Hybrid peptide compounds having a substituted tryptophan residue or a terminal substituent

Abstract

Hybrid peptide compounds having a substituted tryptophan residue or a terminal substituent are described herein.

Description

HYBRID PEPTIDE COMPOUNDS HAVING A SUBSTITUTED TRYPTOPHAN RESIDUE OR A TERMINAL SUBSTITUENTCLAIM OF PRIORITY

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 609,336, filed December 12, 2023, and U.S. Provisional Patent Application No. 63 / 609,340, filed December 12, 2023, each of which is incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present invention relates to hybrid peptide compounds having a substituted tryptophan residue and / or a terminal substituent.BACKGROUND

[0003] Peptide Tyrosine-Tyrosine (PYY) analogues and pharmaceutical compositions including the analogues can be of therapeutic use for the treatment of metabolic diseases and disorders such as diabetes, obesity, and type II diabetes, including the comorbidities and conditions associated with them.SUMMARY

[0004] In one aspect, a peptide can include an amino acid sequence of:X3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID: 143) where:X3can be V, I or P; X4can be R, K or P; X7can be A, K or K*, wherein K* has the structure:whereeach Z1, independently, can be an amino acid residue, sugar residue, -C(O)-Z2-O-, or - C(O)-Z2-NH-; each Z2, independently, can be a 2-8 carbon alkylene linker where 1 or 2 carbon atoms can be optionally independently substituted by -NH2, -OH, or -COOH and where the alkylene linker can be straight or branched and optionally includes a C3-8cycloalkyl moiety; or each Z2, independently, can be -((CH2)a-O-(CH2)b)c-, wherein each a can be independently 1, 2, or 3, each b can be independently 1, 2, or 3, and c can be 1, 2, or 3; n can be 1, 2, 3, 4, or 5;R1can be -Z3-R2or -C(O)-Z3-R2;Z3can be a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2can be -C(O)OH or -P(O)(OH)2;X9can be G or E;X10can be E or K;X11can be D or D*, where D* can be beta-aspartic acid, or d-aspartic acid;Xi3can be A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17can be W or L;X18can be N or Q; X22can be A, D, E, F, I, L, M, or V; X23can be D, S or E; X28can be I, L, or Aib;X30can be W* where W* can be tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31can be V or L;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* can be N(alpha)-methylarginine or beta-homo-arginine; X36can be Y or Z*, where Z* has Formula la, lb, or Ic:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl;or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Ar can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; where the C-terminal amino acid of the peptide can be optionally amidated; or a pharmaceutically acceptable salt thereof

[0005] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 144), where: X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Y or Z*, where Z* has Formula la, lb, or Ic.

[0006] In some embodiments, each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0007] In some embodiments, the peptide can include an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 145), where: X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Y or Z*, where Z* has Formula la, lb, or Ic; each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0008] In some embodiments:X13can be S or T;X22can be I or V; andX35can be R or beta-homo-arginine.

[0009] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 146), where: X7can be K*;X13can be S or T;X22can be I or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan;X35can be R or beta-homo-arginine; X36can be Y or Z*, where Z* has Formula la, lb, or Ic; each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0010] In some embodiments, the peptide can include an amino acid sequence selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 147);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 148);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 149);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 150);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 151);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 152);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 153);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 154);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 155);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 156);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 157);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 158);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 159);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 160);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 161); andPKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 162).

[0011] In some embodiments, R2can be -C(O)OH.

[0012] In some embodiments, R2can be -P(O)(OH)2.

[0013] In some embodiments:K* can have the structure:where Z can be:

[0014] In some embodiments, R1can be -C(O)-(CH2)k-R2.

[0015] In some embodiments, Z* can have the formula la:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substitutedby 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0016] In some embodiments, Z* can have the formula la:whereRaand Rbtaken together with the carbon to which they are attached can form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; andRccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0017] In some embodiments, Z* can have the structurewhere: each R3, independently, can be selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl;i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0018] In some embodiments, Z* can have the structure

[0019] In some embodiments, Z* can have the formula lb:whereRdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Racan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0020] In some embodiments, Z* can have the formula Ic:whereRdcan be H or methyl; andAr can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0021] In some embodiments, W* can be 4-fluorotryptophan, 5 -fluorotryptophan, 6- fluorotryptophan, 7-fluorotry ptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6- cy anotryptophan, or 7-cy anotryptophan.

[0022] In some embodiments, W* can be 7-cyanotryptophan.

[0023] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0025] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0028] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0029] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0030] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0033] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0035] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0037] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0038] In one aspect, a peptide can include an amino acid sequence ofX3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID: 469) whereX3can be V, I or P; X4can be R, K or P; X7can be K*, where K* can have the structure:where each J1, independently, can be an amino acid residue, sugar residue, -C(O)-J2-O-, or -C(O)- J2-NH-; each J2, independently, can be a 2-8 carbon alkylene linker where 1 or 2 carbon atoms can be optionally independently substituted by -NH2, -OH, or -COOH and where the alkylene linker can be straight or branched and optionally can include a C3-8cycloalkyl moiety; or each J2, independently, can be -((CH2)a-O-(CH2)b)c-, where each a can be independently 1, 2, or 3, each b can be independently 1, 2, or 3, and c can be 1, 2, or 3; n can be 1, 2, 3, 4, or 5;R1can be -J3-R2or -C(O)-J3-R2;J3can be a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2can be -C(O)OH or -P(O)(OH)2;X9can be G or E;X10can be E or K;X11can be D or D*, where D* is beta-aspartic acid, or d-aspartic acid;X13can be A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17can be W or L;X18is N or Q; X22can be A, D, E, F, I, L, M, or V; X23can be D, S or E; X28can be I, L, or Aib;X30can be E, L, W, or W*, where W* can be tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31can be V or L;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; X36can be Z*, where Z* has Formula la, lb, or Ic:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -C0C(Ra)(Rb)Rc;Ar can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a pharmaceutically acceptable salt thereof

[0039] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 470), where X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic.

[0040] In some embodiments, each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0041] In some embodiments, the peptide can include an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 471); where X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W or W*, where W* is a halo- or cyano-substituted tryptophan;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic; each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0042] In some embodiments:X13can be S or T; X22can be I or V;X30can be W or W*, where W* can be a halo- or cyano-substituted tryptophan; andX35can be R or beta-homo-arginine.

[0043] In some embodiments, the peptide can include an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 472), where: X7can be K*;X13can be S or T; X22can be I or V;X30can be W or W*, where W* can be a halo- or cyano-substituted tryptophan;X35can be R or beta-homo-arginine; X36can be Z*, where Z* has Formula la, lb, or Ic; each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0044] In some embodiments, the amino acid sequence can be selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 473);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 474);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 475);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 476);PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 477);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 478);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 479);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 480);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 481);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 482);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 483);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 484);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 485);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 486);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 487); andPKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 488).

[0045] In some embodiments, each J1can be independently selected from:n can be 2 or 3;R1can be -C(O)-J3-R2; andJ3can be a straight or branched, saturated 16-20 carbon alkylene linker.

[0046] In some embodiments,R1can be -C(O)-(CH2)k-P(O)(OH)2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0047] In some embodiments,K* can have the structure:where J can be:; andR1can be -C(O)-(CH2)k-R2.

[0048] In some embodiments, R1can be -C(O)-(CH2)k-R2.

[0049] In some embodiments:Z* can have the formula la:whereRacan be H, C1-3alky 1, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0050] In some embodiments,Z* can have the formula la:whereRaand Rbtaken together with the carbon to which they are attached can form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; andRccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

[0051] In some embodiments,Z* can have the structurewhere: each R3, independently, can be selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl; i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0052] In some embodiments,Z* can have the structure

[0053] In some embodiments,Z* can have the formula lb:whereRdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Racan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; ora 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0054] In some embodiments,Z* can have the formula Ic:whereRdcan be H or methyl; andAr can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0055] In some embodiments, W* can be 4-fluorotryptophan, 5 -fluorotryptophan, 6- fluorotryptophan, 7-fluorotry ptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6- cy anotryptophan, or 7-cy anotryptophan.

[0056] In some embodiments, W* can be 7-cyanotryptophan.

[0057] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0060] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0061] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0062] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0063] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0064] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0065] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0066] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0067] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0068] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0070] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0071] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0072] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0074] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0075] In another aspect, a pharmaceutical composition can include a peptide as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0076] In another aspect, a method of treating diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0077] In another aspect, a method of improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof, thereby decreasingfood intake, reducing body weight, suppressing appetite, and / or inducing satiety in the patient.

[0078] In another aspect, a method of treating or preventing binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0079] In another aspect, a method of reducing of gastric motility, delaying gastric emptying, or increasing physical mobility, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0080] In another aspect, a method of treating or preventing comorbidities to obesity, osteoarthritis, or urine incontinence, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0081] In another aspect, the use of a peptide as described herein in the treatment of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea.

[0082] In another aspect, the use of a peptide as described herein for improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression.

[0083] In another aspect, the use of a peptide as described herein in the treatment or prevention of binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid.

[0084] In another aspect, the use of a peptide as described herein for reducing of gastric motility, delaying gastric emptying, or increasing physical mobility.

[0085] In another aspect, the use of a peptide as described herein in the treatment or prevention of comorbidities to obesity, osteoarthritis, or urine incontinence.

[0086] Other aspects, embodiments, and features will be apparent from the following description, the drawings, and the claims.DETAILED DESCRIPTION

[0087] The term “PYY(1-36)” as used herein refers to human Peptide Tyrosine-Tyrosine (PYY) and comprises amino acid residues 1-36 of human PYY. The term “PYY(3-36)” as used herein refers to human PYY and comprises amino acid residues 3-36 of human PYY (SEQ ID NO: 1). The term“analog” as used herein refers to a peptide, compound, or derivative that is a variant of a native peptide or compound, such as native PYY(1-36)or native PYY(3-36). A “variant” of PYY(1-36)or PYY(3-36)refers to a peptide, analog, compound, or derivative in which one or more of the amino acids or molecular components that form PYY(1-36)or PYY(3-36)are modified from their native or original state. In a preferred embodiment, the peptides described herein are PYY(3-36)variants.

[0088] Peptides described herein are human PYY analogs that can be administered as a therapeutic to patients to treat a condition or disorder. In a preferred embodiment, the peptides can interact with a NPY receptor to elicit a therapeutic response. The compounds described herein can be considered hybrid peptides because of some of the modified substituents on the molecule and are sometime referred to as peptides in this description for ease of reference.

[0089] PYY is released primarily from L cells in the gastrointestinal tract, in particular from the ileum and colon. Small amounts of PYY can be secreted from the upper digestive tract, and can be found in some localized regions of the brain. PYY can exert its biological effects through binding to neuropeptide Y (NPY) receptors, of which there are four subtypes: Y1, Y2, Y4, and Y5. These NPY receptors can be found in various regions of the brain, central nervous system, intestines, and some blood vessels.

[0090] PYY has a C-terminal amide and is first released as a 36 amino acid peptide (PYY(1-36)), after which it can be converted to PYY(3-36)through hydrolytic cleavage of its first two N- terminal amino acids (Tyr1-Pro2) by dipeptidyl peptidase-IV (DPP -IV). As referenced herein, the amino acid position number refers to the amino acid residue position in a position 1 through 36 of the reference PYY sequence.

[0091] While PYY(1-36)primarily activates Y1, Y2, and Y5 subtypes with little selectivity, PYY(3-36)is highly selective for the Y2 subtype while showing lower affinity to Y1 and Y5 subtypes. Y2 subtype activation has been shown to reduce appetite and food consumption, while Y1 and Y5 subtype activation has been shown to increase appetite and food consumption.

[0092] Circulating plasma concentrations of PYY(1-36)are dominant during fasting. After food consumption, PYY(3-36)plasma concentrations surpass PYY(1-36), usually within 15 minutes after eating. PYY(3-36)plasma concentrations usually peak within 60-90 minutes and remain elevated for several hours before dropping to baseline concentrations. It is believed that PYY(3-36), via its selectivity for Y2 subtype, reduces appetite and gastric motility, thereby having an anorectic effect,and may also have an impact on insulin sensitivity and blood glucose. This has led PYY(3-36)to be an attractive target as a pharmaceutical for treating various metabolic disorders, such as diabetes, obesity, and type II diabetes.

[0093] PYY(3-36)naturally has a short half-life of below 10 minutes in plasma when applied exogenously due to proteases and other in vivo clearance processes, which reduces its viability as an effective therapeutic agent due to the required frequency of treatment. Thus, there is a significant desire to identify PYY(3-36)analogs with enhanced pharmacokinetic profiles, greater selectivity for, or increased affinity to, NPY receptors, for example, subtype Y2.

[0094] The peptides can act as NPY receptor subtype Y2 agonists. In certain embodiments, the peptides can demonstrate selectivity for the NPY receptor subtype Y2 over other NPY receptor subtypes, such as subtypes Y1, Y4, or Y5. In this regard, peptides being selective for one receptor subtype over another can have at least 2 fold, at least 5 fold, at least 10 fold, at least 20 fold, at least 30 fold, at least 40 fold, at least 50 fold, or at least 100 fold higher potency for one Y receptor over another Y receptor as measured in vitro in an assay for receptor function.

