preparation of Example 7037

[004196] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.7 mg, and its purity estimated by LCMS analysis was 100%.

[004197] Analysis Condition A: Retention time = 1.76 min; ESI-MS(+) m/z = 934.8 (M+2H).

[004198] Analysis Condition B: Retention time = 2.76 min; ESI-MS(+) m/z = 935.2 (M+2H), 945.7 (M+H +Na).

[004199] ESI-HRMS(+) m/z: Calculated: 934.4749, Found: 934.4719 (M+2H). Preparation of Example 7038

[004200] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 40.2 mg, and its purity estimated by LCMS analysis was 100%.

[004201] Analysis Condition A: Retention time = 1.74 min; ESI-MS(+) m/z = 934.8 (M+2H).

[004202] Analysis Condition B: Retention time = 2.76 min; ESI-MS(+) m/z = 934.8 (M+2H).

[004203] ESI-HRMS(+) m/z: Calculated: 934.4749, Found: 934.4719 (M+2H). Preparation of Example 7039

[004204] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.2 mg, and its purity estimated by LCMS analysis was 100%.

[004205] Analysis Condition A: Retention time = 1.89 min; ESI-MS(+) m/z = 937.3 (M+2H).

[004206] Analysis Condition B: Retention time = 2.93 min; ESI-MS(+) m/z = 937.3 (M+2H).

[004207] ESI-HRMS(+) m/z: Calculated: 936.9825, Found: 936.9799 (M+2H). Preparation of Example 7040

[004208] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its purity estimated by LCMS analysis was 100%.

[004209] Analysis Condition A: Retention time = 1.89 min; ESI-MS(+) m/z = 951.7 (M+2H).

[004210] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z = 951.7 (M+2H), 963.8 (M+H+Na). Preparation of Example 7041

[004211] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.6 mg, and its purity estimated by LCMS analysis was 96%.

[004212] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z = 944.1 (M+2H).

[004213] Analysis Condition B: Retention time = 2.45 min; ESI-MS(+) m/z = 944.1 (M+2H). Preparation of Example 7042

[004214] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 30-70% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min.

[004215] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-40% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.9 mg, and its purity estimated by LCMS analysis was 97%.

[004216] Analysis Condition A: Retention time = 1.32 min; ESI-MS(+) m/z = 937.2 (M+2H).

[004217] Analysis Condition B: Retention time = 2.84 min; ESI-MS(+) m/z = 937.1 (M+2H). Preparation of Example 7043

[004218] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 60-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.7 mg, and its purity estimated by LCMS analysis was 100%.

[004219] Analysis Condition A: Retention time = 1.78 min; ESI-MS(+) m/z = 940.7 (M+2H).

[004220] Analysis Condition B: Retention time = 3.01 min; ESI-MS(+) m/z = 940.7 (M+2H). Preparation of Example 7044

[004221] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.0 mg, and its estimated purity by LCMS analysis was 99%.

[004222] Analysis Condition A: Retention time = 2.08. min; ESI-MS(+) m/z = 939.8 (M+2H).

[004223] Analysis Condition B: Retention time = 3.08 min; ESI-MS(+) m/z = 939.3 (M+2H). Preparation of Example 7045

[004224] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 30-70% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.4 mg, and its purity estimated by LCMS analysis was 98%.

[004225] Analysis Condition A: Retention time = 2.18 min; ESI-MS(+) m/z = 976.4 (M+2H).

[004226] Analysis Condition B: Retention time = 3.13 min; ESI-MS(+) m/z = 976.7 (M+2H). Preparation of Example 7046

[004227] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.9 mg, and its purity estimated by LCMS analysis was 100%.

[004228] Analysis Condition A: Retention time = 1.80 min; ESI-MS(+) m/z = 960.7 (M+2H).

[004229] Analysis Condition B: Retention time = 2.75 min; ESI-MS(+) m/z = 960.8 (M+2H). Preparation of Example 7047

[004230] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.3 mg, and its purity estimated by LCMS analysis was 98%.

[004231] Analysis Condition A: Retention time = 1.84 min; ESI-MS(+) m/z = 957.8 (M+2H).

[004232] Analysis Condition B: Retention time = 2.54 min; ESI-MS(+) m/z = 957.9 (M+2H). Preparation of Example 7048

[004233] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 55.7 mg, and its estimated purity by LCMS analysis was 97%.

[004234] Analysis Condition A: Retention time = 1.90 min; ESI-MS(+) m/z = 931.8 (M+2H).

[004235] Analysis Condition B: Retention time = 2. min; ESI-MS(+) m/z = 931.7 (M+2H). Preparation of Example 7049

[004236] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004237] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.8 mg, and its purity estimated by LCMS analysis was 98%.

[004238] Analysis Condition A: Retention time = 1.34 min; ESI-MS(+) m/z = 976.8 (M+2H).

[004239] Analysis Condition B: Retention time = 2.40 min; ESI-MS(+) m/z = 976.8 (M+2H). Preparation of Example 7050

[004240] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.7 mg, and its purity estimated by LCMS analysis was 96%.

[004241] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z = 969.6 (M+2H).

[004242] Analysis Condition B: Retention time = 2.44 min; ESI-MS(+) m/z = 969.8 (M+2H). Preparation of Example 7051

[004243] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.6 mg, and its purity estimated by LCMS analysis was 100%.

[004244] Analysis Condition A: Retention time = 1.83 min; ESI-MS(+) m/z = 966.7 (M+2H).

[004245] Analysis Condition B: Retention time = 3.00 min; ESI-MS(+) m/z = 966.3 (M+2H). Preparation of Example 7052

[004246] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.8 mg, and its purity estimated by LCMS analysis was 99%.

[004247] Analysis Condition A: Retention time = 1.95 min; ESI-MS(+) m/z = 982.5 (M+2H).

[004248] Analysis Condition B: Retention time = 3.13 min; ESI-MS(+) m/z = 982.2 (M+2H). Preparation of Example 7053

[004249] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004250] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.5 mg, and its purity estimated by LCMS analysis was 100%.

[004251] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z = 962.8 (M+2H).

[004252] Analysis Condition B: Retention time = 2.43 min; ESI-MS(+) m/z = 962.2 (M+2H). Preparation of Example 7054

[004253] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.1 mg, and its purity estimated by LCMS analysis was 98%.

[004254] Analysis Condition A: Retention time = 2.04 min; ESI-MS(+) m/z = 965.0 (M+2H).

[004255] Analysis Condition B: Retention time = 3.04 min; ESI-MS(+) m/z = 965.4 (M+2H). Preparation of Example 7055

[004256] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.0 mg, and its estimated purity by LCMS analysis was 95%.

[004257] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z = 930.2 (M+2H).

[004258] Analysis Condition B: Retention time = 2.63 min; ESI-MS(+) m/z = 930.2 (M+2H). Preparation of Example 7056

[004259] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C I 8.5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.5 mg, and its purity estimated by LCMS analysis was 99%.

[004260] Analysis Condition A: Retention time = 1.93 min; ESI-MS(+) m/z = 982.2 (M+2H).

[004261] Analysis Condition B: Retention time = 3.07 min; ESI-MS(+) m/z = 982.2 (M+2H). Preparation of Example 7057

[004262] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.1 mg, and its purity estimated by LCMS analysis was 100%.

[004263] Analysis Condition A: Retention time = 1.90 min; ESI-MS(+) m/z = 955.1 (M+2H).

[004264] Analysis Condition B: Retention time = 3.90 min; ESI-MS(+) m/z = 955.1 (M+2H). Preparation of Example 7058

[004265] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. to 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.9 mg, and its estimated purity by LCMS analysis was 99%.

[004266] Assay Condition A: Retention time = 1. min; ESI-MS(+) m/z = 960.4 (M+2H). Assay Condition B: Retention time = 2.78 min; ESI-MS(+) m/z = 960.8 (M+2H). Preparation of Example 7059

[004267] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.3 mg, and its estimated purity by LCMS analysis was 99%.

[004268] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z = 955.4 (M+2H).

[004269] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z = 955.9 (M+2H). Preparation of Example 7060

[004270] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004271] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.4 mg, and its purity estimated by LCMS analysis was 100%.

[004272] Analysis Condition A: Retention time = 1.82 min; ESI-MS(+) m/z = 963.6 (M+2H).

[004273] Analysis Condition B: Retention time = 2.97 min; ESI-MS(+) m/z = 963.3 (M+2H). Preparation of Example 7061

[004274] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.0 mg, and its purity estimated by LCMS analysis was 99%.

[004275] Analysis Condition A: Retention time = 1.83 min; ESI-MS(+) m/z = 966.2 (M+2H).

[004276] Analysis Condition B: Retention time = 3.04 min; ESI-MS(+) m/z = 966.2 (M+2H). Preparation of Example 7062

[004277] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.8 mg, and its estimated purity by LCMS analysis was 97%.

[004278] Analysis Condition A: Retention time = 1.89 min; ESI-MS(+) m/z = 983.1 (M+2H).

[004279] Analysis Condition B: Retention time = 3.11 min; ESI-MS(+) m/z = 982.2 (M+2H). Preparation of Example 7063

[004280] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.1 mg, and its purity estimated by LCMS analysis was 100%.

[004281] Analysis Condition A: Retention time = 1.92 min; ESI-MS(+) m/z = 957.1 (M+2H).

[004282] Analysis Condition B: Retention time = 3.15 min; ESI-MS(+) m/z = 957.3 (M+2H). Preparation of Example 7064

[004283] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min.

[004284] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 30-70% B over 30 minutes, then a 5 minute hold at 100% B; Flow rate: 20 mL/min.

[004285] The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 5μm, 19 x 200 mm, Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 0-40% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.

[004286] The yield of the product was 7.7 mg, and its estimated purity by LCMS analysis was 99%.

[004287] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z = 951.0 (M+2H).

[004288] Analysis Condition B: Retention time = 2.40 min; ESI-MS(+) m/z = 951.2 (M+2H), 634.5 (M+3H).

[004289] 9000 Series

[004290] All of the 9000 series examples exemplified below were prepared by following "General Synthetic Sequence A" above. Preparation of Example 9001 Example 9001

[004291] The crude material from Example 9001 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg, and its purity estimated by LCMS analysis was 95%.

[004292] Assay Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 964.8(M+2H). Assay Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 964.8(M+2H). Preparation of Example 9002 Example 9002

[004293] The crude material from Example 9002 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 35-75% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.4 mg, and its estimated purity by LCMS analysis was 96%.

[004294] Assay Condition A: Retention time = 1.92 min; ESI-MS(+) m/z 956.6(M+2H). Assay Condition B: Retention time = 2.91 min; ESI-MS(+) m/z 956.6(M+2H). Preparation of Example 9003 Example 9003

[004295] The crude material from Example 9003 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 8.4 mg, and its purity was estimated to be 99% by LCMS analysis.

[004296] Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 957.5(M+2H).

[004297] Analysis Condition B: Retention time = 2.40 min; ESI-MS(+) m/z 957.6(M+2H). Preparation of Example 9004 Example 9004

[004298] The crude material from Example 9004 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 11.3 mg, and its purity was estimated to be 100% by LCMS analysis.

[004299] Analysis Condition A: Retention time = 1.38 min; ESI-MS(+) m/z 957.5(M+2H).

[004300] Analysis Condition B: Retention time = 2.38 min; ESI-MS(+) m/z 957.5(M+2H). Preparation of Example 9005 Example 9005

[004301] The crude material from Example 9005 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.9 mg, and its estimated purity by LCMS analysis was 98%.

[004302] Assay Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 950.1(M+2H). Assay Condition B: Retention time = 2.45 min; ESI-MS(+) m/z 949.9(M+2H). Preparation of Example 9006 Example 9006

[004303] The crude material from Example 9006 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.5 mg, and its purity estimated by LCMS analysis was 100%.

[004304] Assay Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 964.9(M+2H). Assay Condition B: Retention time = 2.40 min; ESI-MS(+) m/z 965.1 (M+2H). Preparation of Example 9007 Example 9007

[004305] The crude material from Example 9007 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 16.6 mg, and its purity was estimated to be 99% by LCMS analysis.

[004306] Analysis Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 965.0 (M+2H).

[004307] Analysis Condition B: Retention time = 2.40 min; ESI-MS(+) m/z 965.5 (M+2H). Preparation of Example 9008 Example 9008

[004308] The crude material from Example 9008 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.5 mg, and its estimated purity by LCMS analysis was 97%.

[004309] Assay Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 957.3 (M+2H). Assay Condition B: Retention time = 2.67 min; ESI-MS(+) m/z 957.2 (M+2H). Preparation of Example 9009 Example 9009

[004310] The crude material from Example 9009 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.6 mg, and its estimated purity by LCMS analysis was 99%.

[004311] Assay Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 957.1 (M+2H). Assay Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 957.5 (M+2H). Preparation of Example 9010 Example 9010

[004312] The crude material from Example 9010 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[004313] Analysis Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 949.3 (M+2H).

[004314] Analysis Condition B: Retention time = 2.46 min; ESI-MS(+) m/z 950.2 (M+2H). Preparation of Example 9011 Example 9011

[004315] The crude material from Example 9011 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.6 mg, and its purity estimated by LCMS analysis was 100%.

[004316] Assay Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 956.1 (M+2H). Assay Condition B: Retention time = 2.53 min; ESI-MS(+) m/z 956.3 (M+2H). Preparation of Example 9012 Example 9012

[004317] The crude material from Example 9012 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.4 mg, and its estimated purity by LCMS analysis was 98%.

[004318] Assay Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 972.7 (M+2H). Assay Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 972.8 (M+2H). Preparation of Example 9013 Example 9013

[004319] The crude material from Example 9013 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 8.4 mg, and its purity was estimated to be 99% by LCMS analysis.

[004320] Analysis Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 964.4 (M+2H).

[004321] Analysis Condition B: Retention time = 2.49 min; ESI-MS(+) m/z 964.0 (M+2H). Preparation of Example 9014 Example 9014

[004322] The crude material from Example 9014 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.8 mg, and its purity was estimated to be 99% by LCMS analysis.

[004323] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 955.3 (M+2H).

[004324] Analysis Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 955.3 (M+2H). Preparation of Example 9015 Example 9015

[004325] The crude material from Example 9015 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.4 mg, and its purity was estimated to be 98% by LCMS analysis.

[004326] Analysis Condition A: Retention time = 1.70 min; ESI-MS(+) m/z 963.9 (M+2H).

[004327] Analysis Condition B: Retention time = 2.84 min; ESI-MS(+) m/z 963.8 (M+2H). Preparation of Example 9016 Example 9016

[004328] The crude material from Example 9016 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.8 mg, and its purity estimated by LCMS analysis was 100%.

[004329] Assay Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 963 (M+2H). Assay Condition B: Retention time = 2.86 min; ESI-MS(+) m/z 963.8 (M+2H). Preparation of Example 9017 Example 9017

[004330] The crude material from Example 9017 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.2 mg, and its purity estimated by LCMS analysis was 100%.

[004331] Assay Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 955.1 (M+2H). Assay Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 954.9 (M+2H). Preparation of Example 9018 Example 9018

[004332] The crude material of Example was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.4 mg, and its purity estimated by LCMS analysis was 100%.

[004333] Assay Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 963.8 (M+2H). Assay Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 963.8 (M+2H). Preparation of Example 9019 Example 9019

[004334] The crude material from Example 9019 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.5 mg, and its purity estimated by LCMS analysis was 100%.

[004335] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 954.9 (M+2H). Assay Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 955.4 (M+2H). Preparation of Example 9020 Example 9020

[004336] The crude material from Example 9020 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.0 mg, and its purity estimated by LCMS analysis was 100%.

[004337] Analysis Condition A: Retention time = 154. min; ESI-MS(+) m/z 969.8 (M+2H). Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z 970.0 (M+2H). Preparation of Example 9021 Example 9021

[004338] The crude material from Example 9021 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.4 mg, and its purity estimated by LCMS analysis was 100%.

[004339] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 963.4 (M+2H). Preparation of Example 9022 Example 9022

[004340] The crude material from Example 9022 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 20 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.6 mg, and its purity was estimated to be 100% by LCMS analysis.

[004341] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 965.8 (M+2H).

[004342] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 965.8 (M+2H). Preparation of Example 9023 Example 9023

[004343] The crude material from Example 9023 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.7 mg, and its purity estimated by LCMS analysis was 100%.

[004344] Assay Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 973.9 (M+2H). Assay Condition B: Retention time = 2.73 min; ESI-MS(+) m/z 973.9 (M+2H). Preparation of Example 9024 Example 9024

[004345] The crude material from Example 9024 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.8 mg, and its purity estimated by LCMS analysis was 100%.

[004346] Assay Condition A: Retention time = 1.40 min; ESI-MS(+) m/z 965.0 (M+2H). Assay Condition B: Retention time = 2.52 min; ESI-MS(+) m/z 965.3 (M+2H). Preparation of Example 9025 Example 9025

[004347] The crude material from Example 9025 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.8 mg, and its purity estimated by LCMS analysis was 100%.

[004348] Assay Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 973.5 (M+2H). Assay Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 973.7 (M+2H). Preparation of Example 9026 Example 9026

[004349] The crude material from Example 9026 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.6 mg, and its purity estimated by LCMS analysis was 100%.

[004350] Assay Condition A: Retention time = 1.34 min; ESI-MS(+) m/z 965.2 (M+2H). Assay Condition B: Retention time = 2.47 min; ESI-MS(+) m/z 965.7 (M+2H). Preparation of Example 9027 Example 9027

[004351] The crude material from Example 9027 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.9 mg, and its estimated purity by LCMS analysis was 97%.

[004352] Assay Condition A: Retention time = 1.74 min; ESI-MS(+) m/z 922.5 (M+2H). Assay Condition B: Retention time = 2.92 min; ESI-MS(+) m/z 922.3 (M+2H). Preparation of Example 9028 Example 9028

[004353] The crude material from Example 9028 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.6 mg, and its estimated purity by LCMS analysis was 99%.

[004354] Assay Condition A: Retention time = 1.67 min; ESI-MS(+) m/z 930.3 (M+2H). Assay Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 930.3 (M+2H). Preparation of Example 9029 Example 9029

[004355] The crude material from Example 9029 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.6 mg, and its estimated purity by LCMS analysis was 99%.

[004356] Assay Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 921.7 (M+2H). Assay Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 921.8 (M+2H). Preparation of Example 9030 Example 9030

[004357] The crude material from Example 9030 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 9.5 mg, and its purity was estimated to be 98% by LCMS analysis.

[004358] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 957.2 (M+2H).

[004359] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 957.4 (M+2H). Preparation of Example 9031 Example 9031

[004360] The crude material from Example 9031 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.9 mg, and its purity estimated by LCMS analysis was 100%.

[004361] Assay Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 971.8 (M+2H). Assay Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 971.4 (M+2H). Preparation of Example 9032 Example 9032

[004362] The crude material from Example 9032 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.5 mg, and its purity estimated by LCMS analysis was 100%.

[004363] Assay Condition A: Retention time = 1.27 min; ESI-MS(+) m/z 935.0 (M+2H). Assay Condition B: Retention time = 2.32 min; ESI-MS(+) m/z 934.9 (M+2H). Preparation of Example 9033 Example 9033

[004364] The crude material from Example 9033 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 100%.

[004365] Assay Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 952.1(M+2H). Assay Condition B: Retention time = 2.48 min; ESI-MS(+) m/z 952.3 (M+2H). Preparation of Example 9034 Example 9034

[004366] The crude material from Example 9034 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.7 mg, and its purity estimated by LCMS analysis was 100%.

[004367] Assay Condition A: Retention time = 1.23 min; ESI-MS(+) m/z 943.3 (M+2H). Assay Condition B: Retention time = 2.24 min; ESI-MS(+) m/z 943.3 (M+2H). Preparation of Example 9035 Example 9035

[004368] The crude material from Example 9035 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water/10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water/10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 13.5 mg, and its purity was estimated to be 100% by LCMS analysis.

[004369] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 965.0 (M+2H).

[004370] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 964.9 (M+2H). Preparation of Example 9036 Example 9036

[004371] The crude material from Example 9036 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water/10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water/10 mM ammonium acetate; Gradient: 35-75% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[004372] Analysis Condition A: Retention time = 1.39. min; ESI-MS(+) m/z 964.1 (M+2H).

[004373] Analysis Condition B: Retention time = 2.52 min; ESI-MS(+) m/z 964.3 (M+2H). Preparation of Example 9037 Example 9037

[004374] The crude material from Example 9037 was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 5-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 24.9 mg, and its purity was estimated to be 92% by LCMS analysis.

[004375] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 963.3 (M+2H).

[004376] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 963.3 (M+2H). Preparation of Example 9038 Example 9038

[004377] The crude material from Example 9038 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water/10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water/10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.0 mg, and its purity was estimated to be 96% by LCMS analysis.

[004378] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 956.3 (M+2H).

[004379] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 956.3 (M+2H). Preparation of Example 9039 Example 9039

[004380] The crude material from Example 9039 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 40 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.9 mg, and its estimated purity by LCMS analysis was 98%.

[004381] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 973.0 (M+2H). Analysis Condition B: Retention time = 2.71 min; ESI-MS(+) m/z 973.0 (M+2H). Preparation of Example 9040 Example 9040

[004382] The crude material from Example 9040 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.2 mg, and its estimated purity by LCMS analysis was 98%.

[004383] Assay Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 957.2 (M+2H). Assay Condition B: Retention time = 2.78 min; ESI-MS(+) m/z 957.7 (M+2H). Preparation of Example 9041 Example 9041

[004384] The crude material from Example 9041 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.5 mg, and its purity estimated by LCMS analysis was 95%.

[004385] Assay Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 949.2 (M+2H). Assay Condition B: Retention time = 2.54 min; ESI-MS(+) m/z 949.3 (M+2H). Preparation of Example 9042 Example 9042

[004386] The crude material from Example 9042 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.8 mg, and its estimated purity by LCMS analysis was 96%.

[004387] Assay Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 965.4 (M+2H). Assay Condition B: Retention time = 2.76 min; ESI-MS(+) m/z 965.8 (M+2H). Preparation of Example 9043 Example 9043

[004388] The crude material from Example 9043 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.1 mg, and its estimated purity by LCMS analysis was 98%.

[004389] Assay Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 958.1 (M+2H). Assay Condition B: Retention time = 2.51 min; ESI-MS(+) m/z 958.0 (M+2H). Preparation of Example 9044 Example 9044

[004390] The crude material from Example 9044 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 40 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity estimated by LCMS analysis was 100%.

[004391] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 943.8 (M+2H).

[004392] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 943.5 (M+2H). Preparation of Example 9045 Example 9045

[004393] The crude material from Example 9045 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.2 mg, and its estimated purity by LCMS analysis was 99%.

[004394] Assay Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 965.8 (M+2H). Assay Condition B: Retention time = 2.71 min; ESI-MS(+) m/z 965.4 (M+2H). Preparation of Example 9046 Example 9046

[004395] The crude material from Example 9046 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.3 mg, and its purity estimated by LCMS analysis was 100%.

[004396] Assay Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 957.2 (M+2H). Assay Condition B: Retention time = 2.49 min; ESI-MS(+) m/z 957.3 (M+2H). Preparation of Example 9047 Example 9047

[004397] The crude material from Example 9047 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 11.5 mg, and its purity was estimated to be 97% by LCMS analysis.

[004398] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 955.0 (M+2H).

[004399] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 955.3 (M+2H). Preparation of Example 9048 Example 9048

[004400] The crude material from Example 9048 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 55-95% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.7 mg, and its estimated purity by LCMS analysis was 99%.

[004401] Assay Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 971.7 (M+2H). Assay Condition B: Retention time = 2.81 min; ESI-MS(+) m/z 971.4 (M+2H). Preparation of Example 9049 Example 9049

[004402] The crude material from Example 9049 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.5 mg, and its estimated purity by LCMS analysis was 98%.

[004403] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 963.3 (M+2H).

[004404] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 963.3 (M+2H). Preparation of Example 9050 Example 9050

[004405] The crude material from Example 9050 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.5 mg, and its estimated purity by LCMS analysis was 98%.

[004406] Assay Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 958.7 (M+2H). Assay Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 958.7 (M+2H). Preparation of Example 9051 Example 9051

[004407] The crude material from Example 9051 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.2 mg, and its estimated purity by LCMS analysis was 97%.

[004408] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 950.3 (M+2H). Assay Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 950.6 (M+2H). Preparation of Example 9052 Example 9052

[004409] The crude material of Example 9052 was purified via LC/MS

[004410] preparative with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: water with 10 mM ammonium acetate; Mobile phase B: 95:5 methane:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.2 mg, and its purity estimated by LCMS analysis was 99%.

[004411] Assay Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 963.5 (M+2H). Assay Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 963.7 (M+2H). Preparation of Example 9053 Example 9053

[004412] The crude material from Example 9053 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 30 min, followed by a 5-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 20.6 mg, and its purity was estimated to be 99% by LCMS analysis.

[004413] Assay Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 935.6 (M+2H). Assay Condition B: Retention time = 2.63 min; ESI-MS(+) m/z 935.3 (M+2H). Preparation of Example 9054 Example 9054

[004414] The crude material from Example 9054 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.0 mg, and its estimated purity by LCMS analysis was 96%.

[004415] Assay Condition A: Retention time = 1.37 min; ESI-MS(+) m/z 927.1 (M+2H). Assay Condition B: Retention time = 2.39 min; ESI-MS(+) m/z 927.2 (M+2H). Preparation of Example 9055 Example 9055

[004416] The crude material from Example 9055 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.8 mg, and its estimated purity by LCMS analysis was 99%.