[0095] In one embodiment, the peptides described herein can bind to the NPY receptor subtype Y2 with specificity over the other subtypes Y1, Y4, and Y5. In particular embodiments, the peptides bind to the NPY receptor subtype Y2 with greater specificity than PYY(1-36)or PYY(3-36). In other embodiments, the peptides fully activate the NPY receptor subtype Y2. In another embodiment, the peptides herein bind to the NPY receptor subtype Y2 with high potency. In particular embodiments, the peptides bind to the NPY receptor subtype Y2 with greater potency than PYY(1-36)or PYY(3-36).

[0096] In other embodiments, the peptides herein demonstrate improved pharmacokinetic properties as compared to PYY(1-36)or PYY(3-36). In such embodiments, the peptides have increased half-life and / or decreased clearance as compared to PYY(1-36)or PYY(3-36). In additional embodiments, the peptides herein are capable of decreasing blood glucose, decreasing food intake or appetite, or decreasing body weight in vivo, either alone or in combination. In some embodiments, the peptides are capable of decreasing blood glucose, decreasing food intake or appetite, or decreasing body weight in vivo, either alone or in combination, to a greater degree than PYY(1-36)or PYY(3-36).

[0097] The peptides described herein are biologically active with high potency against the human NPY receptor subtype Y2. In some embodiments, peptide activity and potency is determined by its performance in one or more human NPY receptor subtype Y2 receptor assays. In one embodiment, this performance is determined using a human NPY receptor subtype Y2 receptor activation assay to determine potency.

[0098] Potency can be described using “half-maximal effective concentration” (EC50), which refers to the concentration at which a compound or molecule can elicit a biological response that is halfway, or 50%, between the baseline and maximum responses using a dose response curve as a reference.

[0099] In vitro potency for the peptides herein may be calculated as described below, with greater potency corresponding to lower EC50value. In some embodiments, the peptides herein bind to the NPY receptor subtype Y2 with high potency..

[0100] In some embodiments, the peptides may comprise up to eight amino acid modifications as compared to PYY(3-36), and may have the C-terminal amino acid optionally amidated. In general throughout this application, when referring to a particular position of a PYY peptide, analog, compound, variant, or derivative, the position that is referred to corresponds with that particular position in PYY(1-36). The expression used throughout this application, that a PYY peptide, analog, compound, variant, or derivative comprises a particular amino acid at a position corresponding to a certain position of PYY(1-36), means that the native (or original) amino acid in that position has been replaced with that particular amino acid or other modification if they are not the same. Therefore, PYY peptides, analogs, compounds, variants, or derivatives described herein may be described with reference to the identity and number of the amino acid residues in human PPY(1-36), e g., the numerical amino acid position that is modified and the native (or original) and final identities of the amino acid at that position.

[0101] Amino acid residues may be identified equivalently by their full name, one-letter code, or three-letter code.

[0102] Peptides described herein are human PYY(3-36)analogs, compounds, or derivatives in which a number of amino acid residues have been modified as compared to PYY(3-36). Such modifications can include amino acid substitutions, insertions, or deletions, independently or in combination. In some embodiments, such modifications can include non-natural or non-proteinogenic amino acid substitutions, insertions, or deletions, independently or in combination. In some embodiments, such modifications can include non-amino acid modifications to an amino acid functional group, a non-natural amino acid functional group, or a non-proteinogenic amino acid functional group, such as the covalent attachment of a substituent to such functional groups.

[0103] The term “amino acid” refers to a molecule consisting of an amine group and a carboxylic acid group, and optionally one or more additional groups often referred to as a side chain. Amino acids can include standard, proteinogenic, coding, or natural amino acids that are the natural molecular units of proteins, including the group of 20 standard amino acids consisting of alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartate (Asp; D), cysteine (Cys; C), glutamine (Gin; Q), glutamate (Glu; E), glycine (Gly; G), histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V). Amino acids can also include non-standard, non-proteinogenic, non-coding, or non-natural amino acids, which include those amino acids not found in nature or that are not encoded by the natural DNA genetic code, or those amino acids not found in natural proteins or not produced naturally within cells. Non-limiting examples of non-standard, non-proteinogenic, non-coding, or non- natural amino acids include beta-homo-arginine, cyanotryptophan (for example, 7-cyano tryptophan, 6-cyano tryptophan, 5-cyano tryptophan, or 4-cyano tryptophan), tryptophan in which a ring C-H is substituted by N, or azatryptophan (for example, 4-aza tryptophan, 5-aza tryptophan, 6-aza tryptophan, 7 -aza tryptophan), tryptophan substituted by halo, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, alpha-aminoisobutryic acid (Aib), beta-(azulenyl)-L- alanine, or any D-isomers of the standard proteinogenic amino acids.

[0104] Unless otherwise stated, the amino acids of the peptides are understood to be L-isomers.

[0105] The term “amino acid modification” used throughout this application refers to a modification to an amino acid as compared to PYY. This can be the result of an amino acid substitution, insertion, deletion, or the covalent attachment of a substituent to the amino acid of the peptide.

[0106] In some embodiments, one or more of the amino acids in the peptides may be substituted. In some embodiments, amino acids may be substituted by “conservative substitution,” which is the replacement of one or more amino acids by another biologically or functionally similaramino acid. For example, a conservative substitution can occur based on amino acid size, acidity, basicity, hydrophobicity, and aromaticity. In other embodiments, the peptides have amino acid substitutions with one or more non-standard, non-proteinogenic, non-coding, or non-natural amino acids, such as amino acid mimetics, in their sequences. In additional embodiments, the peptides have amino acid substitutions that may not be conservative substitutions, but impart preferred functional, physical, or chemical properties to the peptides that are favorable over native or conservatively substituted amino acids.

[0107] In some embodiments, the peptides comprise one or more amino acids with a substituent covalently attached. A “substituent” is a chemical group or moiety attached to the side chain of a natural or non-natural amino acid through its functional group. In some embodiments, the substituent is attached covalently to the side chain via a direct bond or a chemical linker. In some embodiments, the amino acid corresponding to position 7 of PYY(1-36)(which is the fifth amino acid in PYY(3-36)) can be covalently modified with a substituent. In some embodiments, the substituent is a C16-C22fatty acid, diacid, acid phosphonate, or carboxy phosphonate. For example, in some particular embodiments, the amino acid at position 7 is lysine and the substituent can be an oxyethylene glycol fatty acid (C12-C20) group. In other particular embodiments, the amino acid at position 36 can be amidated or otherwise substituted.

[0108] In some embodiments, one or more of the amino acids in the peptides may be deleted as compared to PYY(3-36), which can occur independently or combined with one or more insertions or substitutions.

[0109] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbonatoms. In some embodiments, “cycloaliphatic” (or “carbocycle”) refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0110] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.

[0111] The term “lower alkyl” refers to a C1-4straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0112] The term “lower haloalkyl” refers to a C1-4straight or branched alkyl group that is substituted with one or more halogen atoms.

[0113] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0114] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0115] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A “substituted” alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0116] The term “alkenylene” refers to a bivalent alkenyl group having at least one carboncarbon double bond. Unless otherwise specified, the double bond may be cis or trans. In some embodiments, an alkenylene group has a single carbon-carbon double bond. In some embodiments, the double bond is cis. In some embodiments, the double bond is trans. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0117] The term “alkynylene” refers to a bivalent alkynyl group having at least one carboncarbon triple bond. A carbon-carbon triple bond may be located at an internal or terminal location in the alkynylene group, i.e., at either end or between two carbon atoms internal to the chain or carbon atoms. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. In some embodiments, the triple bond is at the terminal position and the alkynyl hydrogen is optionally replaced by a substituent.

[0118] The term “halogen” means F, Cl, Br, or I.

[0119] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0120] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or9 ring atoms; having 6, 10, or 14 > electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0121] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2H pyrrol yl), NH (as in pyrrolidinyl), or+NR (as in N substituted pyrrolidinyl).

[0122] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H -indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0123] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0124] As described herein, peptides described herein may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents can be those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0125] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2)0-4R1; -(CH2)0-4OR1; -O(CH2)0-4R1, -O-(CH2)0-4C(O)OR1; -(CH2)0-4CH(OR1)2; -(CH2)0-4SR1; -(CH2)0-4Ph, which may be substituted with R1; - (CH2)0-4O(CH2)0-1Ph which may be substituted with R1; -CH=CHPh, which may be substituted with R1; -(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with-NO2; -CN; -N3; (CH2)0-4N(R1)2; -(CH2)0-4N(R1)C(O)R1; -N(R1)C(S)R1; -(CH2)0-4N(R1)C(O)NR12; N(R1)C(S)NR12; - (CH2)0-4N(R1)C(O)OR1; -N(R1)N(R1)C(O)R1; N(R1)N(R1)C(O)NR12; N(R1)N(R1)C(O)OR1; - (CH2)0-4C(O)R1; -C(S)R1; -(CH2)0-4C(O)OR1; -(CH2)0-4C(O)SR1, (CH2)0-4C(O)OSiR13; -(CH2)0-4OC(O)R1; -OC(O)(CH2)0-4SR1- SC(S)SR1; -(CH2)0-4SC(O)R1; -(CH2)0-4C(O)NR12; - C(S)NR12; -C(S)SR1; -SC(S)SR1, (CH2)0-4OC(O)NR12: C(O)N(OR1)R1; -C(O)C(O)R1; - C(O)CH2C(O)R1; -C(NOR1)R1; (CH2)0-4SSR1; -(CH2)0-4S(O)2R1; -(CH2)0-4S(O)2OR1; -(CH2)0-4OS(O)2R1; -S(O)2NR12; (CH2)0-4S(O)R1; N(R1S(O)2NR12; -N(R1)S(O)2R1; -N(OR1)R1; - C(NH)NR12; -P(O)2R1; P(O)R12; OP(O)R12; -OP(O)(OR1)2; SiR13; -(C1-4straight or branched alkylene)O-N(R1)2; or -(C1-4straight or branched alkylene)C(O)O-N(R1)2.

[0126] Each R1independently can be hydrogen, C1-6aliphatic, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R1selected from =O and =S; or each R2is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)0-2R2, -(haloR2), -(CH2)0-2OH, -(CH2)0-2OR2, -(CH2)0-2CH(OR22; O(haloR2), -CN, -N3, -(CH2)0-2C(O)R2, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR2, -(CH2)0-2SR2, - (CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR2-(CH2)0-2NR22, -NO2, -SiR23, -OSiR23, C(O)SR2, - (C1-4straight or branched alkylene)C(O)OR2, or -SSR2.

[0127] Each R2independently can be selected from C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R2is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR32, =NNHC(O)R3, =NNHC(O)OR3, =NNHS(O)2R3, =NR3, =N0R3, -O(C(R32))2-3O-, or - S(C(R32))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is -O(CR32)2-3O-, wherein each independent occurrence of R3is selected from hydrogen, C1-6aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0128] When R3is C1-6aliphatic, R3is optionally substituted with halogen, - R2, -(haloR2), -OH, -OR2, -O(haloR2), -CN, -C(O)OH, -C(O)OR2, -NH2, -NHR2, -NR22, or -NO2, wherein each R2independently can be selected from C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R2is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0129] An optional substituent on a substitutable nitrogen is independently -R4, -NR42, - C(O)R4, -C(O)OR4, -C(O)C(O)R4, -C(O)CH2C(O)R4, -S(O)2R4, -S(O)2NR42, -C(S)NR42, - C(NH)NR42, or -N(R4)S(O)2R4; wherein each R4independently can be hydrogen, C1-6aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences oftaken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R4is C1-6aliphatic, is optionally substituted with halogen, -R2, -(haloR2), -OH, -OR2, -O(haloR2), -CN, -C(O)OH, -C(O)OR2, -NH2, -NHR2, -NR22, or-NO2, wherein each R2is independently selected from C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R2is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0130] For therapeutic applications, including improving solubility, stability, or in vivo compatibility, the peptides described herein may be preferred as a pharmaceutically acceptable salt and composed through a reaction with a variety of inorganic or organic acids or bases. The term “pharmaceutically acceptable salt” refers to salt forms of the peptides described herein that are deemed safe for treating a patient. The salt may be an acidic salt, a basic salt, or a neutral salt. Pharmaceutically acceptable salts and the techniques used to produce them are known to those skilled in the art. Examples of such pharmaceutically acceptable salts may include, but are not limited to, sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfite, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate or pamoate (i.e., 1,1 -methylene-bis-(2 -hydroxy-3 -naphthoate)) salts. Also included are salts formed with free amino groups such as, for example, hydrochloric, phosphoric, acetic, trifluoroacetic, oxalic, or tartaric acids. Also included are salts that may form with free carboxy groups such as, for example sodium, potassium, ammonium, sodium, lithium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, or procaine salts.

[0131] The pharmaceutically acceptable salts may form between an anionic group(s) of a peptide and added cations, or a cationic group(s) of a peptide and added anions. The referred to anionic and cationic groups may be located in any component of a peptide, including but not limited to the peptide backbone, amino acid side chains, amino acid modifications or substituents, or peptide terminal modifications. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (C1-4al kyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0132] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present. Unless otherwise stated, all tautomeric forms of the peptides are within the scope of the compounds described herein. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of compound described herein. Such compounds can be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents as described herein.