[004417] Assay Condition A: Retention time = 1.34 min; ESI-MS(+) m/z 934.9(M+2H). Assay Condition B: Retention time = 2.36 min; ESI-MS(+) m/z 934.9 (M+2H). Preparation of Example 9056 Example 9056

[004418] The crude material from Example 9056 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.4 mg, and its purity estimated by LCMS analysis was 100%.

[004419] Assay Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 943.4 (M+2H). Assay Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 943.7 (M+2H). Preparation of Example 9057 Example 9057

[004420] The crude material from Example 9057 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.6 mg, and its estimated purity by LCMS analysis was 95%.

[004421] Assay Condition A: Retention time = 1.30 min; ESI-MS(+) m/z 934.8 (M+2H). Assay Condition B: Retention time = 2.33 min; ESI-MS(+) m/z 934.8 (M+2H). Preparation of Example 9058 Example 9058

[004422] The crude material from Example 9058 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; Mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 30 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS under the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 1555% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 9.2 mg, and its purity estimated by LCMS analysis was 98%.

[004423] Analysis Condition A: Retention time = 1.49 min; ESI-MS(+) m/z 943.6 (M+2H).

[004424] Analysis Condition B: Retention time = 2.60min; ESI-MS(+) m/z 943.7 (M+2H). Preparation of Example 9059 Example 9059

[004425] The crude material from Example 9059 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 36.4 mg, and its estimated purity by LCMS analysis was 94%.

[004426] Assay Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 936.5 (M+2H). Assay Condition B: Retention time = 2.54 min; ESI-MS(+) m/z 936.3 (M+2H). Preparation of Example 9060 Example 9060

[004427] The crude material from Example 906 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.9 mg, and its estimated purity by LCMS analysis was 96%.

[004428] Assay Condition A: Retention time = 1.73 min; ESI-MS(+) m/z 944.8 (M+2H). Assay Condition B: Retention time = 2.91 min; ESI-MS(+) m/z 944.9 (M+2H). Preparation of Example 9061 Example 9061

[004429] The crude material from Example 9061 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.3 mg, and its estimated purity by LCMS analysis was 96%.

[004430] Assay Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 944.6 (M+2H). Assay Condition B: Retention time = 2.65 min; ESI-MS(+) m/z 944.7 (M+2H). Preparation of Example 9062 Example 9062

[004431] The crude material from Example 9062 was purified via preparative LC/MS under the following conditions: Column: Waters XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: water with 20 mM ammonium acetate; Mobile phase B: 95:5 methane:water with 20 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg, and its purity was estimated to be 100% by LCMS analysis.

[004432] Assay Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 953.3 (M+2H). Assay Condition B: Retention time = 2.88 min; ESI-MS(+) m/z 952.9 (M+2H). Preparation of Example 9063 Example 9063

[004433] The crude material from Example 9063 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.9 mg, and its purity estimated by LCMS analysis was 100%.

[004434] Assay Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 948.5(M+2H). Assay Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 948.8 (M+2H). Preparation of Example 9064 Example 9064

[004435] The crude material from Example 9064 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.4 mg, and its estimated purity by LCMS analysis was 99%.

[004436] Assay Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 956.9 (M+2H). Assay Condition B: Retention time = 2.81 min; ESI-MS(+) m/z 957.3 (M+2H). Preparation of Example 9065 Example 9065

[004437] The crude material from Example 9065 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.4 mg, and its purity estimated by LCMS analysis was 100%.

[004438] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 956.8 (M+2H).

[004439] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 956.8 (M+2H). Preparation of Example 9066 Example 9066

[004440] The crude material from Example 9066 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.7 mg, and its estimated purity by LCMS analysis was 97%.

[004441] Assay Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 964.9 (M+2H). Assay Condition B: Retention time = 2.78 min; ESI-MS(+) m/z 965.2 (M+2H). Preparation of Example 9067 Example 9067

[004442] The crude material from Example 9067 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.8 mg, and its purity estimated by LCMS analysis was 100%.

[004443] Assay Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 934.9 (M+2H). Assay Condition B: Retention time = 2.57 min; ESI-MS(+) m/z 934.4 (M+2H). Preparation of Example 9068 Example 9068

[004444] The crude material from Example 9068 was purified via preparative LC/MS under the following conditions: Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.8 mg, and its purity estimated by LCMS analysis was 100%.

[004445] Assay Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 943.3 (M+2H). Assay Condition B: Retention time = 2.84 min; ESI-MS(+) m/z 943.7 (M+2H). Preparation of Example 9069 Example 9069

[004446] The crude material from Example 9069 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.1 mg, and its purity estimated by LCMS analysis was 100%.

[004447] Assay Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 943.2 (M+2H). Assay Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 943.3 (M+2H). Preparation of Example 9070 Example 9070

[004448] The crude material from Example 9070 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.9 mg, and its purity estimated by LCMS analysis was 100%.

[004449] Assay Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 951.7 (M+2H). Assay Condition B: Retention time = 2.85 min; ESI-MS(+) m/z 951.7 (M+2H). Preparation of Example 9071 Example 9071

[004450] The crude material from Example 9071 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-100% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.6 mg, and its purity estimated by LCMS analysis was 100%.

[004451] Analysis Condition B: Retention time = 2.91 min; ESI-MS(+) m/z 939.8 (M+2H). Preparation of Example 9072 Example 9072

[004452] The crude material from Example 9072 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 405-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.2 mg, and its estimated purity by LCMS analysis was 97%.

[004453] Assay Condition A: Retention time = 1.72 min; ESI-MS(+) m/z 931.8 (M+2H). Assay Condition B: Retention time = 2.93 min; ESI-MS(+) m/z 931.8 (M+2H). Preparation of Example 9073 Example 9073

[004454] The crude material from Example 9073 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.2 mg, and its estimated purity by LCMS analysis was 96%.

[004455] Assay Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 922.7 (M+2H). Assay Condition B: Retention time = 2.74 min; ESI-MS(+) m/z 922.9 (M+2H). Preparation of Example 9074 Example 9074

[004456] The crude material from Example 9074 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.1 mg, and its estimated purity by LCMS analysis was 99%.

[004457] Assay Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 931.0 (M+2H). Assay Condition B: Retention time = 2.98 min; ESI-MS(+) m/z 930.9 (M+2H). Preparation of Example 9075 Example 9075

[004458] The crude material from Example 9075 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.1 mg, and its estimated purity by LCMS analysis was 99%.

[004459] Assay Condition A: Retention time = 1.61 min; ESI-MS(+) m/z 954.5 (M+2H). Assay Condition B: Retention time = 3.18 min; ESI-MS(+) m/z 954.5 (M+2H). Preparation of Example 9076 Example 9076

[004460] The crude material from Example 9076 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 44.3 mg, and its estimated purity by LCMS analysis was 99%.

[004461] Assay Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 958.5 (M+2H). Assay Condition B: Retention time = 3.11 min; ESI-MS(+) m/z 958.5 (M+2H). Preparation of Example 9077 Example 9077

[004462] The crude material from Example 9077 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 30.3 mg, and its purity estimated by LCMS analysis was 100%.

[004463] Assay Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 950.8 (M+2H). Assay Condition B: Retention time = 2.92 min; ESI-MS(+) m/z 950.0(M+2H). Preparation of Example 9078 Example 9078

[004464] The crude material from Example 9078 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 39.1 mg, and its purity estimated by LCMS analysis was 100%.

[004465] Assay Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 966.5 (M+2H). Assay Condition B: Retention time = 3.09 min; ESI-MS(+) m/z 966.4 (M+2H). Preparation of Example 9079 Example 9079

[004466] The crude material from Example 9079 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.7 mg, and its purity estimated by LCMS analysis was 100%.

[004467] Assay Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 957.9(M+2H). Assay Condition B: Retention time = 2.89 min; ESI-MS(+) m/z 958.0 (M+2H). Preparation of Example 9080 Example 9080

[004468] The crude material from Example 9080 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.8 mg, and its estimated purity by LCMS analysis was 99%.

[004469] Assay Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 945.9 (M+2H). Assay Condition B: Retention time = 2.97 min; ESI-MS(+) m/z 945.8 (M+2H). Preparation of Example 9081 Example 9081

[004470] The crude material from Example 9081 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.1 mg, and its purity was estimated to be 100% by LCMS analysis.

[004471] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 931.6 (M+2H).

[004472] Analysis Condition B: Retention time = 2.60 min; ESI-MS(+) m/z 931.7 (M+2H). Preparation of Example 9082 Example 9082

[004473] The crude material from Example 9082 was purified via preparatory LC/MS with the following conditions: Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 1555% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.3 mg, and its purity estimated by LCMS analysis was 98%.

[004474] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 939.7 (M+2H).

[004475] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 939.8 (M+2H). Preparation of Example 9083 Example 9083

[004476] The crude material from Example 9083 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.2 mg, and its purity was estimated to be 99% by LCMS analysis.

[004477] Analysis Condition A: Retention time = 1.46 min; ESI-MS(+) m/z 939.7 (M+2H).

[004478] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 939.7 (M+2H). Preparation of Example 9084 Example 9084

[004479] The crude material from Example 9084 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.7 mg, and its purity estimated by LCMS analysis was 100%.

[004480] Assay Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 948.1 (M+2H). Assay Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 948.1 (M+2H). Preparation of Example 9085 Example 9085

[004481] The crude material from Example 9085 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.8 mg, and its estimated purity by LCMS analysis was 90%.

[004482] Assay Condition A: Retention time = 1.55 min; ESI-MS(+) m/z 889.1 (M+2H)+. Assay Condition B: Retention time = 2.70 min; ESI-MS(+) m/z 889.1 (M+2H)+. Preparation of Example 9086 Example 9086

[004483] The crude material from Example 9086 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.5 mg, and its estimated purity by LCMS analysis was 98%.

[004484] Assay Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 897.4 (M+2H). Assay Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 897.6 (M+2H). Preparation of Example 9087 Example 9087

[004485] The crude material from Example 9087 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.6 mg, and its estimated purity by LCMS analysis was 99%.

[004486] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 897.0 (M+2H). Assay Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 897.0 (M+2H). Preparation of Example 9088 Example 9088

[004487] The crude material from Example 9088 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.3 mg, and its purity estimated by LCMS analysis was 100%.

[004488] Assay Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 905.6 (M+2H). Assay Condition B: Retention time = 2.88 min; ESI-MS(+) m/z 905.2 (M+2H). Preparation of Example 9089 Example 9089

[004489] The crude material from Example 9089 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.5 mg, and its estimated purity by LCMS analysis was 92%.

[004490] Assay Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 931.6 (M+2H). Assay Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 931.7 (M+2H). Preparation of Example 9090

[004491] Example 9090

[004492] The crude material from Example 9090 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.6 mg, and its estimated purity by LCMS analysis was 94%.

[004493] Assay Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 940.1 (M+2H). Assay Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 940.3 (M+2H). Preparation of Example 9091 Example 9091

[004494] The crude material from Example 9091 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.7 mg, and its estimated purity by LCMS analysis was 98%.

[004495] Assay Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 939.7 (M+2H). Assay Condition B: Retention time = 2.51 min; ESI-MS(+) m/z 939.7 (M+2H). Preparation of Example 9092 Example 9092

[004496] The crude material from Example 9092 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.3 mg, and its estimated purity by LCMS analysis was 95%.

[004497] Assay Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 948.1 (M+2H). Assay Condition B: Retention time = 2.69 min; ESI-MS(+) m/z 948.2 (M+2H). Preparation of Example 9093 Example 9093

[004498] The crude material from Example 9093 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 22.4 mg, and its purity estimated by LCMS analysis was 100%.

[004499] Assay Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 889.4 (M+2H). Assay Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 889.0 (M+2H). Preparation of Example 9094 Example 9094

[004500] The crude material from Example 9094 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.9 mg, and its estimated purity by LCMS analysis was 99%.

[004501] Assay Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 897.5 (M+2H). Assay Condition B: Retention time = 2.84 min; ESI-MS(+) m/z 897.6 (M+2H). Preparation of Example 9095 Example 9095

[004502] The crude material from Example 9095 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.3 mg, and its estimated purity by LCMS analysis was 96%.

[004503] Assay Condition A: Retention time = 1.43 min; ESI-MS(+) m/z 896.9 (M+2H). Assay Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 896.8 (M+2H). Preparation of Example 9096 Example 9096

[004504] The crude material from Example 9096 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 27.4 mg, and its estimated purity by LCMS analysis was 95%.

[004505] Assay Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 905.2 (M+2H). Assay Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 905.5 (M+2H). Preparation of Example 9097 Example 9097

[004506] The crude material from Example 9097 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.5 mg, and its estimated purity by LCMS analysis was 96%.

[004507] Assay Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 931.7 (M+2H). Assay Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 931.8 (M+2H). Preparation of Example 9098 Example 9098

[004508] The crude material from Example 9098 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.3 mg, and its estimated purity by LCMS analysis was 98%.

[004509] Assay Condition A: Retention time = 1.67 min; ESI-MS(+) m/z 940.2 (M+2H). Assay Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 940.6 (M+2H). Preparation of Example 9099 Example 9099

[004510] The crude material from Example 9099 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.5 mg, and its estimated purity by LCMS analysis was 98%.

[004511] Analysis Condition A: Retention time = 1. min; ESI-MS(+) m/z 940.7 (M+2H). Analysis Condition B: Retention time = 2. min; ESI-MS(+) m/z 940.3 (M+2H). Preparation of Example 9100 Example 9100

[004512] The crude material from Example 9100 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.7 mg, and its estimated purity by LCMS analysis was 99%.

[004513] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 940.8 (M+2H). Assay Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 940.2 (M+2H). Preparation of Example 9105 Example 9105

[004514] The crude material from Example 9105 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.0 mg, and its estimated purity by LCMS analysis was 98%.

[004515] Assay Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 944.0 (M+2H)+. Assay Condition B: Retention time = 2.50 min; ESI-MS(+) m/z 944.2 (M+2H)+. Preparation of Example 9106 Example 9106

[004516] The crude material from Example 9106 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.8 mg, and its purity estimated by LCMS analysis was 100%.

[004517] Assay Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 952.7 (M+2H). Assay Condition B: Retention time = 2.70 min; ESI-MS(+) m/z 952.6 (M+2H). Preparation of Example 9107 Example 9107

[004518] The crude material from Example 9107 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 4.7 mg, and its purity was estimated to be 100% by LCMS analysis.

[004519] Assay Condition A: Retention time = 1.41 min; ESI-MS(+) m/z 952.2 (M+2H). Assay Condition B: Retention time = 2.49 min; ESI-MS(+) m/z 952.3 (M+2H). Preparation of Example 9108 Example 9108

[004520] The crude material from Example 9108 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.2 mg, and its purity estimated by LCMS analysis was 100%.

[004521] Assay Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 960.2 (M+2H). Assay Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 960.3 (M+2H). Preparation of Example 9109 Example 9109

[004522] The crude material from Example 9109 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.9 mg, and its estimated purity by LCMS analysis was 97%.

[004523] Assay Condition A: Retention time = 1.39 min; ESI-MS(+) m/z 943.8 (M+2H). Assay Condition B: Retention time = 2.44 min; ESI-MS(+) m/z 944.1 (M+2H). Preparation of Example 9110 Example 9110

[004524] The crude material from Example 9110 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 35 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 7.7 mg, and its purity was estimated to be 96% by LCMS analysis.

[004525] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 902.2 (M+2H).

[004526] Analysis Condition B: Retention time = 2.46 min; ESI-MS(+) m/z 902.1 (M+2H). Preparation of Example 9111 Example 9111

[004527] The crude material from Example 9111 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.9 mg, and its purity estimated by LCMS analysis was 100%.

[004528] Assay Condition A: Retention time = 1.59 min; ESI-MS(+) m/z 910.2 (M+2H). Assay Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 910.3 (M+2H). Preparation of Example 9112 Example 9112

[004529] The crude material from Example 9112 was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 35-75% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.4 mg, and its estimated purity by LCMS analysis was 95%.

[004530] Assay Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 952.2 (M+2H). Assay Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 952.5 (M+2H). Preparation of Example 9113 Example 9113

[004531] The crude material from Example 9113 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.0 mg, and its purity was estimated to be 93% by LCMS analysis.

[004532] Analysis Condition A: Retention time = 1.32 min; ESI-MS(+) m/z 951.7 (M+2H).

[004533] Analysis Condition B: Retention time = 2.39 min; ESI-MS(+) m/z 952.1 (M+2H). Preparation of Example 9114 Example 9114

[004534] The crude material from Example 9114 was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 40 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge Shield RP18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water/10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water/10 mM ammonium acetate; Gradient: 35-75% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[004535] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 960.7 (M+2H).

[004536] Analysis Condition B: Retention time = 2.56 min; ESI-MS(+) m/z 960.6 (M+2H). Preparation of Example 10001 Example 10001

[004537] Example 10001 was prepared by following the general synthetic sequence described for the preparation of Example 5001, consisting of the following general procedures: "Prelude Method A: Resin Swelling Procedure", "Prelude Method A: Single Coupling Procedure", "Prelude Method A: Double Coupling Procedure", "Prelude Method A: Chloroacetyl Chloride Coupling Procedure", "Global Deprotection Method A", and "Cyclization Method A".

[004538] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 20 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 15 min, followed by a 4 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.7 mg, and its purity was estimated to be 100% by LCMS analysis.

[004539] Analysis Condition A: Retention time = 1.81 min; ESI-MS(+) m/z 892.6 (M+2H).

[004540] Analysis Condition B: Retention time = 3.01 min; ESI-MS(+) m/z 892.6 (M+2H). Preparation of (1-yl)methoxy)carbonyl)amino)-3-(1-(tert-yl)butanoic acid Scheme: Step 1:

[004541] (E)-3-(1H-Indol-3-yl)acrylic acid (4.2 g, 22.44 mmol), (Boc)20 (10.42 mL, 44.9 mmol), and Et3N (7.82 mL, 56.1 mmol) were stirred in THF (112 mL) followed by the addition of DMAP (0.137 g, 1.122 mmol). The reaction was stirred for 16 h. The reaction was quenched with saturated sodium bicarbonate and stirred vigorously for 10 min. The mixture was diluted with EtOAc and acidified with 1 N HCl. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid which was taken directly to Step 2. Step 2:

[004542] To a solution of (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (7.14 g, 24.85 mmol) in THF (400 mL) at -78 °C were added Et3N (10.39 mL, 74.6 mmol) and pivaloyl chloride (6.12 mL, 49.7 mmol). The mixture was stirred for 15 min at -78 °C and then warmed to 0 °C over 1.5 h. The mixture was cooled to -78 °C, to which n-butyllithium (1.6 M in hexanes) (14 mL, 22.4 mmol) was added, and then (R)-4-phenyl-2-oxazolidinone lithium salt [prepared by adding n-butyllithium (1.6 M in hexanes) (31 mL, 49.7 mmol) to a solution of (R)-4-phenyloxazolidin-2-one (8.11 g, 49.7 mmol)] in THF (200 mL) at -78 °C) was added via a cannula. The reaction was stirred at -78 °C for 2 h and then at room temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution. The organics were removed in vacuo , and the aqueous phase was extracted with EtOAc. The organic layer was collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The product was purified by silica gel chromatography using a 10-20% EtOAc/Hexanes gradient. The product fractions were collected and the solvent was removed in vacuo to give ((R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate, 7.12 g (66%). ESI-MS(+) m/z 433.4 (M+1). Step 3:

[004543] To a mixture of copper(I) bromide methyl sulfide complex (5.08 g, 24.70 mmol) and dimethyl sulfide (15 mL) in THF (30 mL) at -4 °C was added methylmagnesium bromide (3 M in diethyl ether) (5.49 mL, 16.46 mmol). After stirring for 10 min, (R,E)-tert-butyl 3-(3-oxo-3-(2-oxo-4-phenyloxazolidin-3-yl)prop-1-en-1-yl)-1H-indole-1-carboxylate (7.12 g, 16.46 mmol) in THF (70 mL) was added. The mixture was stirred at -4 °C for 1 h and at room temperature for 2 h. The mixture was cooled to -78 °C and NBS (5.86 g, 32.9 mmol) in THF (120 mL) was added to the reaction via a cannula. The reaction was stirred for 1 h at -78 °C for 1 h and then at room temperature for 2 h. The reaction was quenched with 0.5 N NaHSO4 : brine (1 : 1,200 mL). The organic layer was separated and washed with 0.5 N Na2S2O3 (2 × 100 mL). The organic phase was washed with NH4Cl and then brine. The organic layer was collected, dried over sodium sulfate, and concentrated in vacuo. The product was purified by chromatography on silica gel using 1020% EtOAc/hexanes. The product fractions were collected and the solvent was removed in vacuo to give tert-butyl 3-((2S,3R)-3-bromo-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate, 4.0 g, (46%). ESI-MS(+) m/z 549.2 (M+Na). 1H NMR (500MHz, chloroform-d)DDD8.16 (d, J=7.3 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.48 (s, 1H), 7.43 - 7.22 (m, 7H), 6.18 (d, J=10.9 Hz, 1H), 5.16 (dd, J=8. 8, 4.3 Hz, 1H), 4.45 (t, J=8.9 Hz, 1H), 4.16 (dd, J=8.9, 4.3 Hz, 1H), 3.75 (dq, J=10.8, 7.0 Hz, 1H), 1.69 (s, 9H), 1.60 (d, J=7.1 Hz, 3H). Step 4:

[004544] tert-Butyl 3-((2S,3R)-3-bromo-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate (4 g, 7.58 mmol) was dissolved in DMSO (50.6 mL) followed by the addition of NaN3 (1.972 g, 30.3 mmol). The reaction was stirred for 2 h. The reaction was diluted with EtOAc and water. The organic layer was collected, washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo to give the crude product which was purified by chromatography on silica gel using a 15-20% EtOAc/Hexanes gradient. The product fractions were collected and the solvent was removed in vacuo to give tert-butyl 3-((2S,3S)-3-azido-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate, 3.4 g (91%). 1H NMR (400MHz, chloroform-d)DDD8.16 (d, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.37 - 7.20 (m, 7H), 5.55 (d, J=8.8 Hz, 1H), 5.51 (dd, J=8.8 , 4.4 Hz, 1H), 4.79 (t, J=8.9 Hz, 1H), 4.38 (dd, J=8.9, 4.3 Hz, 1H), 3.68 - 3.57 (m, 1H), 1.69 - 1.66 (m, 9H), 1.27 (d, J=6.8 Hz, 3H). Step 5:

[004545] To a mixture of tert-butyl 3-((2S,3S)-3-azido-4-oxo-4-((R)-2-oxo-4-phenyloxazolidin-3-yl)butan-2-yl)-1H-indole-1-carboxylate (3.38 g, 6.90 mmol) in water (29 mL) and THF (86 mL) at 0 °C was added hydrogen peroxide (4.67 mL, 45.7 mmol), followed by lithium hydroxide (0.331 g, 13.81 mmol). The reaction was stirred for 2 h. The reaction was quenched with Na 2 SO 3 (7 g) in 40 mL of water. The reaction was stirred for 30 min at room temperature. The solvent was removed in vacuo , and then the reaction was diluted with EtOAc and water. The pH was adjusted to 2. The organic phase was collected, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a residue which was triturated in Et2O to give a solid which was collected by filtration and dried to give (2S,3S)-2-azido-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 2.38 g (100%). ESI-MS(- ) m/z 343.3 (M-HAH NMR (500MHz, chloroform-d)DDD8.15 (d, J=5.5 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.33 (td, J=7.7, 1.1 Hz, 1H), 7.27 -7.23 (m, 1H), 4.29 (d, J=6.5 Hz, 1H), 3.68 (quin, J=6.9 Hz, 1H), 1.70 (s, 9H), 1.51 (d, J=7.1 Hz, 3H).

[004546] 10% Pd on carbon (1.19 g, 1.118 mmol) was placed in a flask under a N2 (g) blanket. The catalyst was wetted with MeOH (5 mL). To the flask was added (2S,3S)-2-azido-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid (2.38 g, 6.91 mmol) as a solution in MeOH (69.1 mL). The flask was evacuated and then charged with H2 (g). The reaction was stirred for 2 h. The flask was evacuated and purged with 2X N2 (g). The reaction was filtered through CELI-TE® and the filter cake was washed with MeOH. The organics were concentrated in vacuo to give (2S,3S)-2-amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid which was used in Step 7 as is. ESI-MS(+) m/z 319.4 (M+H). Step 7:

[004547] (2S,3S)-2-Amino-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid (2197 mg, 6.9 mmol) was dissolved in a mixture of water (35 mL) and THF (100 mL). Sodium bicarbonate (2174 mg, 25.9 mmol) and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidine-1-carboxylate (4434 mg, 13.80 mmol) were added to the solution and the reaction was stirred for 16 h. A saturated ammonium chloride solution (200 mL) was added to the reaction and the solvent was then removed in vacuo . The remaining aqueous layer was extracted with EtOAc. The organic layer was then collected, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by a BIOTAGE® C-18 reversed-phase column using a 20-80% ACN/water gradient with 0.1% TFA modifier over 20 min. The product fractions were collected, diluted with water, and extracted with EtOAc. The organic layer was washed with water, then brine, dried over sodium sulfate, and concentrated in vacuo to give (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid, 500 mg (13%). ESI-MS(+) m/z 541.5 (M+H). 1H NMR (500MHz, DMSO-d6)DDDl2.79 (br. s., 1H), 8.03 (d, J=8.2 Hz, 1H), 7.90 - 7.85 (m, 2H), 7.73 (dd, J=8.1, 4.7 Hz, 2H), 7.62 (d, J=7.4 Hz, 7.5), 6 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.39 (td, J=7.4, 4.0 Hz, 2H), 7.35 - 7.30 (m, 1H), 7.28 - 7.18 (m, 3H), 4.45 (t, J=8.2 Hz, 1H), 4.30 - 4.25 (m, 1H), 4.21 - 4.15 (m, 1H), 4.15 - 4.09 (m, 1H), 3.48 (quin, J=7.2 Hz, 1H), 1.57 (s, 9H), 1.34 (d, J=7.3 Hz, 3H). Preparation of Example 10501 Example 10501

[004548] Example 10501 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004549] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 15 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.1 mg, and its purity estimated by LCMS analysis was 97%.