[0133] The peptides described herein can be made by traditional peptide synthesis techniques. The peptides described herein may be purified by any number of methods known to someone skilled in the art. These methods may include, but are not limited to, chromatography (e.g., reverse-phase high performance liquid, flash, ion-exchange, hydrophilic interaction, hydrophobic interaction, gel filtration, and size exclusion chromatographies), electrophoretic protocols, or extraction.

[0134] According to embodiments described herein, the deprotection of a protecting group (e.g., PG or PG1) above, or the addition of a protecting group, includes those protecting groups and methods described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, the entirety of each of which is herein incorporated by reference. In some embodiments, the protecting group is a suitable amino protection group.

[0135] As used herein, the phrase “suitable amino protecting group” is well known in the art and when taken with the nitrogen to which it is attached, include, but are not limited to, aralkylamines, carbamates, allyl amines, amides, and the like. Examples of mono-protection groups for amines include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethyloxycarbonyl (Fmoc), acetyl, chloroacetyl, di chloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, benzoyl, and the like. Examples of di-protection groups for amines include amines that are substituted with two substituents independently selected from those described above as mono-protection groups, and further include cyclic imides, such as phthalimide, maleimide, succinimide, 2,2,5,5-tetramethyl-l,2,5-azadisilolidine, azide, and the like. It will be appreciated that upon acid hydrolysis of an amino protecting groups, a salt compound thereof is formed. For example, when an amino protecting group is removed by treatment with an acid such as hydrochloric acid, then the resulting amine compound would be formed as its hydrochloride salt. One of ordinary skill in the art would recognize that a wide variety of acids are useful for removing amino protecting groups that are acid-labile and therefore a wide variety of salt forms are contemplated.

[0136] In some embodiments, the deprotection comprises hydrogenolysis, contacting with acid (e.g., HCl), contacting with base (e.g., piperidine, ammonia, K2CO3, or methylamine), or heating. According to embodiments described herein, the deprotection of a protecting group (e.g., PG) above includes those protecting groups and methods for their deprotection described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, JohnWiley & Sons, 1999, the entirety of which is herein incorporated by reference. In some embodiments, the protecting group is a suitable amino protection group. The deprotection may be performed in any solvent described infra. In some embodiments, the deprotection is performed in an alcohol selected from methanol, ethanol, propanol, butanol, pentanol, or hexanol. In some embodiments, the deprotection is performed in ethanol.

[0137] In any of the methods of preparing, the reactions may be run neat or in a solvent. A suitable medium is a solvent or a solvent mixture that, in combination with the combined compounds, may facilitate the progress of the reaction therebetween. The suitable solvent may solubilize one or more of the reaction components, or, alternatively, the suitable solvent may facilitate the agitation of a suspension of one or more of the reaction components. Examples of suitable solvents can include a protic solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof. Such mixtures include, for example, mixtures of protic and non-protic solvents such as benzene / methanol / water; benzene / water; DME / water, and the like.

[0138] These and other such suitable solvents may be interchanged are well known in the art, e g., see, "Advanced Organic Chemistry", Jerry March, 5thedition, John Wiley and Sons, N.Y.

[0139] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0140] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepoly oxypropylene-block polymers, polyethylene glycol and wool fat.

[0141] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a peptide described herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a peptide described herein or active metabolite or residue thereof.

[0142] The method of administering can be any method known to effectively deliver compounds such as the peptides or compositions herein to a desired location or systemically in a body. This includes administering the peptides or compositions parenterally, such as by intravenous injection, intramuscular injection, or subcutaneous injection, orally, by inhalation, intranasally, intraperitoneally, intrathecally, transdermally, sublingually, rectally, bucally, sublingually, or transmucosally. In some embodiments, the peptides herein may be administered all at once or by timed-release methods. In other embodiments, the peptides herein may be administered by implantation devices. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions can be administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0143] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonlyused in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0144] Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0145] Alternatively, pharmaceutically acceptable compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0146] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0147] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0148] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of peptides described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0149] Pharmaceutically acceptable compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0150] Most preferably, pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food.

[0151] The amount of compound that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0152] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

[0153] The peptides described herein can be prepared to form pharmaceutical compositions for therapeutic applications. The formulations of, and methods for, preparing such pharmaceutical compositions based on the modes of administration previously described are known to those skilled in the art. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Peptides described herein can be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated.It will be understood, however, that the total daily usage of the compound and compositions described herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0154] Pharmaceutical compositions of the peptides described herein may also be composed of pharmaceutically acceptable carriers, diluents, or excipients, known to those skilled in the art. Pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the peptides described herein may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0155] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0156] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0157] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0158] In order to prolong the effect of a peptide described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of peptide release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0159] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0160] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0161] The active compound can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0162] Dosage forms for topical or transdermal administration peptides described herein can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being suitable dosage forms. Additionally, the use of transdermal patches can have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. For example, for intramuscular or subcutaneous administration, an injectable composition may be prepared; for oral administration, tablets or capsules, in immediate or time release form, may be prepared; for inhalation, an inhalant may be prepared; for transdermal administration, creams, lotions, or dermal patches may be prepared. In particular embodiments, the pharmaceutical compositions are administered subcutaneously. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0163] The peptides described herein are biologically active with high potency as described through binding to the human NPY receptor, in particular to subtype Y2. This receptor binding can be determined as described below.

[0164] The peptides described herein are biologically active with high potency as described through in vivo animal model experimentation and clinical trials. In some embodiments, these experiments are performed using mouse models. In further embodiments, these experiments in mouse models demonstrate the biological activity and high potency of the peptides herein through the lowering of blood glucose, reduction of food intake, or decrease in body weight, individually or in combination. This in vivo biological activity can be determined as described below. The activity and assays can be compared to PKPEKTEEDASPEEWQRYYIELRHYLNWLTRQRY- NH2, where K1is Lys-(oeg)-γ-Glu-Ci8 diacid (SEQ ID NO. 163) which is identified herein as Compound Z.

[0165] In some embodiments, the peptides described herein may have improved pharmacokinetic profiles, for example increased half-life or decreased clearance compared to PYY(1-36)or PYY(3-36). In some such embodiments, the peptides have a half-life that is from about 5 hours to about 24 hours longer than PYY(1-36)or PYY(3-36), in particular about 12 hours longer.This means that the peptides described herein may not be removed through a body’s clearance mechanisms in vivo as quickly as PYY(1-36)or PYY(3-36), effectively increasing the amount of time the peptides are present in a body at therapeutic concentrations and therefore increasing the duration of the peptides’ pharmacological effect.

[0166] Pharmacokinetic properties or profiles for compounds such as the peptides described herein are generally determined through in vivo pharmacokinetic studies to understand their ability to be absorbed, distributed, and cleared from the body, and how this affects the concentration and duration of the compound in a body. Such studies can be performed using a number of different animal models known in the art, including mouse, rat, monkey, canine, or pig, to measure the pharmacokinetic properties of the peptides herein.

[0167] The pharmacokinetic properties and profiles of the peptides can be determined as described below.

[0168] The term “treatment” refers to the prevention (i.e., prophylaxis), reduction, alleviation, or cure of a disease, disorder, or condition. In some embodiments, the peptides or compositions described herein may be used as a treatment for a number of diseases, disorders, or conditions. In some embodiments, the peptides or compositions described herein can be used as a medication for the treatment of a disease, disorder, or condition. Methods can include but are not limited to administering a therapeutically effective quantity, frequency, and duration of the peptides or compositions described herein to a patient in need thereof for treatment. It also describes a number of modes of administering the peptides or compositions to a patient in need thereof in ways that are known to those skilled in the art.

[0169] In some embodiments, the methods can include administering the peptides or compositions once a day, once every two days, three times a week, two times a week, once weekly, once every two weeks, or once a month.

[0170] In some embodiments, a subject may have one or more forms or stages of diabetes, including hyperglycemia, insulin resistance, prediabetes, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, mature onset diabetes of the young, gestational diabetes, or elevated HbAlC levels.

[0171] In another embodiment, the PYY analog can be used to treat a subject with Prader Willi syndrome. Prader Willi syndrome is a rare, complex genetic condition that is associated with insatiable hunger, low muscle tone, short stature, cognitive deficits and problematic behaviors.

[0172] In another embodiment, a subject may have one or more forms or stages of obesity or obesity-related disorders, including being overweight.

[0173] In another embodiment, a subject may require treatment to improve β-cell function, including reducing β-cell apoptosis, increasing β-cell numbers or mass, or restoring β-cell glucose sensitivity.

[0174] In another embodiment, a subject may have an eating disorder, such as obesity, binge eating, or bulimia nervosa. In some embodiments, such disorders may be the result of a side effect of the use of another medication, such as antipsychotic or steroid medications.

[0175] In another embodiment, a subject may require a decrease in gastric mobility or gastric emptying.

[0176] In another embodiment, a subject may have one or more lipid disorders such as dyslipidemia, elevated serum lipids, elevated low density lipoprotein, elevated very low density lipoprotein, reduced high density lipoprotein, elevated triglycerides, elevated cholesterol, elevated serum lipoprotein, or high apolipoprotein A generation.

[0177] In another embodiment, a subject may have metabolic disease.

[0178] In another embodiment, a subject may have cardiovascular disease.

[0179] In another embodiment, a subject may have sleep apnea.

[0180] In other embodiments, a subject may have comorbidities or complications that may accompany any of the aforementioned disorders, including but not limited to neuropathy, angiopathy, peripheral neuropathy, retinopathy, osteoarthritis, or urine incontinence.

[0181] In certain embodiments, a subject may have type 2 diabetes or obesity.

[0182] In certain embodiments, a subject may have Prader Willi syndrome.

[0183] Improving the potency or selectivity of a PYY analog can impact its therapeutic potential in numerous metabolic diseases, including diabetes and obesity. A modification substituting the tryptophan corresponding to W30 in PYY(1-36)with substituted tryptophan can improve the potency or selectivity of PYY analogs toNPY receptor subtype Y2. This improvement can be further enhanced when incorporated in combination with other PYY analog modifications.

[0184] In one aspect, a peptide can include an amino acid sequence of:X3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID NO: 143) where:X3can be V, I or P; X4can be R, K or P; X7can be A, K or K*, wherein K* has the structure:where each Z1, independently, can be an amino acid residue, sugar residue, -C(O)-Z2-O-, or - C(O)-Z2-NH-; each Z2, independently, can be a 2-8 carbon alkylene linker where 1 or 2 carbon atoms can be optionally independently substituted by -NH2, -OH, or -COOH and where the alkylene linker can be straight or branched and optionally includes a C3-8cycloalkyl moiety; or each Z2, independently, can be -((CH2)a-O-(CH2)b)c-, wherein each a can be independently 1, 2, or 3, each b can be independently 1, 2, or 3, and c can be 1, 2, or 3; n can be 1, 2, 3, 4, or 5;R1can be -Z3-R2or -C(O)-Z3-R2;Z3can be a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2can be -C(O)OH or -P(O)(OH)2;X9can be G or E;X10can be E or K;X11can be D or D*, where D* can be beta-aspartic acid, or d-aspartic acid;X13can be A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17can be W or L;X18can be N or Q;X22can be A, D, E, F, I, L, M, or V; X23can be D, S or E; X28can be I, L, or Aib;X30can be W* where W* can be tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31can be V or L;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* can be N(alpha)-methylarginine or beta-homo-arginine; X36can be Y or Z*, where Z* has Formula la, lb, or Ic:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherethe 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Ar can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; where the C-terminal amino acid of the peptide can be optionally amidated; or a pharmaceutically acceptable salt thereof

[0185] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 144), where: X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan; andX35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine.In some embodiments, each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0186] In some embodiments, the peptide can include an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 145), where: X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y;X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan; X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Y or Z*, where Z* has Formula la, lb, or Ic; each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0187] In some embodiments:X13can be S or T;X22can be I or V; andX35can be R or beta-homo-arginine.

[0188] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 146), where: X7can be K*;X13can be S or T;X22can be I or V;X35can be R or beta-homo-arginine; each Z1independently can be selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

[0189] In some embodiments, the peptide can include an amino acid sequence selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 147);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 148);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 149);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 150);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 151);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 152);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 153);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 154);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 155);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 156);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 157);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 158);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 159);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 160);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 161); andPKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 162).

[0190] In some embodiments, R2can be -C(O)OH.

[0191] In some embodiments, R2can be -P(O)(OH)2.

[0192] In some embodiments:K* can have the structure:where Z can be:

[0193] In some embodiments, R1can be -C(O)-(CH2)k-R2.

[0194] In some embodiments, Z* can have the formula la:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0195] In some embodiments, Z* can have the formula la:whereRaand Rbtaken together with the carbon to which they are attached can form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; andRccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0196] In some embodiments, Z* can have the structurewhere: each R3, independently, can be selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl; i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0197] In some embodiments, Z* can have the structure

[0198] In some embodiments, Z* can have the formula lb:whereRdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Racan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form:a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0199] In some embodiments, Z* can have the formula Ic:whereRdcan be H or methyl; andAr can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0200] In some embodiments, W* can be 4-fluorotryptophan, 5 -fluorotryptophan, 6- fluorotryptophan, 7-fluorotry ptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6- cy anotryptophan, or 7-cy anotryptophan.

[0201] In some embodiments, W* can be 7-cyanotryptophan.