[004550] Analysis Condition A: Retention time = 1.60 min; ESI-MS(+) m/z 950.6 (M+2H).

[004551] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 950.5 (M+2H). Preparation of Example 10502 Example 10502

[004552] Example 10502 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004553] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.4 mg, and its purity estimated by LCMS analysis was 95%.

[004554] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 944.3 (M+2H).

[004555] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 944.0 (M+2H). Preparation of Example 10503 Example 10503

[004556] Example 10503 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004557] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 × 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 44.9 mg, and its purity was estimated to be 95% by LCMS analysis.

[004558] Analysis Condition A: Retention time = 1.47 min; ESI-MS(+) m/z 937.4 (M+2H).

[004559] Analysis Condition B: Retention time = 2.61 min; ESI-MS(+) m/z 937.0 (M+2H). Preparation of Example 10504 Example 10504

[004560] Example 10504 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004561] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 49.9 mg, and its purity estimated by LCMS analysis was 100%.

[004562] Analysis Condition A: Retention time = 1.45 min; ESI-MS(+) m/z 930.3 (M+2H).

[004563] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 930.4 (M+2H). Preparation of Example 10505 Example 10505

[004564] Example 10505 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004565] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 15.2 mg, and its purity estimated by LCMS analysis was 99%.

[004566] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 951.2 (M+2H).

[004567] Analysis Condition B: Retention time = 2.64 min; ESI-MS(+) m/z 951.3 (M+2H). Preparation of Example 10506 Example 10506

[004568] Example 10506 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004569] Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.3 mg, and its purity estimated by LCMS analysis was 100%.

[004570] Analysis Condition A: Retention time = 1.53 min; ESI-MS(+) m/z 930.3 (M+2H).

[004571] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 930.4 (M+2H). Preparation of Example 10507 Example 10507

[004572] Example 10507 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004573] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 13.2 mg, and its purity estimated by LCMS analysis was 100%.

[004574] Analysis Condition A: Retention time = 1.50 min; ESI-MS(+) m/z 944.3 (M+2H).

[004575] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 943.7 (M+2H). Preparation of Example 10508 Example 10508

[004576] Example 10508 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004577] Column: Waters XBridge c-18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 50-90% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 40 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 2.7 mg, and its purity was estimated to be 79% by LCMS analysis.

[004578] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 937.4 (M+2H).

[004579] Analysis Condition B: Retention time = 2.68 min; ESI-MS(+) m/z 937.3 (M+2H). Preparation of Example 10509 Example 10509

[004580] Example 10509 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004581] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.0 mg, and its purity estimated by LCMS analysis was 100%.

[004582] Analysis Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 929 A (M+2H).

[004583] Analysis Condition B: Retention time = 2.82 min; ESI-MS(+) m/z 929.8 (M+2H). Preparation of Example 10510 Example 10510

[004584] Example 10510 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004585] Column: XBridge C18, 19 × mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.0 mg, and its purity estimated by LCMS analysis was 100%.

[004586] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 922.5 (M+2H).

[004587] Analysis Condition B: Retention time = 2.83 min; ESI-MS(+) m/z 922.8 (M+2H). Preparation of Example 10511 Example 10511

[004588] Example 10511 was prepared following “General Synthetic Sequence A”. The crude material was purified via preparative LC/MS under the following conditions:

[004589] Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.4 mg, and its purity estimated by LCMS analysis was 100%.

[004590] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 915.8 (M+2H).

[004591] Analysis Condition B: Retention time = 2.84 min; ESI-MS(+) m/z 915.8 (M+2H). Preparation of Example 10512 Example 10512

[004592] Example 10512 was prepared following “General Synthetic Sequence A”. The material was further purified via preparatory LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-50% B over 40 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 25.8 mg, and its estimated purity by LCMS analysis was 99%.

[004593] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 908.4 (M+2H).

[004594] Analysis Condition B: Retention time = 2.81 min; ESI-MS(+) m/z 908.4 (M+2H). Preparation of Example 10513 Example 10513

[004595] Example 10513 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". (2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid was used in the sixth amino acid coupling step. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, and then a 5-minute retention at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 10.8 mg, and its purity estimated by LCMS analysis was 96%.

[004596] ESI-HRMS(+) m/z: Calculated: 954.4950 (M+2H); Found: 954.4874 (M+2H). Preparation of Example 10514 Example 10514

[004597] Example 10514 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". (2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid was used in the sixth amino acid coupling step. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, and then a 5-minute retention at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 14.4 mg, and its purity estimated by LCMS analysis was 100%.

[004598] Analysis Condition A: Retention time = 1.52 min; ESI-MS(+) m/z 962.9 (M+2H).

[004599] Analysis Condition B: Retention time = 2.58 min; ESI-MS(+) m/z 962.9 (M+2H).

[004600] ESI-HRMS(+) m/z: Calculated: 962.4880 (M+2H); Found: 962.4851 (M+2H). Preparation of Example 10515 Example 10515

[004601] Example 10515 was prepared by following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". (2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)butanoic acid was used in the eighth amino acid coupling step. The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 minutes, and then a 5-minute retention at 100% B; Flow rate: 20 mL/min. The fractions containing the desired product were combined and dried via centrifugal evaporation. The product yield was 15.1 mg, and its purity estimated by LCMS analysis was 97%.

[004602] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 963.0 (M+2H).

[004603] ESI-HRMS(+) m/z: Calculated: 962.4880 (M+2H); Found: 962.4844 (M+2H). Preparation of Example 10516 Example 10516

[004604] Example 10516 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.4 mg, and its purity estimated by LCMS analysis was of 97%.

[004605] Analysis Condition A: Retention time = 1.58 min; ESI-MS(+) m/z 976.2 (M+2H).

[004606] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 976.4 (M+2H). Preparation of Example 10517 Example 10517

[004607] Example 10517 was prepared following “General Synthetic Sequence A" but using “Cyclization Method B" in place of “Cyclization Method A". The crude material was purified via preparative LC/MS using the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.4 mg, and its purity estimated by LCMS analysis was of 97%.

[004608] Analysis Condition A: Retention time = 1.57 min; ESI-MS(+) m/z 983.8 (M+2H).

[004609] Analysis Condition B: Retention time = 2.77 min; ESI-MS(+) m/z 983.8 (M+2H).

[004610] ESI-HRMS(+) m/z: Calculated: 983.0012 (M+2H); Found: 982.9986 (M+2H). Analytical Data:

[004611] Mass Spectrometry: "ESI-MS(+)" means electrospray ionization mass spectrometry performed in positive ion mode; "ESI-MS(-)" means electrospray ionization mass spectrometry performed in negative ion mode; "ESI-HRMS(+)" means electrospray ionization high-resolution mass spectrometry performed in positive ion mode; "ESI-HRMS(-)" means electrospray ionization high-resolution mass spectrometry performed in negative ion mode. Detected masses are reported using the “m/z” unit designation. Compounds with exact masses greater than 1000 were frequently detected as doubly or triply charged ions. Analysis Condition A:

[004612] Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B, 0-100% B over 3 min, then a 0.5 min hold at 100% B; Flow rate: 1 mL/min; Detection: UV at 220 nm. Assay Condition B:

[004613] Column: Waters BEH C18, 2.0 x 50 mm, 1.7-μm particles; Mobile phase A: 5:95 methane:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methane:water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0% B, 0-100% B over 3 min, then a 0.5 min hold at 100% B; Flow rate: 0.5 mL/min; Detection: UV at 220 nm. General Procedures for Examples 13001-14008:

[004614] All manipulations were performed with automation on a Symphony-X peptide synthesizer (Protein Technologies). All procedures, unless noted, were performed in a 10 mL polypropylene tube equipped with a bottom frit. The tube is connected to the Prelude peptide synthesizer through the bottom and top of the tube. DMF and DCM can be added through the top of the tube, which evenly coats the sides of the tube. The remaining reagents are added through the bottom of the tube and run up the frit to contact the resin. All solutions are removed through the bottom of the tube. "Periodic agitation" describes a brief pulse of N2 gas through the bottom frit; the pulse lasts approximately 5 seconds and occurs every 30 seconds. Chloroacetyl chloride solutions in DMF were used within 24 hours of preparation. Amino acid solutions were generally not used beyond 3 weeks of preparation. The HATU solution was used within 5 days of preparation. DMF = dimethylformamide; HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate; DIPEA = diisopropylethylamine; Rink = (2,4-dimethoxyphenyl)(4-alkoxyphenyl)methanamine, where "4-alkoxy” describes the position and type of connectivity to the polystyrene resin. The resin used is Merrifield polymer (polystyrene) with a Rink linker (Fmoc-protected on nitrogen); 100-200 mesh, 1% DVB, 0.56 mmol/g loading. Common amino acids used are listed below with side chain protecting groups indicated in parentheses. Fmoc-Ala-OH; Fmoc-Arg(Pbf)-OH; Fmoc-Asn(Trt)-OH; Fmoc-Asp(OtBu)-OH; Fmoc-Bzt-OH; Fmoc-Cys(Trt)-OH; Fmoc-Dab(Boc)- OH; Fmoc-Dap(Boc)-OH; Fmoc-Gln(Trt)-OH; Fmoc-Gly-OH; Fmoc-His(Trt)-OH; Fmoc-Hyp(tBu)-OH; Fmoc-Ile-OH; Fmoc-Leu-OH; Fmoc-Lys(Boc)-OH; Fmoc-Nle-OH; Fmoc-Met-OH; Fmoc-[N-Me]Ala-OH; Fmoc-[N-Me]Nle-OH; Fmoc-Phe-OH; Fmoc-Pro-OH; Fmoc-Sar-OH; Fmoc-Ser(tBu)-OH; Fmoc-Thr(tBu)-OH; Fmoc-Trp(Boc)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Val-OH

[004615] The procedures describe an experiment performed on a 0.100 mmol scale, where the scale is determined by the amount of Rink linker bound to the resin. This scale corresponds to approximately 178 mg of the Rink-Merrifield resin described above. Prior to amino acid coupling, all peptide synthesis sequences began with a resin swelling procedure, described below as "Resin Swelling Procedure". Coupling of amino acids to the N-terminus of a primary amine used the "Simple Coupling Procedure" described below.

[004616] Coupling of amino acids to the N-terminus of a secondary amine used the "Double Coupling Procedure" described below. Coupling of chloroacetyl chloride to the N-terminus of the peptide is described by the "Chloroacetyl Chloride Coupling Procedure" detailed below. Resin Swelling Procedure:

[004617] To a 10 mL polypropylene solid phase reaction vessel was added Merrifield:Rink resin (178 mg, 0.100 mmol). The resin was washed (swollen) three times as follows: to the reaction vessel was added DMF (2.0 mL), after which the mixture was stirred periodically for 10 min before the solvent was drained through the frit. Simple coupling procedure:

[004618] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.0 mL) was added to the upper part of the vessel (not through the lower frit) and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.4 M in DMF, 1.0 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added to the upper part of the vessel (not through the lower frit), and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. Acetic anhydride (2.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel (not through the lower frit) and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was used directly in the next step. Double coupling procedure:

[004619] To the reaction vessel containing the resin from the previous step was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. To the reaction vessel was added piperidine:DMF (20:80 v/v, 2.0 mL). The mixture was stirred periodically for 3 minutes and then the solution was drained through the frit. The resin was washed successively six times as follows: for each wash, DMF (2.0 mL) was added to the upper part of the vessel (not through the lower frit) and the resulting mixture was stirred periodically for 30 seconds before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.4 M in DMF, 1.0 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added to the upper part of the vessel (not through the lower frit), and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. To the reaction vessel was added the amino acid (0.2 M in DMF, 1.0 mL, 2 eq.), followed by HATU (0.2 M in DMF, 1.0 mL, 2 eq.), and finally DIPEA (0.4 M in DMF, 1.0 mL, 4 eq.). The mixture was stirred periodically for 15 min, and then the reaction solution was drained through the frit. The resin was washed twice as follows: for each wash, DMF (2.0 mL) was added to the upper part of the vessel (not through the lower frit), and the resulting mixture was stirred periodically for 30 s before the solution was drained through the frit. Acetic anhydride (2.0 mL) was added to the reaction vessel. The mixture was stirred periodically for 10 min, and then the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel (not through the lower frit) and the resulting mixture was stirred periodically for 90 seconds before the solution was drained through the frit. The resulting resin was used directly in the next step. Chloroacetyl chloride coupling procedure:

[004620] To the reaction vessel was added DIPEA (0.4M in DMF, 3.0 mL, 24 eq.), followed by chloroacetyl chloride (0.8M in DMF, 1.5 mL, 13.2 eq.). The mixture was stirred periodically for 30 min, and then the solution was drained through the frit. The resin was washed successively three times as follows: for each wash, DMF (2.0 mL) was added to the top of the vessel (not through the bottom frit) and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resin was washed successively four times as follows: for each wash, CH2Cl2 (2.0 mL) was added to the top of the vessel (not through the bottom frit) and the resulting mixture was stirred periodically for 90 s before the solution was drained through the frit. The resulting resin was placed in a current of N2 for 15 minutes and the resin became rigid and was easily manipulated. Global deprotection procedure:

[004621] A “deprotection solution” was prepared by combining trifluoroacetic acid (22 mL), phenol (1.325 g), water (1.25 mL), and triisopropylsilane (0.5 mL) in a 40 mL glass vial. The resin was removed from the reaction vessel and transferred to a 40 mL glass vial. To the vial was added the “deprotection solution” (2.0 mL). The mixture was mixed vigorously on a shaker (1000 rpm for 1 minute, then 500 rpm for 1.5 hour). The mixture was filtered through a 0.2 μ syringe filter into an 18X150 mm test tube, and the solids were extracted with a second portion of the “deprotection solution” (1.0 mL). The combined filtrates in the 18X150 mm test tube were diluted with Et2O (15 mL) and a significant amount of a white solid precipitated. The mixture was centrifuged for 2 minutes, and then the solution was decanted. The solids were suspended in Et2O (20 mL); the mixture was centrifuged for 5 minutes; and the solution was decanted. For a final period, the solids were suspended in Et2O (20 mL); the mixture was centrifuged for 5 minutes; and the solution was decanted. Cyclization procedure:

[004622] The solids were dissolved in 20 mL of 0.1 M aqueous MeCN:NH4OAc (1 : 1), and the solution was cautiously adjusted to pH = 8.5-9.0 using aqueous NaOH (1.0 M). The solution was then allowed to stand (stirring not necessary) overnight (approximately 18 h. 1 mL of DMSO was added, and the reaction solution was concentrated in a SPEED VAC® centrifuge-evaporator overnight with gentle heating. Approximately 1 mL of MeOH was added to the residue, and the resulting solution was purified by the methods described in the individual examples. Preparation of (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-phenylpyrrolidine-2-carboxylic acid Scheme: Step 1:

[004623] To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid (1.20 g, 4.12 mmol) in CH2Cl2 (20.59 mL) was added TFA (4.13 mL, 53.5 mmol). The resulting solution was stirred at room temperature. When LC/MS analysis showed the reaction to be complete, the volatiles were removed in vacuo, toluene (10 mL) was added, and the volatiles were again removed. Step 2:

[004624] The residue from Step 1 was taken up in 1 M aqueous Na2CO3 (24.71 mL, 24.71 mmol) with ~5 mL of THF added for solubility. FMOC-OSU (1.667 g, 4.94 mmol) was then added, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted twice with ether (discarded). The pH was adjusted to ~2 with the addition of 1 M HCl, and the resulting suspension was extracted three times into EtOAc. The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-phenylpyrrolidine-2-carboxylic acid was used as is for further chemistry. Preparation of Example 13001 Example 13001

[004625] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans 4-fluoro-L-proline]-Trp-[N-Me]Nle-[N-Me]Nle-Dab-Cys-Gly

[004626] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004627] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 32.6 mg, and its purity estimated by LCMS analysis was 100%.

[004628] Analysis Condition A: Retention time = 1.42 min; ESI-MS(+) m/z 943.7 (M+2H), most abundant ion.

[004629] Analysis Condition B: Retention time = 2.62 min; ESI-MS(+) m/z 943.7 (M+2H), most abundant ion.

[004630] ESI-HRMS(+) m/z: Calculated: 942.9543 (M+2H); Found: 942.9517 (M+2H). Preparation of Example 13002 Example 13002

[004631] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Glu-[trans 4-fluoro-1-proline]-Trp-Dab- Trp-[N-Me]Nle-[N-Me]Nle-Ala-Cys-Gly

[004632] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004633] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 26.7 mg, and its purity estimated by LCMS analysis was 100%.

[004634] Analysis Condition A: Retention time = 1.44 min; ESI-MS(+) m/z 929.3 (M+2H).

[004635] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 929.8 (M+2H), most abundant ion.

[004636] ESI-HRMS(+) m/z: Calculated: 928.9331 (M+2H); Found: 928.9306 (M+2H). Preparation of Example 13003 Example 13003

[004637] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-fluoro-1-proline]-Trp-Ser-Trp-[N-Me]Nle-[N-Me]Nle-Om-Cys-Gly

[004638] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004639] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 39.6 mg, and its purity estimated by LCMS analysis was 100%.

[004640] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 910.3 (M+2H).

[004641] Analysis Condition B: Retention time = 2.59 min; ESI-MS(+) m/z 910.3 (M+2H).

[004642] ESI-HRMS(+) m/z: Calculated: 909.9616 (M+2H); Found: 909.9587 (M+2H). Preparation of Example 13004 Example 13004

[004643] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans 4-(2H-tetrazol-5-yl)-1-proline]-Trp-Dab-Trp-[N-Me]Nle-[N-Me]Nle-Dab-Cys-Gly

[004644] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004645] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 3.0 mg, and its purity was estimated to be 100% by LCMS analysis.

[004646] Analysis Condition A: Retention time = 1.36 min; ESI-MS(+) m/z 968.2 (M+2H).

[004647] Analysis Condition B: Retention time = 2.55 min; ESI-MS(+) m/z 968.3 (M+2H).

[004648] ESI-HRMS(+) m/z: Calculated: 967.9652 (M+2H); Found: 967.9616 (M+2H). Preparation of Example 13005 Example 13005

[004649] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-phenyl-1-proline]-Trp-Ser- Trp-[N-Me]Nle- [N-Me]Nle-Orn-Cys-Gly

[004650] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004651] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.8 mg, and its purity estimated by LCMS analysis was 95%.

[004652] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 939.6 (M+2H), most abundant ion.

[004653] Analysis Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 939.6 (M+2H), most abundant ion.

[004654] ESI-HRMS(+) m/z: Calculated: 938.9820 (M+2H); Found: 938.9804 (M+2H). Preparation of Example 13006 Example 13006

[004655] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys[trans 4-phenyl-1-proline]-Trp-Lys- Trp-[N-Me]Nle- [N-Me]Nle-Glu-Cys-Gly

[004656] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004657] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 10-45% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The material was further purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, followed by a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 28.0 mg, and its purity was estimated to be 98% by LCMS analysis.

[004658] Analysis Condition A: Retention time = 1.51 min; ESI-MS(+) m/z 1001.1 (M+2H), most abundant ion.

[004659] Analysis Condition B: Retention time = 2.67 min; ESI-MS(+) m/z 1001.1 (M+2H), most abundant ion.

[004660] ESI-HRMS(+) m/z: Calculated: 1000.4980 (M+2H); Found: 1000.4955 (M+2H). Preparation of Example 13007 Example 13007

[004661] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans 4-benzyl-1-proline]-Trp-Dab-Trp-[N-Me]Nle-[N-Me]Nle-Dab-Cys-Gly

[004662] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004663] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 34.7 mg, and its purity estimated by LCMS analysis was 99%.

[004664] Analysis Condition A: Retention time = 1.62 min; ESI-MS(+) m/z 979.3 (M+2H), most abundant ion.

[004665] Analysis Condition B: Retention time = 2.86 min; ESI-MS(+) m/z 979.7 (M+2H), most abundant ion.

[004666] ESI-HRMS(+) m/z: Calculated: 978.9825 (M+2H); Found: 978.9810 (M+2H). Preparation of Example 13008 Example 13008

[004667] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Glu-[trans 4-benzyl-1-proline]-Trp-Dab-Trp-[N-Me]Nle-[N-Me]Nle-Ala-Cys-Gly

[004668] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004669] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 31.1 mg, and its purity estimated by LCMS analysis was 95%.

[004670] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 965.3 (M+2H).

[004671] Analysis Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 965.7 (M+2H), most abundant ion.

[004672] ESI-HRMS(+) m/z: Calculated: 964.9613 (M+2H); Found: 964.9582 (M+2H). Preparation of Example 10039 Example 13009

[004673] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-benzyl-1-proline]-Trp-Ser-Trp-[N-Me]Nle-[N-Me]Nle—Orn-Cys-Gly

[004674] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004675] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 25-65% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.5 mg, and its purity estimated by LCMS analysis was 99%.

[004676] Analysis Condition A: Retention time = 1.67 min; ESI-MS(+) m/z 946.5 (M+2H).

[004677] Analysis Condition B: Retention time = 2.78 min; ESI-MS(+) m/z 946.5 (M+2H).

[004678] ESI-HRMS(+) m/z: Calculated: 945.9898 (M+2H); Found: 945.9875 (M+2H). Preparation of Example 13010 Example 13010

[004679] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys-[trans 4-benzyl-1-proline]-Trp-Lys-Trp-[N-Me]Nle-[N-Me]Nle-Glu-Cys-Gly

[004680] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004681] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 33.3 mg, and its purity estimated by LCMS analysis was 99%.

[004682] Analysis Condition A: Retention time = 1.56 min; ESI-MS(+) m/z 1008.3 (M+2H), most abundant ion.

[004683] Analysis Condition B: Retention time = 2.75 min; ESI-MS(+) m/z 1008.3 (M+2H), most abundant ion.

[004684] ESI-HRMS(+) m/z: Calculated: 1007.5058 (M+2H); Found: 1007.5027 (M+2H). Preparation of Example 13011 Example 13011

[004685] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans 4-(4-fluorobenzyl)-1-proline]-T rp-Dab-T rp-[N-Me]Nle-[N-Me]Nle-Dab-Cys-Gly

[004686] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004687] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 41.7 mg, and its purity estimated by LCMS analysis was 99%.

[004688] Analysis Condition A: Retention time = 1.63 min; ESI-MS(+) m/z 988.6 (M+2H).

[004689] Analysis Condition B: Retention time = 2.84 min; ESI-MS(+) m/z 988.7 (M+2H), most abundant ion.

[004690] ESI-HRMS(+) m/z: Calculated: 987.9778 (M+2H); Found: 987.9758 (M+2H). Preparation of Example 13012 Example 13012

[004691] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans 4-(4-fluorobenzyl)-1-proline]-T rp-Dab-T rp-[N-Me]Nle-[N-Me]Nle-Ala-Cys-Gly

[004692] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004693] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.5 mg, and its purity estimated by LCMS analysis was 98%.

[004694] Analysis Condition A: Retention time = 1.68 min; ESI-MS(+) m/z 974.8 (M+2H), most abundant ion.

[004695] Analysis Condition B: Retention time = 2.90 min; ESI-MS(+) m/z 974.4 (M+2H). ESI-HRMS(+) m/z: Calculated: 973.9565 (M+2H); Found: 973.9538 (M+2H). Preparation of Example 13013 Example 13013

[004696] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-(4-fluorobenzyl)-1-proline]-Trp-Ser-Trp-[N-Me]Nle-[N-Me]Nle-Om-Cys-Gly

[004697] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004698] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.1 mg, and its purity estimated by LCMS analysis was 97%.

[004699] Analysis Condition A: Retention time = 1.69 min; ESI-MS(+) m/z 955.5 (M+2H).

[004700] Analysis Condition B: Retention time = 2.78 min; ESI-MS(+) m/z 955.8 (M+2H), most abundant ion.

[004701] ESI-HRMS(+) m/z: Calculated: 954.9851 (M+2H); Found: 954.9819 (M+2H). Preparation of Example 13014 Example 13014

[004702] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys-[trans 4-(4-fluorobenzyl)-1-proline]-T rp-Lys-T rp-[N-Me]Nle-[N-Me]Nle-Glu-Cys-Gly

[004703] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004704] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 18.1 mg, and its purity estimated by LCMS analysis was 100%.

[004705] Analysis Condition A: Retention time = 1.54 min; ESI-MS(+) m/z 1017.3 (M+2H), most abundant ion.

[004706] Analysis Condition B: Retention time = 2.76 min; ESI-MS(+) m/z 1016.9 (M+2H). ESI-HRMS(+) m/z: Calculated: 1016.5011 (M+2H); Found: 1016.4991 (M+2H). Preparation of Example 14001 Example 14001

[004707] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-phenyl-1-prolinal-Trp-Ser- Trp-[N-Me]Nle- [N-Me]Nle—Orn-Cys-Gly

[004708] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004709] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.9 mg, and its purity estimated by LCMS analysis was 96%.

[004710] Analysis Condition A: Retention time = 1.64 min; ESI-MS(+) m/z 940.2 (M+2H), most abundant ion.

[004711] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 939.6 (M+2H), most abundant ion.

[004712] ESI-HRMS(+) m/z: Calculated: 938.9820 (M+2H); Found: 938.9799 (M+2H). Preparation of Example 14002 Example 14002

[004713] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys-[trans 4-phenyl-1-proline]-Trp-Lvs- Trp-[N-Me]Nle- [N-Me]Nle-Glu-Cys-Gly

[004714] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004715] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 51.0 mg, and its estimated purity by LCMS analysis was 99%.