[0202] In certain embodiments, the substituted lysine can have a structure K-ε-Lys-γ-Glu- Cm+2-Z” (where m is 15, 16, 17, 18, 19, or 20 and Z” can be carboxylate, sulfonate or phosphonate)K-(oeg)i-γ-Glu-Cm+2-Z” (where m is 15, 16, 17, 18, 19, or 20 and i is 1, 2 or 3 and Z” can be carboxylate, sulfonate or phosphonate)K-Gluc-Cm+1-Z” (where m is 15, 16, 17, 18, 19, or 20 and i is 1, 2 or 3 and Z” can be carboxylate, sulfonate or phosphonate)

[0203] In some embodiments, substituted lysine can include a 6-aminohexanoic acid spacer before an oeg or a Glu group.

[0204] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0205] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0206] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0207] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0208] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0209] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0210] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0211] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0212] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0213] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0214] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0215] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0216] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0217] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0218] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0219] Improving the potency or selectivity of a PYY analog can impact its therapeutic potential in numerous metabolic diseases, including diabetes and obesity. A modification at the C- terminus can alter the potency or selectivity of PYY analogs to NPY receptor subtype Y2. In certain circumstances, the modification at the C-terminus can have no significant impact on potency or selectivity.

[0220] In one aspect, a peptide can include an amino acid sequence of:X3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID NO: 469) whereX3can be V, I or P; X4can be R, K or P; X7can be K*, where K* can have the structure:where each J1, independently, can be an amino acid residue, sugar residue, -C(O)-J2-O-, or -C(O)- J2-NH-; each J2, independently, can be a 2-8 carbon alkylene linker where 1 or 2 carbon atoms can be optionally independently substituted by -NH2, -OH, or -COOH and where the alkylene linker can be straight or branched and optionally can include a C3-8cycloalkyl moiety; or each J2, independently, can be -((CH2)a-O-(CH2)b)c-, where each a can be independently 1, 2, or 3, each b can be independently 1, 2, or 3, and c can be 1, 2, or 3; n can be 1, 2, 3, 4, or 5;R1can be -J3-R2or -C(O)-J3-R2;J3can be a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2can be -C(O)OH or -P(O)(OH)2;X9can be G or E;X10can be E or K;X11can be D or D*, where D* is beta-aspartic acid, or d-aspartic acid;X13can be A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17can be W or L;X18is N or Q;X22can be A, D, E, F, I, L, M, or V;X23can be D, S or E;X28can be I, L, or Aib;X30can be E, L, W, or W*, where W* can be tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31can be V or L;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; X36can be Z*, where Z* has Formula la, lb, or Ic:whereRacan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; ora 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -C0C(Ra)(Rb)Rc;Ar can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a pharmaceutically acceptable salt thereof

[0221] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 470), where X7can be K*; X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W*, where W* is a halo- or cyano-substituted tryptophan; X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic.

[0222] In some embodiments, each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0223] In some embodiments, the peptide can include an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 471); where X7can be K*;X13can be A, C, K, M, N, P, R, S, T, W, or Y; X22can be A, D, E, F, I, L, M, or V;X30can be W or W*, where W* is a halo- or cyano-substituted tryptophan;X35can be C, G, H, K, L, M, P, R, R*, Q, T, or W, where R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic; each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0224] In some embodiments:X13can be S or T; X22can be I or V;X30can be W or W*, where W* can be a halo- or cyano-substituted tryptophan; andX35can be R or beta-homo-arginine.

[0225] In some embodiments, the peptide can include an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 472), where: X7can be K*;X13can be S or T; X22can be I or V;X30can be W or W*, where W* can be a halo- or cyano-substituted tryptophan;X35can be R or beta-homo-arginine; X36can be Z*, where Z* has Formula la, lb, or Ic; each J1can be independently selected from:R1can be -(CH2)k-R2or -C(O)-(CH2)k-R2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0226] In some embodiments, the amino acid sequence can be selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 473);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 474);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 475);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 476);PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 477);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 478);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 479);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 480);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 481);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 482);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 483);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 484);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 485);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 486);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 487); andPKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 488).

[0227] In some embodiments, each Z1can be independently selected from:n can be 2 or 3;R1can be -C(O)-J3-R2; andJ3can be a straight or branched, saturated 16-20 carbon alkylene linker.

[0228] In certain embodiments, the substituted lysine can have a structure K-ε-Lys-γ-Glu-Cm+2-Z” (where m is 15, 16, 17, 18, 19, or 20 and Z” can be carboxylate, sulfonate or phosphonate)K-(oeg)i-γ-Glu-Cm+2-Z” (where m is 15, 16, 17, 18, 19, or 20 and i is 1, 2 or 3 and Z” can be carboxylate, sulfonate or phosphonate)K-Gluc-Cm+1-Z (where m is 15, 16, 17, 18, 19, or 20 and i is 1, 2 or 3 and Z” can be carboxylate, sulfonate or phosphonate)or

[0229] In some embodiments, substituted lysine can include a 6-aminohexanoic acid spacer before an oeg or a Glu group.

[0230] In some embodiments,R1can be -C(O)-(CH2)k-P(O)(OH)2; and k can be 16, 17, 18, 19, 20, 21, or 22.

[0231] In some embodiments,K* can have the structure:where J can be:; andR1can be -C(O)-(CH2)k-R2.

[0232] In some embodiments, R1can be -C(O)-(CH2)k-R2.

[0233] In some embodiments:Z* can have the formula la:whereRacan be H, C1-3alky 1, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or a 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0234] In some embodiments,Z* can have the formula la:whereRaand Rbtaken together with the carbon to which they are attached can form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; andRccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

[0235] In some embodiments,Z* can have the structurewhere: each R3, independently, can be selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl; i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0236] In some embodiments,Z* can have the structure

[0237] In some embodiments,Z* can have the formula Ib:whereRdcan be H or methyl;Recan be a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Recan be -COC(Ra)(Rb)Rc;Racan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbcan be H, C1-3alkyl, or C1-3alkenyl, where alkyl or alkenyl can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached can form: a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and - O-C1-3alkyl; a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heterocyclic group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, where the 5-6 membered heteroaryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; ora 6 membered aryl group, where the 6 membered aryl group can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rccan be phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, where Rccan be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl; or Rccan be absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

[0238] In some embodiments,Z* can have the formula Ic:whereRdcan be H or methyl; andAr can be a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, where Ar can be optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)- C1-3alkyl, -OH, and -O-C1-3alkyl.

[0239] In some embodiments, W* can be 4-fluorotryptophan, 5 -fluorotryptophan, 6- fluorotryptophan, 7-fluorotry ptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6- cy anotryptophan, or 7-cy anotryptophan.

[0240] In some embodiments, W* can be 7-cyanotryptophan.

[0241] In some embodiments, X30can be D-7-CN-Trp, 2-aza-7-CN-Trp, 4-aza-Trp, 5-aza-Trp, 6-aza-Trp, 7-aza-Trp, beta-(azulenyl)-L-alanine, beta-homo-Trp, 7-NAc-Trp, 7-CN-β-Me-Trp, 4- CN-indazole-N-L-alanine, 7-N-Acetyl-3H-indol-L-alanine, 4-CN-indole-N-D-alanine, 4-CN- benzotriazole-N-L-alanine, 7-CN-benzofuran-3-L-alanine, 3-CN-azulenyl-L-alanine, or 7-CN- benzothiophene-3-L-alanine.

[0242] In some embodiments, X35can be N-ω-methyl Arg, pyrrolidine- Arg, alpha-Me-Arg, orN-Me-Arg.

[0243] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0244] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0245] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0246] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0247] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0248] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0249] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0250] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0251] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0252] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0253] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0254] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0255] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0256] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0257] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0258] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0259] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0260] In another aspect, a peptide can have the structure:or a pharmaceutically acceptable salt thereof.

[0261] In another aspect, a pharmaceutical composition can include a peptide as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0262] In another aspect, a method of treating diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0263] In another aspect, a method of improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof, thereby decreasing food intake, reducing body weight, suppressing appetite, and / or inducing satiety in the patient.

[0264] In another aspect, a method of treating or preventing binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0265] In another aspect, a method of reducing of gastric motility, delaying gastric emptying, or increasing physical mobility, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0266] In another aspect, a method of treating or preventing comorbidities to obesity, osteoarthritis, or urine incontinence, can include administering a therapeutically effective amount of a peptide as described herein to a patient in need thereof.

[0267] In another aspect, the use of a peptide as described herein in the treatment of diabetesand related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea.

[0268] In another aspect, the use of a peptide as described herein for improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression.

[0269] In another aspect, the use of a peptide as described herein in the treatment or prevention of binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid.

[0270] In another aspect, the use of a peptide as described herein for reducing gastric motility, delaying gastric emptying, or increasing physical mobility.

[0271] In another aspect, the use of a peptide as described herein in the treatment or prevention of comorbidities to obesity, osteoarthritis, or urine incontinence.

[0272] Exemplary compounds are listed in Tables 1A, IB and 1C. Additional Modifications indicate an amino acid charge at the respective PYY(3-36)amino acid position.Table 1ATable 1BTable 1C

[0273] Biological activity data for the exemplary compounds are listed in Tables 2A, 2B and 2C. Tables 3A, 3B and 3C show analysis and purity data for the exemplary compounds.Table 2ATable 2BTable 2CTable 3ATable 3BTable 3C

[0274] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.General Procedures

[0275] The following general procedures were used for synthesis of peptides.General Procedure 1 (G1)

[0276] Peptides were synthesized with microwave-assisted solid-phase peptide synthesis (SPPS) techniques using Fmoc / t-Bu strategy on a Liberty Blue Microwave Peptide Synthesizer (CEM Corporation). Deprotections were carried out using 20% piperidine in 0.1 M Oxyma / DMF solutions. Amino acid couplings were performed using a 5-fold excess of reagent. Fmoc-amino acids (0.2 M solution in DMF), DIC (0.5 or 1.0 M solution in DMF) and Oxyma (0.5 or 1.0 M solution in DMF) were employed on 0.05 or 0.1 mmol scale on Rink Amide ProTide Resin (LL) resin. N-Boc protected amino acid was employed at the N-terminus.General Procedure 2 (G2)

[0277] Peptides including the sequence Leu31-Thr32-Arg33-Gln34-Arg35 and a non-natural C-terminal modification were synthesized on Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)- Dap(mtt)-Rink Amide Resin with microwave-assisted solid-phase peptide synthesis (SPPS) techniques using Fmoc / t-Bu strategy on a Liberty Blue Microwave Peptide Synthesizer (CEM Corporation). Deprotections were carried out using 20% piperidine in 0.1 M Oxyma / DMF solutions. Amino acid couplings were performed using a 5-fold excess of reagent. Fmoc-amino acids (0.2 M solution in DMF), DIC (0.5 or 1.0 M solution in DMF) and Oxyma (0.5 or 1.0 M solution in DMF) were employed on 0.05 or 0.1 mmol scale on Fmoc-Leu-Thr(tBu)-Arg(Pbf)- Gln(Trt)-Arg(Pbf)-Dap(mtt)-Rink Amide Resin. Dap was deprotected and modified according to procedure F1 (see below). N-Boc protected amino acid was employed at the N-terminus.General Procedure 3 (G3)

[0278] Peptides including the sequence Leu3 l-Thr32-Arg33-Gln34-β-homoArg35 and a nonnatural C-terminal modification were synthesized on Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β-homoArg(Pbf)-Dap(mtt)-Rink Amide Resin with microwave-assisted solid-phase peptide synthesis (SPPS) techniques using Fmoc / t-Bu strategy on a Liberty Blue Microwave Peptide Synthesizer (CEM Corporation). Deprotections were carried out using 20% piperidine in 0.1 M Oxyma / DMF solutions. Amino acid couplings were performed using a 5-fold excess of reagent. Fmoc-amino acids (0.2 M solution in DMF), DIC (0.5 or 1.0 M solution in DMF) and Oxyma (0.5 or 1.0 M solution in DMF) were employed on 0.05 or 0.1 mmol scale on Fmoc-Leu-Thr(tBu)- Arg(Pbf)-Gln(Trt)-β-homoArg(Pbf)-Dap(mtt)-Rink Amide Resin. Dap was deprotected and modified according to procedure F1. N-Boc protected amino acid was employed at the A -terminus.Procedure S1 (PYY Position 7, 30, 35 when non-standard amino acids occur)

[0279] N-Fmoc deprotection was carried out using 20% piperidine in DMF (3 x 4 mL, 20 min cycles for 0.05 mmol scale). The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The special amino acid (2 equiv, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equiv., 0.4 mL, 0.5 M in DMF) and Oxyma (2 equiv., 0.2 mL, 0.5 M in DMF) at 23 °C. Upon completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0280] For example, (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid was used to install 7-cy anotry ptophan at position 30 in some peptides, and the amino acid (S)-6-{[(2-{2-[(S)-4-tert-butoxycarbonyl-4-(16-tert- butoxycarbonylhexadecylcarbonylamino)butyrylamino]ethoxy}ethoxy)methyl]carbonylamino}- 2-{[(9H-fluoren-9-yl)methyl](oxycarbonylamino)}hexanoic acid was used at position 7 in some peptides, as described further below.Procedure S2 Fmoc-Dap(mtt)-resin and Fmoc-Dap(ivDde)-resin

[0281] Rink Amide ProTide Resin (LL) resin 0.05 mmol was deprotected using 20% piperidine in DMF (3 x 4 mL, 20 min cycles for 0.05 mmol scale). The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The special amino acid (Fmoc-Dap(mtt)-OH or Fmoc- Dap(ivDde)-OH, 2 equiv, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equiv., 0.4 mL, 0.5 M in DMF) and Oxyma (2 equiv., 0.2 mL, 0.5 M in DMF) at 23 °C. Upon completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).Procedure S3 (C-Terminal modifications)Peptide-MeNbz-G-Rink Amide:

[0282] Fmoc-MeDbz-G-Rink amide was prepared using S1 on a 0.1 mmol scale. The remaining protected peptide was prepared using the procedure outlined in G1. DCM (10 mL) and 4-nitrophenyl chloroformate (200 mg, 1.0 mmol, 10 equiv.) were added to this resin-bound peptide, and gently shaken for 1 hour at 23 °C. The solution was filtered, and the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The resin was treated with DCM (10 mL) and 4- nitrophenyl chloroformate (200 mg, 1.0 mmol, 10 equiv.) a second time and gently shaken for 1 hour at 23 °C. The solution was filtered, and the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The resin was shaken with DIPEA (2 mL) in DMF (10 mL) for 1 hour at 23 °C. The solution was filtered, and the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL) and dried to afford activated Peptide-MeNbz-G-Rink Amide resin.Fragment addition:

[0283] To the activated resin (0.0125 mmol scale) was added the special amine (10 equiv.) and Et3N (20 equiv.) in 2:1 CH3CN / DCM (1.5 mL). The slurry was heated to 50 °C and gently stirred for 18 hours. The slurry was filtered, rinsed with a minimal amount of 2:1 CH3CN / DCM and concentrated to yield the crude protected peptide. The peptide was globally deprotected using procedure Cl, and the crude material was purified using purification procedures Pl and P2.Fragment Attachment (PYY Position 7, 36)Procedure F1 — mtt

[0284] The Mtt group was deprotected with HFIP:TIS:DCM (15:1 :34 v / v / v) (3 x 5 mL, 15 min cycles for 0.05 mmol scale). The resin was washed with DCM (3 x 5 mL) and DMF (3x5 mL). The acid (2 equiv, 0.1 mmol)(e.g., 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acid) in DMF (1 mL) was coupled with DIC (4 equiv., 0.4 mL, 0.5 M in DMF) and Oxyma (2 equiv., 0.2 mL, 0.5 M in DMF) at 23 °C. Upon completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).Procedure F2 -- ivDde

[0285] IvDde was deprotected with 5% hydrazine in DMF (3 x 5 mL, 30 min cycles for 0.05 mmol scale). The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The acid (2 equiv, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equiv., 0.4 mL, 0.5 M in DMF) and Oxyma (2 equiv., 0.2 mL, 0.5 M in DMF) at 23 °C. Upon completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).Cleavage and Work-up ConditionsProcedure Cl

[0286] Side chain protecting group removal with concomitant cleavage from the resin and was carried out in a TFA / TIS / H2O / PhOH (88:2:5:5 v / v / v / v) solution (10 mL / 0.05 mmol) for 3 hours at room temperature. Cold diethyl ether (30 mL / 0.05 mmol) was used to precipitate the peptide, which was isolated by centrifugation (3000 rpm, 10 min).Purification Conditions

[0287] Crude peptide was iteratively purified by RP-HPLC until >95% purity was obtained. Purification conditions are listed as follows; suitable fractions were pooled and lyophilized. The purity of the PYY analog was examined by analytical RP-HPLC, and identity confirmed using LCMS.Procedure P1:Procedure P2:Procedure P3:Procedure P4:Procedure P5:Analytical Conditions

[0288] The purity of peptides was examined by analytical RP-HPLC, and identity confirmed using LCMS with the following conditions.Intermediates ACW-8&9 P1, P2(cyclobutylidene(ethoxy)methoxy)trimethylsilane

[0289] To a solution of LDA (2 M, 41.0 mL) in THF (100 mL) was added a solution of ethyl cyclobutanecarboxylate (10 g, 78.0 mmol, 10.8 mL) in THF (20 mL) at -70 °C. The reaction mixture was stirred at -65 °C for 1 hour. A solution of TMSCI (10.5 mL, 82.7 mmol) in THF (20 mL) was added at -65 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated and filtered to afford the crude(cyclobutylidene(ethoxy)methoxy)trimethylsilane (8 g, 51% yield) as colorless oil. ethyl 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate)

[0290] To a solution of [cyclobutylidene(ethoxy)methoxy]trimethylsilane (15.0 g, 74.9 mmol) and tetrahydropyran-2-yl acetate (2.7 g, 18.7 mmol) in DCM (50 mL) was added TMSOTf (6.7 g, 30.0 mmol, 5.4 mL) at -65 °C. The reaction mixture was stirred at -40 °C for 2 hours. On completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and then extracted with DCM (50 mL). The organic extract was washed with brine (20 mL), dried over anhydrous Na2SO4,and concentrated under reduced pressure to afford a residue that was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 95: 5) and the product obtained was further purified by preparative HPLC (column: Welch Xtimate C18 250 x 100 mm, 10μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 20 min) to afford ethyl 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate (3.7 g, crude) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 4.26 - 4.12 (m, 2H), 4.09 - 3.99 (m, 1H), 3.57 - 3.32 (m, 2H), 2.51 - 2.42 (m, 1H), 2.40 - 2.13 (m, 4H), 2.10 - 1.91 (m, 1H), 1.90 - 1.76 (m, 3H), 1.54 - 1.47 (m, 2H), 1.39 - 1.21 (m, 4H). 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylic acid

[0291] To a solution of ethyl l-tetrahydropyran-2-ylcyclobutanecarboxylate (3.4 g, 16.0 mmol) in THF (10 mL), MeOH (10 mL) and H2O (20 mL) was added NaOH (4.48 g, 112.1 mmol). The mixture was stirred at 45 °C for 24 hours. Additional NaOH (1.28 g, 32.0 mmol) was then added. The mixture was stirred at 45 °C for 8 hours. On completion, the reaction mixture was concentrated to remove THF and MeOH. The reaction mixture was adjusted to pH ~4 with HCl (3 M, 48 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 7: 1) to afford 1-(tetrahydro-2H-pyran-2- yl)cyclobutane-1-carboxylic acid (1.7 g, 58% yield) as a white solid.1H NMR (400 MHz, DMSO- d6) δ 12.17 (br s, 1H), 3.93 (br dd, J = 2.0, 10.8 Hz, 1H), 3.45 - 3.35 (m, 2H), 2.30 - 2.13 (m, 2H), 2.11 - 2.00 (m, 2H), 1.83 - 1.62 (m, 3H), 1.51 - 1.36 (m, 4H), 1.28 - 1.11 (m, 1H).Benzyl 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate

[0292] To a solution of l-tetrahydropyran-2-ylcyclobutanecarboxylic acid (1.7 g, 9.23 mmol) in DMF (20 mL) was added benzyl bromide (1.89 g, 11.1 mmol, 1.3 mL) and K2CO3(2.55 g, 18.5 mmol). The reaction mixture was stirred at 25 °C for 16 hours. After completion, the reaction mixture was quenched with H2O (50 mL) and then extracted with EtOAc (50 mL). The organicextract was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 10: 1) to afford benzyl 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1- carboxylate (2.4 g, 95% yield).1H NMR (400 MHz, CDCl3) δ = 7.37 - 7.27 (m, 5H), 5.24 - 5.13 (m, 2H), 4.03 - 4.00 (m, 1H), 3.56 - 3.53 (m, 1H), 3.36 - 2.29 (m, 4H), 1.85 - 1.84 (m, 3H), 1.49 - 1.47 (m, 4H), 1.47 - 1.27 (m, 1H).Benzyl (S)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate and benzyl (R)- 1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate (5_P1,and 5_P2)

[0293] (±)-Benzyl-1-(tetrahydro-2H-pyran-2-yl) cyclobutane- 1 -carboxylate (2.4 g, 8.74 mmol) was further separated by preparative Chiral HPLC (column: DAICEL CHIRALPAK AD (250 x 30 mm, 10 μm); mobile phase: [Hexane-IPA]; B%:3%, 8 min) to afford 5_Pl,and 5_P2, as colorless oils.5 P1: Yield: 900 mg. RT = 2.09 min;1H NMR (400 MHz, CDCI3) δ 7.40 - 7.29 (m, 5H), 5.29 - 5.07 (m, 2H), 4.10 - 3.94 (m, 1H), 3.59 - 3.50 (m, 1H), 3.46 - 3.37 (m, 1H), 2.42 - 2.27 (m, 3H), 2.26 - 2.14 (m, 1H), 1.92 - 1.76 (m, 3H), 1.51 - 1.26 (m, 5H).5 P2: Yield: 950 mg. RT = 2.30 min;1H NMR (400 MHz, CDCI3) δ 7.40 - 7.29 (m, 5H), 5.28 - 5.09 (m, 2H), 4.06 - 3.96 (m, 1H), 3.57 - 3.51 (m, 1H), 3.42 (dt, J = 2.4, 11.3 Hz, 1H), 2.42 - 2.26 (m, 3H), 2.24 - 2.15 (m, 1H), 1.92 - 1.77 (m, 3H), 1.52 - 1.45 (m, 4H), 1.38 - 1.25 (m, 1H).(S)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylic acid(ACW-8&9 Pl)

[0294] To a solution of benzy1-(S)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate (900 mg, 3.28 mmol) in MeOH (15 mL) was added Pd / C (50 mg, 10% w / w) under Argon atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(50 Psi) at 25 °C for 16 hours. After completion, the reaction mixture was filtered through a Celite pad and the filter cake was washed with MeOH (30 mL x 5). The filtrate and washes were combined and concentrated to a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Petroleum ether: Ethyl acetate = 1 : 0~5: 1) to afford (S)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylic acid (420 mg, 2.20 mmol, 67% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ 11.04 - 9.08 (m, 1H), 4.15 (br dd, J = 1.7,10.9 Hz, 1H), 3.63 (dd, J= 1.5, 11.6 Hz, 1H), 3.54 (dt, J = 3.9, 10.9 Hz, 1H), 2.67 - 2.55 (m, 1H), 2.38 - 2.21 (m, 2H), 2.09 - 1.82 (m, 4H), 1.76 - 1.43 (m, 4H), 1.31 - 1.16 (m, 1H).(R)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylic acid(ACW-8&9 P2)

[0295] To a solution of benzyl (R)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylate (950 mg, 3.46 mmol) in MeOH (15 mL) was added Pd / C (950 mg, 10 wt%) under Argon atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 Psi) at 25 °C for 16 hours. After completion, the reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (30 mL x 5). The filtrate and washes were combined and concentrated to a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Petroleum ether: Ethyl acetate = 1: 0~5: l) to give (R)-1-(tetrahydro-2H-pyran-2-yl)cyclobutane-1-carboxylic acid (320 mg, 1.68 mmol, 49% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ 11.17 - 9.02 (m, 1H), 4.20 - 4.11 (m, 1H), 3.63 (dd, J = 1.8, 11.6 Hz, 1H), 3.54 (dt, J= 4.0, 11.0 Hz, 1H), 2.69 - 2.49 (m, 1H), 2.38 - 2.21 (m, 2H), 2.09 - 1.82 (m, 4H), 1.76 - 1.43 (m, 4H), 1.32 - 1.16 (m, 1H).Intermediate ACW-11

[0296] To a solution of cyclobutanecarboxylic acid (1 g, 10 mmol, 952 μL) in THF (10 mL) was added LDA (2 M, 11 mL) at -65 °C. The reaction mixture was warm to 25 °C and stirred for 1 hour and then cooled to 0-5 °C. 4-iodotetrahydropyran (2.12 g, 1.0 equiv.) was added and the reaction mixture was allowed to warm to 25 °C and stirred for 3 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with HCl (2 M, ~25 mL) and extracted with EtOAc (30 mL). The organic extract was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Petroleum ether: Ethyl acetate = 1 : 0~3 : 1). The material afforded was further purified by trituration with petroleum ether (5 mL)and filtration. The filter cake was dried in vacuo to afford ACW-11, 1 -tetrahydropyran -4- ylcyclobutanecarboxylic acid (102.6 mg, 6% yield) as a white solid, m / z (ESI, -ve ion) = 183.2 [M-H]-.1H NMR (400 MHz, CHLOROFORM-d) δ 4.15 - 4.00 (m, 2H), 3.40 (dt, J = 2.0, 11.7 Hz, 2H), 2.51 - 2.35 (m, 2H), 2.16 - 2,03 (m, 2H), 1.99 - 1.88 (m, 2H), 1.87 - 1.77 (m, 1H), 1.66 - 1.58 (m, 2H), 1.56 - 1.44 (m, 2H).Intermediate ACW-131-cyclohexylcyclobutane-1-carboxylic acid