[004716] Analysis Condition A: Retention time = 1.48 min; ESI-MS(+) m/z 1000.8 (M+2H).

[004717] Analysis Condition B: Retention time = 2.71 min; ESI-MS(+) m/z 1001.2 (M+2H). ESI-HRMS(+) m/z: Calculated: 1000.4980 (M+2H); Found: 1000.4958 (M+2H). Preparation of Example 14003 Example 14003

[004718] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans 4-benzyloxy-1-prolinal-Trp-Ser-Trp-[N-Me]Nle-[N-Me]Nle-Orn-Cys—Gly

[004719] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004720] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 15-55% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 23.4 mg, and its estimated purity by LCMS analysis was 96%.

[004721] Analysis Condition A: Retention time = 1.66 min; ESI-MS(+) m/z 954.6 (M+2H), most abundant ion.

[004722] Analysis Condition B: Retention time = 2.79 min; ESI-MS(+) m/z 954.3 (M+2H). Preparation of Example 14004 Example 14004

[004723] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys-[trans 4-benzyloxy-1-proline]-Trp-Lys-Trp-[N-Me]Nle-[N-Me]Nle-Glu-Cys-Gly

[004724] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004725] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 40-80% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 35.6 mg, and its purity estimated by LCMS analysis was 94%.

[004726] Analysis Condition A: Retention time = 1.65 min; ESI-MS(+) m/z 1015.7 (M+2H).

[004727] Analysis Condition B: Retention time = 2.66 min; ESI-MS(+) m/z 1016.2 (M+2H), most abundant ion.

[004728] ESI-HRMS(+) m/z: Calculated: 1015.5033 (M+2H); Found: 1015.5008 (M+2H). Preparation of Example 14005 Example 14005

[004729] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-His-Glu-[trans-4-cyclohexyl-1-proline]-Trp-Dab-Trp-[N-Me]Nle-[N-Me]Nle-Dab-Cys-Gly

[004730] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004731] The crude material was purified via preparatory LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 24.4 mg, and its purity estimated by LCMS analysis was 99%.

[004732] Analysis Condition A: Retention time = 1.76 min; ESI-MS(+) m/z 975.0 (M+2H).

[004733] Analysis Condition B: Retention time = 2.87 min; ESI-MS(+) m/z 975.1 (M+2H).

[004734] ESI-HRMS(+) m/z: Calculated: 974.9982 (M+2H); Found: 974.9954 (M+2H). Preparation of Example 14006 Example 14006

[004735] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Glu-[trans-4-cyclohexyl-1-proline]-Trp-Dab-Trp-[N-Me]Nle-[N-Me]Nle-Ala-Cys-Gly

[004736] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004737] The crude material was purified via preparative LC/MS under the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B for 30 min, then 5-min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.2 mg, and its purity estimated by LCMS analysis was 99%.

[004738] Analysis Condition A: Retention time = 1.71 min; ESI-MS(+) m/z 961.3 (M+2H).

[004739] Analysis Condition B: Retention time = 2.99 min; ESI-MS(+) m/z 961.4 (M+2H).

[004740] ESI-HRMS(+) m/z: Calculated: 960.9769 (M+2H); Found: 960.9749 (M+2H). Preparation of Example 14007 Example 14007

[004741] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asn-Pro-Dap-Leu-[trans-4-cyclohexyl-1-proline]-Trp-Ser-Trp-[N-Me]Nle- [N-Me]Nle—Orn-Cys-Gly

[004742] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004743] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Gradient: 20-60% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.3 mg, and its purity estimated by LCMS analysis was 98%.

[004744] Analysis Condition A: Retention time = 1.77 min; ESI-MS(+) m/z 942.8 (M+2H), most abundant ion.

[004745] Analysis Condition B: Retention time = 2.91 min; ESI-MS(+) m/z 942.8 (M+2H), most abundant ion. Preparation of Example 14008 Example 14008

[004746] The peptide was synthesized according to the above procedures. The underlined steps employed the double coupling procedure. ClAc-Tyr-[N-Me]Ala-Asp-Pro-His-Lys-[trans-4-cyclohexyl-1-proline]-Trp-Lys-Trp-[N-Me]Nle-[N-Me]Nle-Glu-Cys-Gly

[004747] After deprotection and cyclization according to the above procedures, the compound was purified as follows:

[004748] The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5 μm particles; Mobile phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile phase B: 95:5 methanol:water with 10 mM ammonium acetate; Gradient: 45-85% B over 30 min, then a 5 min hold at 100% B; Flow rate: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 21.7 mg, and its estimated purity by LCMS analysis was 99%.

[004749] Analysis Condition A: Retention time = 1.74 min; ESI-MS(+) m/z 1003.9 (M+2H).

[004750] Analysis Condition B: Retention time = 2.74 min; ESI-MS(+) m/z 1004.2 (M+2H), most abundant ion.

[004751] ESI-HRMS(+) m/z: Calculated: 1003.5215 (M+2H); Found: 1003.5189 (M+2H). EXAMPLE 120 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDES TO COMPETE FOR BINDING OF PD-1 TO PD-L1 USING HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) BINDING ASSAYS

[004752] The ability of the macrocyclic peptides of the present invention to bind to PD-L1 was investigated using a homogeneous time-resolved fluorescence (HTRF) assay of PD-1/PD-L1 binding. A schematic representation of this assay is shown in Figure 1. Methods

[004753] Homogeneous time-resolved fluorescence (HTRF) assays of binding of soluble PD-1 to soluble PD-L1. Soluble PD-1 and soluble PD-L1 refer to proteins with carboxyl-terminal truncations that remove transmembrane-spanning regions and are fused to heterologous sequences, specifically the Fc portion of the human immunoglobulin G (Ig) sequence or the hexahistidine (His) epitope tag. All binding studies were performed in an HTRF assay buffer consisting of dPBS supplemented with 0.1% (w/v) bovine serum albumin and 0.05% (v/v) Tween-20. For the PD-1-Ig/PD-L1-His binding assay, inhibitors were preincubated with PD-L1-His (10 nM final) for 15 min in 4 μl assay buffer, followed by the addition of PD-1-Ig (20 nM final) in 1 μl assay buffer and further incubation for 15 min. PD-L1 fusion proteins from humans, cynomolgus monkeys, or mice were used. Detection of HTRF was achieved using a europium cryptate-labeled anti-Ig monoclonal antibody (1 nM final) and an allophycocyanin (APC)-labeled anti-His monoclonal antibody (20 nM final). The antibodies were diluted in HTRF detection buffer, and 5 μl was dispensed on top of the binding reaction. The reaction was allowed to equilibrate for 30 minutes and the signal (665nm/620nm ratio) was obtained using an EnVision fluorometer. Additional binding assays were set up between PD-1-Ig/PD-L2-His (20 and 5 nM, respectively), CD80-His/PD-L1-Ig (100 and 10 nM, respectively), and CD80-His/CTLA4-Ig (10 and 5 nM, respectively). Competition studies between biotinylated Compound #71 and human PD-L1-His were performed as follows. Macrocyclic peptide inhibitors were preincubated with PD-L1-His (10 nM final) for 60 minutes in 4 μL assay buffer followed by the addition of biotinylated Compound #71 (0.5 nM final) in 1 μL assay buffer. The binding was allowed to equilibrate for 30 min followed by the addition of europium cryptate-labeled streptavidin (2.5 pM final) and APC-labeled anti-His (20 nM final) in 5 μl of HTRF buffer. The reaction was allowed to equilibrate for 30 min and the signal (665nm/620nm ratio) was obtained using an EnVision fluorometer.

[004754] Recombinant Proteins. Carboxyl-truncated human PD-1 (amino acids 25-167) with a C-terminal human Ig epitope tag [hPD-1(25-167)-3S-IG] and human PD-L1 (amino acids 18-239) with a C-terminal His epitope tag [hPD-L1(19-239)-tobacco vein spot virus (TVMV) protease cleavage site-His] were expressed in HEK293T cells and purified sequentially by rProteinA affinity chromatography and size exclusion chromatography. Human PD-L2-His (Sino Biologicals), CD80-His (Sino Biologicals), CTLA4-Ig (RnD Systems) were all obtained from commercial sources.

[004755] Recombinant Human PD-1-Ig Sequence hPD1(25-167)-3S-IG 1 LDSPDPWNP FTPSPALLVV TEGDNATFTC SFSNTSSSFV LNWYRMSPSN 51 QTBKLAAFPE DRSQPGQDCR FRVTOLPNGR DFHMSVVRAR RDSGTYLCG 101 AISLAPKAQI KBSLASLRV TERRAEVPTA HPSPSPRPAG QFQGSGGGG 151 GREPKSSDKT HTSPPSPAPE LLGGSSVFLF PPKPKTJTLMI SRTPEVTCVV 201 VDVSHEDPEV KFNKYVDGVE VHNAKTKPRE EQYKSTYRVV SVLTVLHQDW 251 LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP SRDELTKNQV 301 SLTCLVKGFY PSDIAVEWES NGQPENNYKT TFPVLDSDGS FFLYSKLTVD 351 KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK (SEQ ID NO: 1)

[004756] Recombinant Human PD-L1-TVMV-His Sequence (PD-L1-His) hPDL1(19-239)TVMV-His 1 PTVTVPKDLY VVEYGSNMTI ECKFPVEKQL DLAALIVYWE MED-KNIIQFV 51 HGEEDLKVQH SSYRQPARLL KDQLSLGNAA LQITDVKLQD AGVYRCMISY 101 GGADYKRITV KVNAPYHKIN QRILVVDPVT SEHELTCQAE GYPKAEVIWT 151 SSDHQVLSGK TTTTNSKREE KLFNVTSTLR INTTTNEIFY CTFRRLDPEE 201 NHTAELVIPE LPLAHPPNER TGSSETVRFQ GHHRHHH (SEQ ID NO: 2)

[004757] The results are shown in Table 6. As shown, the macrocyclic peptides of the present invention demonstrated potent inhibition of the binding activity of PD-1-lg to PD-L1-TVMV-His (PD-L1-His). Table 6 (t.n.: glossary: compound No.; human PD-L1/PD-1 binding assay by HTRF.) EXAMPLE 121 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDE VARIANTS OF COMPOUND No. 99 TO BIND TO PD-L1 USING HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) BINDING ASSAYS

[004758] The ability of macrocyclic peptide variants of the peptide Compound No. 99 of the present invention to inhibit the binding of PD-1-lg to PD-L1-His was investigated in order to establish structure-activity relationships.

[004759] HTRF experiments were performed essentially as described above. Variant macrocyclic peptides were generated in the manner described herein.

[004760] The results are shown in Table 7. The results for each parent macrocyclic peptide from the other tables have been included in this table for comparison. As shown, the variant macrocyclic peptides of the present invention demonstrated potent inhibition of PD-1-Ig binding to PD-L1, and regions in which activity was sensitive and resistant to variation were identified. Table 7 - Macrocyclic Peptide Variants of Compound No. 99 (t.n.: glossary: compound no.; human PD-L1/PD-1 binding assay by HTRF.) EXAMPLE 122 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDE VARIANTS OF COMPOUND NO. 1 TO INHIBIT PD-1 BINDING TO PD-L1 USING HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) BINDING ASSAYS

[004761] The ability of macrocyclic peptide variants of Compound No. 1 of the present invention to inhibit the binding of PD-1 to PD-L1 was investigated in order to establish structure-activity relationships.

[004762] HTRF experiments were performed essentially as described above. Variant macrocyclic peptides were generated in the manner described herein.

[004763] The results are shown in Table 8. The results for each parent macrocyclic peptide from the other tables have been included in this table for comparison purposes. As shown, the variant macrocyclic peptides of the present invention demonstrated potent inhibition of PD-1 binding to PD-L1, and sensitive and resistant regions of variation were identified. Table 8 - Variant Macrocyclic Peptides of Compound No. 1 (t.n.: glossary: compound No.; human PD-L1/PD-1 binding assay by HTRF.) EXAMPLE 123 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDE VARIANTS OF COMPOUND No. 71 TO INHIBIT PD-1 BINDING TO PD-L1 USING HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) BINDING ASSAYS

[004764] The ability of macrocyclic peptide variants of Compound No. 71 of the present invention to inhibit the binding of PD-1 to PD-L1 was investigated in order to establish structure-activity relationships.

[004765] HTRF experiments were performed essentially as described above. Variant macrocyclic peptides were generated in the manner described herein.

[004766] The results are shown in Table 9. The results for each parental macrocyclic peptide from the other tables have been included in this table for comparison. As shown, the variant macrocyclic peptides of the present invention demonstrated potent inhibition of PD-1 binding to PD-L1, and sensitive and resistant regions of variation were identified. Table 9 (t.n.: glossary: compound No.; human PD-L1/PD-1 binding assay by HTRF.) EXAMPLE 124 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDE VARIANTS OF COMPOUND No. 116 TO BIND TO PD-L1 USING HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) BINDING ASSAYS

[004767] The ability of macrocyclic peptide variants of Compound No. 116 of the present invention to bind to PD-L1 was investigated in order to establish structure-activity relationships.