[0297] To a solution of cyclobutanecarboxylic acid (1 g, 10 mmol, 952.4 μL) in THF (15 mL) was added LDA (2 M, 11 mL) at -65 °C. The reaction mixture was allowed to warm to 25 °C and stirred for 1 hour, then cooled to 0-5 °C. lodocyclohexane (2.10 g, 1.0 equiv.) was added and the reaction mixture allowed to warm to 25 °C and stirred for 3 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with HCl (2 M, ~25 mL) and then extracted with EtOAc (30 mL x 2). The combined organic extracts was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford a residue, which was purified by flash silica gel chromatography (Petroleum ether : Ethyl acetate =1:0~3:1) to afford ACW-13, 1- cyclohexylcyclobutane-1 -carboxylic acid (117 mg, 6% yield, 94.6% purity) as a white solid, m / z (ESI, +ve ion) = 181.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ ppm 2.34 - 2.46 (m, 2 H) 2.04 - 2.14 (m, 2 H) 1.60 - 1.94 (m, 8 H) 0.97 - 1.36 (m, 6 H).Intermediate ACW-15[(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysinate

[0298] A solution of N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L- lysine (41.46 g, 82.50 mmol, 1.5 equiv.) in DCM (500 mL) was added to a slurry of chlorotrityl resin (55 g, 1 mmol / g) and DIPEA (10 equiv.) in DCM (600 mL). The reaction mixture wasagitated for 16 hours at ambient temperature under nitrogen, then filtered. The resin was washed with DCM (3 x 400 mL), DMF (2 x 400 mL), MeOH (3 x 400 mL) and DMF (400 mL), then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate

[0299] To [(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysinate (42.86 g, 55 mmol) was added 20% v / v piperidine in DMF (500 mL). The slurry was agitated for 15 minutes at ambient temperature under nitrogen. The reaction mixture was filtered and the resin was washed with DMF (300 mL). To test for completion of the Fmoc deprotection, 0.1 mL of filtrate was added to 0.5 mL of water, affording a precipitate. The treatment with piperidine was repeated, and dilution of the filtrate as described above afforded no precipitate. The resin was further washed with DMF (3 x 600 mL) and DCM (3 x 600 mL), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)-1-(9H- fluoren-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oate

[0300] 1-(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecan-12-oic acid (31.80 g, 82.5 mmol, 1.5 equiv.) was dissolved in anhydrous DMF (400 mL). HCTU (34.13 g, 82.5 mmol 1.5 equiv.), HOBt (11.15 g, 82.50 mmol, 1.5 equiv.) and DIPEA (165.0 mmol, 28.7 mL, 3 equiv.) were added and the reaction mixture was stirred at 25 °C for 30 minutes. This reaction mixturewas added to a solution of [(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate (30.64 g, 55.0 mmol,) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours. To monitor the reaction for completion an aliquot of the reaction mixture was filtered and the filter cake was washed with DMF (2 mL*3), DCM (2 mL*3), then dried to give a residue of resin. The resin was suspended in 1 mL of 1%TFA in anhydrous DCM for 1 minute and filtered. The filtrate was diluted in MeOH and monitored by LCMS (MS=648.3), which showed complete consumption of starting resin and one main peak with desired MS. The reaction mixture was filtered and the filter cake was washed with DMF (500 mL*3), DCM (500 mL*3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N2-((benzyloxy)carbonyl)-L-lysinate

[0301] A mixture of [(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)- 1-(9H-fluoren-9-yl)-3,12-di oxo-2, 7, 10-trioxa-4, 13 -diazanonadecan- 19-oate (50.85 g, 55.0 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated at 25 °C for 15 minutes. The reaction mixture was filtered and the filter cake was washed with DMF (300 mL); the filtrate was a light yellow transparent liquid. To test for completion of the Fmoc deprotection, 0.1 mL of filtrate was added to 0.5 mL of water, affording a precipitate. The treatment with piperidine was repeated, and dilution of the filtrate as described above afforded no precipitate. The filter cake was washed with DMF (500 mL*3), DCM (500 mL*3), and then taken forward to the next step. 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15- diazahenicosanedioate

[0302] A mixture of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5- oxopentanoic acid (35.1 g, 82.50 mmol, 1.5 equiv.), HCTU (34.1 g, 82.5 mmol 1.5 equiv.), HOBt (11.2 g, 82.5 mmol, 1.5 equiv.), DIPEA (28.7 mL, 3 equiv.) in DMF (400 mL) was stirred at 25 °C for 30 minutes. The reaction mixture was then added to a slurry of resin [(2- chlorophenyl)diphenylmethyl]-N6-(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N2- ((benzyloxy)carbonyl)-L-lysinate (38.6 g, 55.0 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours. An aliquot of the reaction mixture was filtered and the filter cake was washed with DMF (2 mL*3), DCM (2 mL*3), and then dried to give a residue of resin. The resin was suspended in 1 mL of 1%TFA in DCM for 1 minute and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of starting resin with one main peak with desired MS (m / z = 833.4). The bulk reaction mixture was filtered, and the filter cake was washed with DMF (500 mL x3), DCM (500 mL x 3), and then was taken forward to the next step. 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0303] A slurry of 1 -(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12- dioxa-6,15-diazahenicosanedioate (61.0 g, 55 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated at 25 °C for 15 minutes. The reaction mixture was filtered, and the cake was washed with DMF (300 mL* 1), the filtrate was a light yellow transparent liquid. To test for completion of the Fmoc deprotection, 0.1 mL of filtrate was added to 0.5 mL of water, affording a precipitate. The treatment with piperidine was repeated two additional times, and dilution of the filtrate as described above afforded no precipitate. The bulk resin was washed with DMF (600 mL x3), DCM (600 mL x3), and then taken forward to the next step.23,41-di-tert-butyl 5-[(2-chlorophenyl)diphenylmethyl] (5S,23S)-3,ll,20,25-tetraoxo- l-phenyl-2,13,16-trioxa-4,10,19,24-tetraazahentetracontane-5,23,41-tricarboxylate

[0304] A mixture of 18-(tert-butoxy)-18-oxooctadecanoic acid (30.57 g, 82.5 mmol, 1.5 equiv.), HCTU (34.1 g, 1.5 equiv.), HOBt (11.2 g, 1.5 equiv.), DIPEA (28.7 mL, 3 equiv.) in DMF (400 mL) was stirred at 25 °C for 30 minutes. The reaction mixture was then added to a slurry of 1-(tert-butyl)-21-[(2-chlorophenyl)diphenylmethyl]-(2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate (48.8 g, 55 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours. An aliquot of the reaction mixture was filtered and the filter cake was washed with DMF (2 mL x 3), DCM (2 mL x 3), and then dried to give a residue of resin. The resin was suspended in 1 mL of 1%TFA in DCM for 1 minute and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of starting resin with one main peak with desired MS (m / z = 963.5). The bulk reaction mixture was filtered and the filter cake was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then was taken forward to the next step.(23S,41 S)-41-(((benzyloxy)carbonyl)amino)-23-(tert-butoxycarbonyl)-2,2-dimethyl- 4,21,26,35-tetraoxo-3,30,33-trioxa-22,27,36-triazadotetracontan-42-oic acid

[0305] A mixture of 23,41-di-tert-butyl 5-[(2-chlorophenyl)diphenylmethyl] (5S,23S)- 3,11 ,20,25-tetraoxo- 1 -phenyl-2, 13,16-trioxa-4, 10, 19,24-tetraazahentetracontane-5,23 ,41 - tricarboxylate (68.2 g, 55 mmol) in TFA (5 mL) and DCM (500 mL) was agitated at 15 °C for 10 minutes under N2atmosphere. The reaction mixture was filtered, additional TFA in DCM wasadded to the resin and the cleavage process was repeated three times. The combined filtrates with diluted in in MeOH and monitored by LCMS, which showed complete consumption of starting resin. Sodium bicarbonate (5.67g) in H2O (100 mL) was added, and the aqueous phase was extracted with DCM (100 mL*3). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product (70 g, crude) as a yellow oil.(23S,41S)-41-amino-23-(tert-butoxycarbonyl)-2,2-dimethyl-4,21,26,35-tetraoxo- 3,30,33-trioxa-22,27,36-triazadotetracontan-42-oic acid

[0306] To a solution of (2S)-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4- [(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (40 g, 41.53 mmol) in MeOH (500 mL) was added Pd / C (25 g, 10% w / w) and HCl (0.1 M, 622.9 mL) under N2atmosphere. The suspension was degassed and purged with H2) 3 times. The mixture was stirred under H2(50 Psi) at 30 °C for 2 hours. On completion, the reaction mixture was filtered through a Celite pad, NaHCO3, (5.23 g) was added, and the filtrate was concentrated to afford the crude product (60 g), which was taken forward to the next step without further purification; m / z (ESI, +ve ion) = 829.5 [M+H]+.(23S,41S)-41-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-23-(tert-butoxycarbonyl)-2,2- dimethyl-4,21,26,35-tetraoxo-3,30,33-trioxa-22,27,36-triazadotetracontan-42-oic acid(ACW-15)

[0307] To a solution of (2S)-2-amino-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18- oxo-octadecanoyl)amino]-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (34.43 g, 41.53 mmol) in dioxane (200 mL) and H2O (200 mL) was added Fmoc-OSu (15.41 g, 45.68 mmol) and Na2CO3(40 g, 377.4 mmol) at 5 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion of the reaction, HCl (377.9mL, 1 M) was added, and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (Ethyl acetate : Methanol =1 :0~3: 1) to afford the desired product (26 g, 24.04 mmol, 58% yield, 97.2% purity), m / z (ESI, +ve ion) = 1051.4 [M+H]+.1HNMR (400 MHz, DMSO-d6) δ ppm 8.16 (br d, >7.34 Hz, 1 H) 8.07 - 8.13 (m, 1 H) 7.82 - 7.95 (m, 2 H) 7.58 - 7.78 (m, 3 H) 7.41 (t, J = 7.3 Hz, 2 H) 7.28 - 7.36 (m, 2 H) 7.02 (br s, 1 H) 4.13 - 4.34 (m, 3 H) 4.02 (br d, J = 4.2 Hz, 1 H) 3.84 (s, 2 H) 3.76 (br s, 1 H) 3.53 (br d, J = 1.8 Hz, 4 H) 3.40 (br t, J = 5.9 Hz, 3 H) 3.15 - 3.22 (m, 2 H) 3.01 - 3.12 (m, 2 H) 2.05 - 2.18 (m, 6 H) 1.82 - 1.95 (m, 1 H) 1.64 - 1.82 (m, 2 H) 1.51 - 1.63 (m, 2 H) 1.45 (br d, J = 6.6 Hz, 5 H) 1.38 (d, J = 2.7 Hz, 17 H) 1.26 (br s, 2 H) 1.21 (s, 22 H).Synthesis of ACW-17:

[0308] The synthesis of ACW-17 involved 12 steps as depicted in the following scheme.

[0309] The chemical structure of the target compound was confirmed by test cleavage from resin and analysis by NMR and LC-MS with the purity > 95% (HPLC 220 & 254 nm).Step 1: Preparation of compound ACW-17-1A:

[0310] A slurry of Rink Amide resin (0.35 mmol / g in resin, 14.28 g resin) in piperidine / DMF (20% v / v, 100 mL) and DMF (80 mL) was agitated by bubbling nitrogen for 15 minutes at 20 °C. The resin was filtered and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), then washed with DCM (3 X 2 min). The resin bound Compound ACW-17-1A was taken forward to the next step.Step 2: Preparation of compound ACW-17-2A:

[0311] To a solution of compound ACW-17-1 (4.66 g, 8.0 mmol, 1.6 equiv. relative to the resin bound compound ACW-17-1A) in DMF (60 mL) was added HOBt (1.08 g, 1.6 equiv.), DIEA (3.23 g, 5.0 equiv.), and HCTU (3.31 g, 1.6 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes. The above solution was added to compound ACW-17-1A (1.37 g, 5 mmol). The mixture was agitated under nitrogen for 16.5 hours at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). The resin was suspended in DMF, and Pyridine (395.5 mg, 5.00 mmol) was added, followed by Ac2O (510.5 mg, 5.00 mmol). The reaction mixture was agitated under nitrogen for 0.5 hours at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). The resin tested negative for free amines using the Ninhydrin / Kaiser test. Resin bound Compound ACW-17-2A was taken forward to the next step.Step 3: Preparation of compound ACW-17-2B:

[0312] A slurry of compound ACW-17-2A (5.0 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional Piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-17-2B was taken forward to the next step.Step 4: Preparation of compound ACW-17-3A:

[0313] To a solution of compound ACW-17-2 (4.87 g, 7.5 mmol), and HOBt (1.01 g, 7.5 mmol) in DMF (80 mL) was added DIEA (3.23 g, 25.0 mmol) and HCTU (3.10 g, 7.5 mmol). The reaction mixture was stirred at 25 °C for 20 minutes. The above solution was added to compound ACW-17-2 (3.08 g, 5.0 mmol). The reaction mixture was agitated under nitrogen for 16 hours at 25 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and monitored by LCMS indicating that compound ACW-17- 2 was consumed completely. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) DCM to afford resin bound compound ACW-17-3A, which was taken forward to the next step.Step 5: Preparation of compound ACW-17-3B:

[0314] A slurry of compound ACW-17-3A (5.0 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-17-3B was taken forward to the next step.Step 6: Preparation of compound ACW-17-4A:

[0315] To a solution ofcompound ACW-17-3 (6.11 g, 10.0 mmol), HOBt (1.35 g, 10.0 mmol) and DIEA (3.23 g, 25.0 mmol) in DMF (80 mL) was added HCTU (4.14 g, 10.0 mmol). The reaction mixture was stirred at 25 °C for 30 minutes. The above solution was added to resin bound compound ACW-17-3B (5.12 g, 5.0 mmol). The reaction mixture was agitated under nitrogen for 16.5 hours at 25 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW-17-3B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-17-4A, which was taken forward to the next step.Step 7 : Preparation of compound ACW-17-4B:

[0316] A slurry of compound ACW-17-4A (8.08 g, 5.0 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-17-4B was taken forward to the next step.Step 8 : Preparation of compound ACW-17-5A:

[0317] To a solution of compound ACW-17-4 (4.86 g, 7.5 mmol), HOBt (1.01 g, 7.5 mmol) and DIEA (3.23 g, 25.0 mmol) in DMF (80 mL) was added HCTU (3.10 g, 7.5 mmol). The reaction mixture was stirred at 20 °C for 30 minutes. The above solution was then added to resin bound compound ACW-17-4B (6.97 g, 5.0 mmol). The reaction mixture was agitated under nitrogen for 16.5 hours at 20 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW-17-4B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-17-5A, which was taken forward to the next step.Step 9: Preparation of compound ACW-17-5B:

[0318] A slurry of compound ACW-17--5A (10.12 g, 5.0 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-17-5B was taken forward to the next step.Step 10: Preparation of compound ACW-17-6A:

[0319] To a solution of compound ACW-17-5 (3.97 g, 10.0 mmol), HOBt (1.35 g, 10.O mmol) and DIEA (3.23 g, 25.0 mmol) in DMF (80 mL) was added HCTU (4.13 g, 10.0 mmol). The reaction mixture was stirred at 25 °C for 10 minutes. The above solution was then added to resin bound compound ACW-17-5B (9.01 g, 5.0 mmol). The mixture was agitated under nitrogen for 16 hours at 20 °C. The reaction mixture was agitated under nitrogen for 16 hours at 20 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW- 17-5B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-17-6A, which was taken forward to the next step.Step 11 : Preparation of compound ACW-17-6B:

[0320] A slurry of compound ACW-17-6A (10.91 g, 5.0 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-17-6B was taken forward to the next step.Step 12 : Preparation of compound ACW-17:

[0321] To a solution ofcompound ACW-17-6 (3.53 g, 10.0 mmol), HOBt (1.35 g, 10.O mmol) and DIEA (3.23 g, 25.0 mmol) in DMF (80 mL) was added HCTU (4.14 g, 10.0 mmol). The mixture was stirred at 25 °C for 30 minutes. The above solution was then added to compound ACW-17-6B (9.80 g, 5.0 mmol). The mixture was agitated under nitrogen for 6 hours at 25 °C. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW-17-6B. The resin was filtered and washed with DMF (3 x 2 min), DCM (3 x 2 min) and MeOH (3 x 2 min), then dried to afford resin-bound compound ACW-17 (21.25 g, -3.85 mmol) as a yellow solid.Intermediates ACW-23 P1, P2(Cyclobutylidene(ethoxy)methoxy)trimethylsilane

[0322] To a solution of LDA (2 M, 41 mL, 1.05 equiv.) in THF (100 mL) was added a solution of ethyl cyclobutanecarboxylate (10 g, 78mmol, 10.8 mL) in THF (20 mL) at -70°C. The reaction mixture was stirred for 1 hour while allowing it to warm to 25 °C for 1 hour. The reaction mixture was cooled to -70 °C and a solution of TMSC1 (8.99 g, 10.50 mL, 1.06 equiv.) in THF (20 mL) was added. The reaction mixture was allowed to warm to 25 °C and stirred for 1 hour. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated to afford crude (cyclobutylidene(ethoxy)methoxy)trimethylsilane (16 g) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ 3.82 (q, J = 7.1 Hz, 1H), 3.75 (ddd, J = 2.5, 4.2, 6.5 Hz, 1H), 2.70 (tt, J = 1.5, 7.8 Hz, 1H), 2.61 - 2.52 (m, 2H), 1.96 - 1.83 (m, 3H), 1.29 - 1.18 (m, 3H), 0.22 - 0.04 (m, 9H).Ethyl 1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate

[0323] To a solution of [cyclobutylidene(ethoxy)methoxy]-trimethylsilane (5.54 g, 3.0 equiv. mmol) and tetrahydrofuran-2-yl acetate (1.2 g, 9.22 mmol) in DCM (50 mL) that had been cooled to -65 °C was added TMSOTf (3.28 g, 2.67 mL, 1.6 equiv.). The reaction mixture was allowed to warm to -40°C and stirred for 2 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (30 mL). The phases were separated and the aqueous phase was extracted with DCM (30 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4)and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 95: 5) to afford ethyl 1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate (1.5 g, 82% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 4.25 - 4.08 (m, 3H), 3.96 - 3.74 (m, 2H), 2.43 - 2.25 (m, 3H), 2.12 (ddd, J = 7.0, 9.7, 11.6 Hz, 1H), 1.95 - 1.84 (m, 5H), 1.66 - 1.52 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). 1-(Tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid

[0324] To a solution of ethyl l-tetrahydrofuran-2-ylcyclobutanecarboxylate (2 g, 10.09 mmol) in THF (5 mL), MeOH (5 mL) and H2O (10 mL) was added NaOH (4.04 g, 10.0 equiv.). The reaction mixture was stirred at 45 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The aqueous phase was acidified to pH ~4 with HCl (3 M, ~33 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were concentrated under reduced pressure toafford 1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid (1.7 g, 99% yield) as a colorless oil.NMR (400 MHz, CHLOROFORM-d) δ 4.21 (dd, J = 6.2, 9.3 Hz, 1H), 4.10 - 3.98 (m, 1H), 3.94 - 3.78 (m, 1H), 2.68 - 2.55 (m, 1H), 2.47 - 2.36 (m, 1H), 2.31 - 2.18 (m, 1H), 2.13 - 1.91 (m, 7H), 1.62 - 1.48 (m, 1H).Benzyl 1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate

[0325] To a solution of 1-(tetrahydrofuran-2-yl)cyclobutanecarboxylic acid (1.7 g, 9.99 mmol) in DMF (20 mL) was added BnBr (2.05 g, 1.2 equiv.) and K2CO3(1.66 g, 1.2 equiv.). The reaction mixture was stirred at 25 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with H2O (30 mL) and then extracted with MTBE (30 mL). The organic extract was dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 94: 6) to afford benzyl 1-(tetrahydrofuran-2-yl)cyclobutanecarboxylate (2 g, 77% yield) as colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ 7.41 - 7.29 (m, 3H), 5.24 - 5.12 (m, 2H), 4.19 - 4.09 (m, 1H), 3.91 - 3.74 (m, 2H), 2.49 - 2.27 (m, 3H), 2.20 - 2.09 (m, 1H), 2.00 - 1.77 (m, 5H), 1.65 - 1.45 (m, 2H).Benzyl (S)-1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate or benzyl (R)-1- (tetrahydrofuran-2-yl)cyclobutane-1-carboxylate

[0326] Benzyl l-tetrahydrofuran-2-ylcyclobutanecarboxylate (2 g, 7.68 mmol) was separated by preparative SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 20%, 6 min) to give benzy 1-(S)-1-(tetrahydrofuran -2-yl )cy cl obutane-1- carboxylate or benzy1-(R)-1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate (900 mg, 3.46 mmol, 45% yield) as a colorless oil. RT = 0.977 min, ee: 96.2%.1H NMR (400 MHz, CHLOROFORM-d) δ 7.42 - 7.30 (m, 5H), 5.24 - 5.11 (m, 2H), 4.19 - 4.11 (m, 1H), 3.90 - 3.74 (m, 2H), 2.42 - 2.26 (m, 3H), 2.19 - 2.08 (m, 1H), 1.97 - 1.77 (m, 6H).

[0327] Benzyl l-tetrahydrofuran-2-ylcyclobutanecarboxylate (2 g, 7.68 mmol) was separated by preparative SFC (column: DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm); mobile phase: [Neu-IPA]; B%: 20%, 6 min) to give ACW-23 P1, P2-5_P2 (900 mg, ee: 69.5%). This material was further separated by preparative SFC (column: DAICEL CHIRALPAK IC (250 mmx30 mm, 10μm); mobile phase: [Neu-IPA]; B%: 20%-, 6 min) to afford benzy1-(S)-1-(tetrahydrofuran- 2-yl)cyclobutane-1-carboxylate or benzyl (R)-1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylate (600 mg, 2.30 mmol, 30% yield) as a colorless oil. RT = 1.085 min, ee: 97.3%.1H NMR (400 MHz, CHLOROFORM-d) δ 7.44 - 7.29 (m, 5H), 5.24 - 5.11 (m, 2H), 4.19 - 4.10 (m, 1H), 3.90 - 3.73 (m, 2H), 2.46 - 2.26 (m, 3H), 2.21 - 2.06 (m, 1H), 2.00 - 1.76 (m, 5H), 1.64 - 1.57 (m, 1H).(S)-1-(Tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid or (R)-1- (tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid (ACW-23 P1), first enantiomer

[0328] To a solution of benzyl-1-[(2S)-tetrahydrofuran-2-yl]cy cl obutanecarboxylate (700 mg, 2.69 mmol) in MeOH (10 mL) was added Pd / C (10 wt%, 0.3 g, 0.1 equiv.) under an Ar atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 psi) at 25 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to a residue, which was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to afford (S)-1-(tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid or (R)-1-(tetrahydrofuran-2- yl)cyclobutane-1-carboxylic acid (220 mg, 47% yield) as a colorless oil. m / z (ESI, -ve ion) = 169.1 [M-H]-1H NMR (400 MHz, CHLOROFORM-d) δ 4.21 (dd, J = 62, 9.3 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.93 - 3.83 (m, 1H), 2.68 - 2.56 (m, 1H), 2.47 - 2.37 (m, 1H), 2.31 - 2.19 (m, 1H), 2.13 - 1.92 (m, 6H), 1.60 - 1.50 (m, 1H).(S)-1-(Tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid or (R)-1- (tetrahydrofuran-2-yl)cyclobutane-1-carboxylic acid (ACW-23 P2), second enantiomer

[0329] To a solution of benzyl- l-[(2R)-tetrahy drofuran-2-yl]cy cl obutanecarboxylate (550 mg, 2.11 mmol) in MeOH (10 mL) was added Pd / C (10 wt%, 0.3 g, 0.1 equiv.) under an Ar atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(50 psi) at 25 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to afford a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to (S)-1- (tetrahydrofuran-2-yl)cyclobutane- 1 -carboxylic acid or (R)- 1 -(tetrahydrofuran-2-yl)cyclobutane- 1-carboxylic acid (300 mg, 83% yield) as a colorless oil. m / z (ESI, -ve ion) = 169.1 [M-H]- 1H NMR (400 MHz, CHLOROFORM-d) δ 4.21 (dd, J = 6.3, 9.3 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.92 - 3.83 (m, 1H), 2.67 - 2.55 (m, 1H), 2.46 - 2.35 (m, 1H), 2.30 - 2.18 (m, 1H), 2.13 - 1.91 (m, 6H), 1.62 - 1.49 (m, 1H).Intermediates ACW-24 P1, P2Ethyl 1-(1-methoxyethyl)cyclobutane-1-carboxylate

[0330] To a solution of 1,1 -dimethoxy ethane (5.2 g, 57.70 mmol, 6.1 mL) and [cyclobutylidene(ethoxy)methoxy]trimethylsilane (23.1 g, 2.0 equiv.) in DCM (300 mL) that had been cooled to 0-5 °C was added DMF (9.7 mL, 2.2 equiv.) and BF3.Et2O (40% w / v solution in DCM, 41 g, 2.0 equiv). The reaction mixture was stirred at 0-5 °C for 1 hour, at which point thereaction was deemed complete. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (60 mL) and then extracted with DCM (60 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 0 to 95: 5) to afford ethyl 1-(1 -methoxy ethyl)cy cl obutane-1 -carboxylate (2.37 g, 22% yield) as a yellow oil.NMR (400 MHz, CHLOROFORM-d) δ 4.19 (q, J= 7.2 Hz, 2H), 3.56 (q, J= 6.3 Hz, 1H), 3.38 (s, 3H), 2.42 - 2.32 (m, 1H), 2.30 - 2.21 (m, 2H), 2.13 (ddd, J = 7.0, 9.6, 11.8 Hz, 1H), 1.90 - 1.77 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H). 1-(1-Methoxyethyl)cyclobutane-1-carboxylic acid

[0331] To a solution of ethyl 1-(1-m ethoxy ethyl)cyclobutanecarboxylate (2.6 g, 13.96 mmol) in THF (5 mL), MeOH (5 mL) and H2O (10 mL) was added NaOH (5.58 g, 10.0 equiv.). The reaction mixture was stirred at 45 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was concentrated to remove THF and MeOH. The aqueous phase was acidified to pH ~4 with HCl (3 M, ~47 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were concentrated under reduced pressure to afford crude 1-(1- m ethoxy ethyl)cy cl obutane-1 -carboxylic acid (2.2 g, quantitative yield) as a yellow oil, which was taken forward to the next step without further purification.Benzyl l-(1-methoxyethyl)cyclobutane-1-carboxylate