[004768] HTRF experiments were performed essentially as described above. Variant macrocyclic peptides were generated in the manner described herein.

[004769] The results are shown in Table 10. The results for each parent macrocyclic peptide from the other tables have been included in this table for comparison purposes. As shown, the variant macrocyclic peptides of the present invention demonstrated potent PD-L1 binding activity and variation-sensitive and -resistant regions were identified. Table 10 - Variant Macrocyclic Peptides of Compound No. 116 (t.n.: glossary: compound No.; human PD-L1/PD-1 binding assay by HTRF.) EXAMPLE 125 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDES TO PROMOTE INTERFERON GAMMA (IFNγ) SECRETION IN A CYTOMEGALOVIRUS (CMV)-SPECIFIC CELL FUNCTION ASSAY

[004770] The ability of the macrocyclic peptides of the present invention to promote IFNγ secretion by CMV-specific T cells in a dose-dependent manner was investigated. Methods

[004771] CMV-specific T-cell function assay. Peripheral blood mononuclear cells from a donor who was seropositive for CMV (PBMC, Astarte Biologies, Redmond, WA) were cultured at 2.5 x 105 cells/well in tissue culture (TC)-treated 96-well round-bottom plates in the presence of 0.5 μg/ml CMV+ cell lysate (Microbix Biosystems, Mississauga, Ontario) with or without increasing concentrations of anti-PD-L1 antibody or the indicated macrocyclic peptides. AIM-V medium (Life Technologies, Grand Island, NY) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Sigma, St Louis, MO) was used in a total volume of 200 μl/well in triplicate. Cells were cultured for 4 days at 37 °C, 5% CO2 and then the culture supernatant was harvested for determination of secreted IFNγ by ELISA (OptEIA hlFNγ ELISA Kit, BD Biosciences, San Jose, CA). As shown in Figures 10A–C, both the anti-PD-L1 antibody and the peptides were shown to promote IFNγ secretion by CMV-specific T cells in a dose-dependent manner. The most robust response was generated by the PD-L1-directed antibody (MDX-1105, EC50 0.6 nM) followed by Compound #71 (EC50 300 nM), Compound #1 (EC50 400 nM), Compound #2 (EC50 400 nM), and Compound #99 (EC50 >10,000 nM). These results show that ligation of PD-L1 with macrocyclic peptide inhibitors can enhance IFNγ release in a population of memory T cells generated from prior exposure to a persistent antigen. EXAMPLE 126 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDES TO PROMOTE IFNγ SECRETION IN AN ASSAY OF HIV-SPECIFIC T CELL FUNCTION

[004772] The ability of the macrocyclic peptides of the present invention to promote IFNγ secretion by HIV-specific T cells in a dose-dependent manner was investigated. Methods

[004773] HIV-specific T cell function assay. Human PBMC (Bioreclamation LLC, Westbury, NY) derived from a viremic HIV+ donor in the chronic stage of infection were cultured at 2.0 x 106 cells/well in TC-treated 48-well plates. Cells were stimulated with an HIV-Gag (capsid, Gag = group-specific antigen) peptide library (Prolmmune, Sarasota, FL) consisting of 6 pools of 20 overlapping peptides (15-mers overlapping by 11 residues) each. The final concentration in culture was 2μg/mL per peptide. HIV-Gag antigen stimulation was done +/- anti-PD-L1 antibody (0.1 μL final) or Compound #71 peptide (7.5μL final). RPMI medium (Life Technologies, Grand Island, NY) supplemented with 10% heat-inactivated FBS (Sigma, St Louis, MO) and 10 U/ml rIL-2 (Peprotech, Rocky Hill, NJ) was used in a total volume of 1 ml/well. Cells were cultured for 6 days at 37 °C, 5% CO at which time the cultures were washed and restimulated on anti-IFNγ-coated ELISpot plates (hlFNγELISpot PRO Kit, Mabtech, Mariemont, OH) for 18 h at 37 °C, 5% CO . For restimulation, in vitro expanded cells were cultured at 2.0 × 10 5 cells/well in RPMI medium devoid of rIL-2 in a total volume of 100 μl/well. The final concentrations of HIV-Gag antigen and anti-PD-L1 inhibitors were the same as those indicated above. ELISpot plates were air-dried for 5 days and read using an ImmunoSpot S6 Fluorospot analyzer (C.T.L., Shaker Heights, OH).

[004774] As shown in Figure 2, both anti-PD-L1 antibody and peptides were shown to promote IFNγ secretion by HIV-specific T cells in a dose-dependent manner. The mean number of IFNγ spot forming cells (SFC) per well was calculated from duplicate wells and any background present in unstimulated wells (<25 SFC) was subtracted. Data are also presented as the proportional increase relative to DMSO control treatment. Both anti-PD-L1 antibody and peptide increased IFNγ secretion by HIV-specific T cells responding to at least 1 of the 6 HIV-Gag antigen clusters. These results demonstrate that ligation of PD-L1 with a peptide inhibitor can increase IFNγ release from the T cell population responding to an existing chronic viral infection, similar to anti-PD-L1 antibody. EXAMPLE 127 - METHODS FOR TESTING THE ABILITY OF MACROCYCLIC PEPTIDES TO BIND TO PD-L1 IN CELL BINDING ASSAYS

[004775] The ability of the macrocyclic peptides of the present invention to bind to the mouse Jurkat B cell line (LK35.2), and to a human lung adenocarcinoma cell line (L2987) was investigated. Methods

[004776] Jurkat-PD-1 cell binding assay. Phycoerythrin (PE) was covalently linked to the Ig epitope tag of human PD-L1-Ig and fluorescently labeled PD-L1-Ig was used for binding studies with a Jurkat cell line overexpressing human PD-1 (Jurkat-PD-1).

[004777] In brief, recombinant PD-L1-Ig (10 nM final) was pre-incubated with inhibitor for 15 minutes in a volume of 30 μl of RPMI supplemented with 2% fetal calf serum. 1x105 Jur-kat-PD-1 cells were layered over PD-L1-Ig and inhibitor in 20 μl of RPMI supplemented with 2% fetal calf serum and binding was allowed to occur for 1 hour at room temperature. Cells were washed 3x in dPBS. Cells were resuspended in 200 μl of dPBS and binding was measured by flow cytometry.

[004778] LK35.2-hPD-L1 Cell Binding Assay. Phycoerythrin (PE) was covalently linked to the Ig epitope tag of human PD-1-Ig and fluorescently labeled PD-1-Ig was used for binding studies with a mouse B cell line (LK35.2) stably overexpressing human PD-L1 (LK35.2-hPD-L1). Briefly, 1x105 LK35.2-hPD-L1 cells were preincubated with inhibitor for 15 minutes in a volume of 30 μl of RPMI supplemented with 2% fetal calf serum. 20 μl of PE-labeled PD-1-Ig (2 nM final), diluted in RPMI supplemented with 2% fetal calf serum, was dispensed over the cells and inhibitor and binding was allowed to occur for 1 h at room temperature. Cells were washed 3x in dPBS. Cells were resuspended in 200 μl dPBS and binding was measured by flow cytometry.

[004779] L2987 Coelomic Cell Binding Assay. Phycoerythrin (PE) was covalently linked to the Ig epitope tag of human PD-1-Ig and fluorescently labeled PD-1-Ig was used for binding studies with a human lung adenocarcinoma cell line (L2987) that naturally expresses PD-L1. Briefly, 12,000 L2987 cells were seeded in 96-well clear black bottom plates in 50 μL DMEM supplemented with 5% fetal calf serum. The next day, inhibitors were diluted in serum-free DMEM and 25 μL was dispensed over the cells. After 15 min of incubation, sPD-1-Ig (30 nM final) was dispensed over the cells and inhibitor in 25 μL serum-free DMEM. Samples were incubated for 1 hour at 37 °C followed by 2 washes in dPBS and fixation for 30 minutes with 4% paraformaldehyde. Samples were further washed 2x in dPBS. Hoechst (final 1 μg/ml) was added to the final wash to stain nuclei. Plates were processed using a Cellomics ARRAYSCAN®.

[004780] The results are shown in Figures 2 through 9. As shown, representative macrocyclic peptides of the present invention were each capable of binding to the mouse Jurkat B cell line, (LK35.2), and the human lung adenocarcinoma cell line (L2987) that were tested, and further, the PD-L1 macrocyclic peptides appeared to bind to the same PD-L1 binding site as each other as well as to an in-house developed anti-PD-L1 monoclonal antibody.

[004781] The results of additional binding assays for the Compound No. 99, Compound No. 1, and Compound No. 71 series of peptides are shown in Tables 11 through 13, respectively. Table 11 - Cell Binding Data for the Compound No. 99 Series of Peptides (t.n.: glossary: compound No.; Hu PD-L1/PD-1 cell binding.) Table 12 - Cell binding data for the Compound No. 1 series of peptides (t.n.: glossary: compound No.; Hu PD-L1/PD-1 cell binding.) Table 13 - Cell binding data for the Compound No. 71 series of peptides (t.n.: glossary: compound No.; Hu PD-L1/PD-1 cell binding.) EXAMPLE 128 Methods

[004782] High-content screening assay of LK35.2-hPD-L1 cells binding. Phycoerythrin (PE) was covalently linked to the Ig epitope tag of human PD-1-Ig and fluorescently labeled PD-1-Ig was used for binding studies with a mouse B cell line (LK35.2) stably overexpressing human PD-L1 (LK35.2-hPD-L1). In brief, 3x 103 LK35.2-hPD-L1 cells were seeded in 384-well plates in 20 μl of RPMI supplemented with 10% fetal calf serum and cultured overnight. 125 nl of compound was added to the cells, followed by 5 μl of PE-labeled PD-1-Ig (1 nM final), diluted in RPMI supplemented with 10% fetal calf serum, followed by incubation at 37°C for 1 hour. Cells were washed 3x in 100 μl of dPBS followed by fixation with 30 μl of 4% paraformaldehyde in dPBS containing 10 μg/ml Hoechst 33342 for 30 minutes at room temperature. Cells were washed 3x in 100 μl of dPBS followed by the final addition of 15 μl of dPBS. Data were collected and processed using a Cell Insight NXT High Content Imager and associated software.

[004783] High-content screening assay of 293T-hPD-L1 cells binding. Phycoerythrin (PE) was covalently linked to the human PD-1-Ig epitope tag and fluorescently labeled PD-1-Ig was used for binding studies with a human embryonic kidney cell line (293T) stably overexpressing human PD-L1 (293T-hPD-L1). In brief, 2x103 293T-hPD-L1 cells were seeded in 384-well plates in 20 μl of DMEM supplemented with 10% fetal calf serum and cultured overnight. 125 nL of compound was added to the cells followed by 5 μL of PE-labeled PD-1-Ig (0.5 nM final) diluted in DMEM supplemented with 10% fetal calf serum, followed by incubation at 37°C for 1 hour. Cells were washed 3x in 100 μL of dPBS followed by fixation with 30 μL of 4% paraformaldehyde in dPBS containing 10 μg/ml Hoechst 33342 for 30 minutes at room temperature. Cells were washed 3x in 100 μL of dPBS followed by the final addition of 15 μL of dPBS. Data were collected and processed using a Cell Insight NXT High Content Imager and associated software. Table 14 Biological Data for Examples 1001-10517 (t.n.: glossary: example No.; “cluster” (groupings); not performed (nd); “HTRF IC50 cluster plus” values; “CBA IC50 cluster plus” values; “CMV Recall EC50 cluster plus” values.)

[004784] Numerous modifications and variations of the subject matter described and claimed in this report are possible in light of the above teachings. It is therefore understood that within the scope of the appended claims, the subject matter recited in the claims may be practiced differently than that specifically described in this report.

[004785] The present invention is not limited in scope by the embodiments described in this report, which are merely illustrations of individual aspects of the invention, and all those that are functionally equivalent are within the scope of the invention. Various modifications of the models and methods of the invention, in addition to those described in this report, will become apparent to those skilled in the art from the foregoing description and teachings, and are also intended to be encompassed by the scope of the invention. Such modifications or other embodiments may be practiced without departing from the scope and spirit of the invention.

[004786] The full text of each document cited in this report (including patents, patent applications, journal articles, abstracts, laboratory manuals, books, GENBANK® accession numbers, SWISS-PROT® accession numbers, or other descriptions) is incorporated herein by reference. In addition, a printed copy of the Sequence Listing presented with the specification, as well as its corresponding computer-readable form, are incorporated herein in their entirety by reference.

Claims (2)

1. Compound, characterized by the fact that it presents the formula: or a pharmaceutically acceptable salt thereof. 2. Compound, characterized by the fact that it is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.