[0332] To a solution of l-(1-methoxyethyl)cyclobutanecarboxylic acid (2.2 g, 13.91 mmol) in DMF (20 mL) was added K2CO3(2.31 g, 1.2 equiv.) and BnBr (2.85 g, 1.2 equiv.). The reaction mixture was stirred at 25 °C for 16 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with H2O (50 mL) and extracted with MTBE (50 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by column chromatography ( Si O2, Petroleum ether: Ethyl acetate = 1 : 0 to 94: 6) to afford benzyl 1-(1 -methoxy ethyl)cyclobutane-1-carboxylate (3.4 g, 99% yield) as a colorless oil.Benzyl-(S)-1-(1-methoxyethyl)cydobutane-1-carboxylate or benzyl-(R)-1-(1- methoxyethyl)cyclobutane-1-carboxylate

[0333] Benzyl- 1-(1-m ethoxy ethyl)cy cl obutane-1 -carboxylate (3.4 g, 13.69 mmol) was separated by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm×50 mm, 10 μm); mobile phase: [0.1%NH3in H2O / IPA]; B%: 11%, 2.1 min) to afford benzy1-(S)-1-(1- methoxyethyl)cyclobutane- 1 -carboxylate or benzyl-(R)- 1 -(1-m ethoxy ethyl)cyclobutane- 1 - carboxylate (1.5 g, 44% yield) as a yellow oil. RT = 0.69 min, ee: 100%.1H NMR (400 MHz, CHLOROFORM-d) δ 7.41 - 7.29 (m, 5H), 5.31 - 5.05 (m, 2H), 3.58 (q, J = 6.3 Hz, 1H), 3.35 (s, 3H), 2.42 - 2.35 (m, 1H), 2.33 - 2.23 (m, 2H), 2.20 - 2.09 (m, 1H), 1.95 - 1.77 (m, 2H), 1.09 (d, J = 6.3 Hz, 3H).

[0334] Benzyl- 1-(1-m ethoxy ethyl)cy cl obutane-1 -carboxylate (3.4 g, 13.69 mmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm×50 mm, 10 μm); mobile phase: [0.1%NH3inH2O / IPA]; B%: 11%, 2.1 min) to afford benzyl-(S)-1-(1-methoxyethyl)cyclobutane- 1-carboxylate or benzyl-(R)-1-(1-methoxyethyl)cyclobutane-1-carboxylate(1.23 g, 36% yield) as a yellow oil. RT = 0.76 min, ee: 97.4%.1H NMR (400 MHz, CHLOROFORM-d) δ 7.40 - 7.28 (m, 5H), 5.25 - 5.09 (m, 2H), 3.58 (q, J = 6.3 Hz, 1H), 3.35 (s, 3H), 2.46 - 2.34 (m, 1H), 2.34 - 2.23 (m, 2H), 2.21 - 2.08 (m, 1H), 1.97 - 1.76 (m, 2H), 1.09 (d, J = 6.3 Hz, 3H).(S)-1-(1-Methoxyethyl)cyclobutane-1-carboxylic acid or (R)-1-(1- methoxyethyl)cyclobutane-1-carboxylic acid (ACW-24 P1), first enantiomer

[0335] To a solution of benzyl-(S)-1-(l -methoxy ethyl)cy cl obutane-1 -carboxylate or benzyl- (R)-1-(1-m ethoxy ethyl)cy cl obutane-1 -carboxylate (1.4 g, 5.64 mmol) in MeOH (20 mL) was added Pd / C (10 wt%, 1 g, 16 mol%) under an Ar atmosphere. The suspension was degassed and purged with H2three times. The reaction mixture was stirred at 35 °C for 3 hours under H2(15 Psi), at which point the reaction was deemed complete. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to afford (S)-1-(1-methoxyethyl)cyclobutane-1-carboxylic acid or (R)- 1-(1 -methoxy ethyl)cy cl obutane-1-carboxylic acid (0.8 g, 90% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) 53.68 (q, J = 6.3 Hz, 1H), 3.49 (s, 3H), 2.69 - 2.57 (m, 1H), 2.37 - 2.20 (m, 2H), 2.08 - 1.97 (m, 1H), 1.95 - 1.79 (m, 2H), 1.16 (d, J = 6.3 Hz, 3H).(S)-1-(1-Methoxyethyl)cyclobutane-1-carboxylic acid or (R)-1-(1- methoxyethyl)cyclobutane-1-carboxylic acid (ACW-24_P2), second enantiomer

[0336] To a solution of benzyl-(S)-1-(l -methoxy ethyl)cy cl obutane-1 -carboxylate or benzyl- (R)- 1-(1-m ethoxy ethyl)cy cl obutane-1 -carboxylate (1.2 g, 4.83 mmol) in MeOH (20 mL) was added Pd / C (10 wt%, 1 g, 19 mol%) under an Ar atmosphere. The suspension was degassed and purged with H2three times. The reaction mixture was stirred at 35 °C for 3 hours under H2(15 Psi), at which point the reaction was deemed complete. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1: 0 to 0: 1) to afford (S)-1-(1-methoxyethyl)cyclobutane-1-carboxylic acid or (R)- 1-(1 -methoxy ethyl)cy cl obutane-1- carboxylic acid (600 mg, 79% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ3.69 (q, J = 6.3 Hz, 1H), 3.50 (s, 3H), 2.71 - 2.59 (m, 1H), 2.39 - 2.20 (m, 2H), 2.10 - 1.98 (m, 1H), 1.97 - 1.77 (m, 2H), 1.16 (d, J = 6.3 Hz, 3H).Synthesis of ACW-40:

[0337] The synthesis of ACW-40 involved 12 steps as depicted in the following scheme.

[0338] The chemical structure of the target compound was confirmed by NMR and LC-MS with the purity > 95% (HPLC 220 & 254 nm).Step 1: Preparation of compound ACW-40-1A.

[0339] A slurry of Rink Amide resin (0.35 mmol / g in resin, 14.29 g resin) in piperidine (20 mL) and DMF (80 mL) was agitated by bubbling nitrogen for 15 min at 20 °C. The resin was filtered and additional piperidine (20 mL) and DMF (80 mL) was added. The mixture was agitated with nitrogen for 15 min at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), then washed with DCM (3 X 2 min). The resin bound Compound ACW-40-1A was taken forward to the next step.Step 2: Preparation of compound ACW-40-2A.

[0340] To a solution of compound ACW-40-1 (5.83 g, 10.00 mmol) in DMF (80 mL) was added HOBt (1.35 g, 10.00 mmol), DIEA (3.23 g, 25.00 mmol), and HCTU (4.14 g, 10.00 mmol). The mixture was stirred at 20 °C for 10 min. The mixture was added to compound ACW-40-1A (1.37 g, 5 mmol). The mixture was agitated under nitrogen for 16 h at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). The resin was suspended in DMF, and Pyridine (395.5 mg, 5.00 mmol) was added, followed by Ac2O (510.5 mg, 5.00 mmol). The reaction mixture was agitated under nitrogen for 0.5 hours at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). The resin tested negative for free amines using the Ninhydrin / Kaiser test. Resin bound Compound ACW-40-2A was taken forward to the next step.Step 3 : Preparation of compound ACW-40-2B.

[0341] A slurry of compound ACW-40-2A (4.19 g, 5.00 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 min at 20 °C. The resin was filtered and additional Piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-40-2B was taken forward to the next step.Step 4: Preparation of compound ACW-40-3A.

[0342] To a solution of compound ACW-40-2 (6.63 g, 10.00 mmol), and HOBt (1.35 g, 10.00 mmol) in DMF (80 mL) was added DIEA (3.23 g, 25.01 mmol) and HCTU (4.14 g, 10.00 mmol). The mixture was stirred at 20 °C for 30 min. The above solution was added to compound ACW-40-2B (3.08 g, 5.0 mmol). The reaction mixture was agitated under nitrogen for 16.5 hours at 25 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and monitored by LCMS indicating that compound ACW-40-2B was consumed completely. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) DCM to afford resin bound compound ACW-40-3A, which was taken forward to the next step.Step 5: Preparation of compound ACW-40-3B.

[0343] A slurry of compound ACW-40-3A (6.30 g, 5.00 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-40-3B was taken forward to the next step.Step 6: Preparation of compound ACW-40-4A

[0344] To a solution of compound ACW-40-3 (6.11 g, 10.00 mmol) in DMF (80 mL) was added HOBt (1.35 g, 10.00 mmol), DIEA (3.23 g, 24.99 mmol) and HCTU (4.14 g, 10.00 mmol). The mixture was stirred at 20 °C for 30 min. The above solution was added to resin bound compound ACW-40-3B (5.19 g, 5.00 mmol). The reaction mixture was agitated under nitrogen for 16 hours at 25 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed completeconsumption of compound ACW-40-3B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-40-4A, which was taken forward to the next step.Step 7 : Preparation of compound ACW-40-4B

[0345] A slurry of compound ACW-40-4A (8.15 g, 5.00 mmol) in DMF (80 mL) and piperidine (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-40-4B was taken forward to the next step.Step 8 : Preparation of compound ACW-40-5A

[0346] To a solution of compound ACW-40-4 (6.48 g, 9.99 mmol) in DMF (80 mL) was added HOBt (1.35 g, 9.99 mmol), DIEA (3.23 g, 24.99 mmol) and HCTU (4.13 g, 9.99 mmol).The mixture was stirred at 20 °C for 30 min. The mixture was added to compound ACW-40-4B (7.04 g, 5.00 mmol). The above solution was then added to resin bound compound ACW-40-4B (6.97 g, 5.0 mmol). The reaction mixture was agitated under nitrogen for 16 hours at 20 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW- 40-4B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-40-5A, which was taken forward to the next step.Step 9 : Preparation of compound ACW-40-5B

[0347] A slurry of compound ACW-40-5A (10.19 g, 5.00 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered the resin and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-40-5B was taken forward to the next step.Step 10 : Preparation of compound ACW-40-6A

[0348] To a solution of compound ACW-40-5 (3.97 g, 9.99 mmol) in DMF (80 mL) was added HOBt (1.35 g, 9.99 mmol), DIEA (3.23 g, 24.98 mmol) and HCTU (4.13 g, 9.99 mmol). The mixture was stirred at 20 °C for 30 min. The above solution was then added to resin bound compound ACW-40-5B (9.08 g, 5.00 mmol). The reaction mixture was agitated under nitrogen for 16 hours at 20 °C. The resin was suspended in 0.5 mL of 30% TFA in dry DCM for 20 minutes and filtered. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW-40-5B. The resin was filtered and washed with DMF (3 x 2 min) and DCM (3 x 2 min) to afford resin bound compound ACW-40-6A, which was taken forward to the next step.Step 11 : Preparation of compound ACW-40-6B

[0349] A slurry of compound ACW-40-6A (10.98 g, 5.00 mmol) in piperidine (20 mL) and DMF (80 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered and additional piperidine (20 mL) and DMF (80 mL) was added. The reaction mixture was agitatedwith nitrogen for 15 minutes at 20 °C. The resin was filtered and washed with DMF (3 x 2 min), and DCM (3 x 2 min). Resin bound compound ACW-40-6B was taken forward to the next step.Step 12 : Preparation of compound ACW-40

[0350] To a solution of compound ACW-40-6 (3.53 g, 10.00 mmol) in DMF (80 mL) was added HOBt (1.35 g, 10.00 mmol), DIEA (3.23 g, 24.99 mmol) and HCTU (4.14 g, 10.00 mmol). The mixture was stirred at 20 °C for 30 min. The above solution was then added to compound ACW-40-6B (9.87 g, 5.00 mmol). The mixture was agitated under nitrogen for 6 hours at 25 °C. The filtrate was diluted in MeOH and analysis by LCMS showed complete consumption of compound ACW-40-6B. The resin was filtered and washed with DMF (3 x 2 min), DCM (3 x 2 min) and MeOH (3 x 2 min), then dried to afford resin-bound compound ACW-40 (23.82 g, -5.29 mmol) as a yellow solid.Intermediate ACW-41Methyl 17-bromoheptadecanoate

[0351] To a solution of 17-bromoheptadecanoic acid (9.5 g, 27.2 mmol) in DCM (100 mL) and DMF (19.9 mg) was added (COCl)2(3.45 g, 1.0 equiv.) at 15 °C under N2. The reaction mixture was stirred at 15 °C for 1.5 hours, then concentrated under reduced pressure at 40 °C to remove DCM and (COCl)2. The reaction mixture was redissolved in DCM (100 mL), pre-cooled to 0-5 °C and MeOH (0.87 g, 1.0 equiv.) was added. The reaction mixture was allowed to warm to 15 °C and stirred for 2 hours. After completion, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (100 mL) and then extracted with DCM (100 mL x 2). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered andconcentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 10: 1) to afford methyl 17-bromoheptadecanoate (7 g, 71% yield) as a white solid. Tf NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 3.42 (t, J = 6.8 Hz, 2H), 2.31 (t, J= 7.5 Hz, 2H), 1.86 (quin, J= 7.1 Hz, 2H), 1.66 - 1.58 (m, 2H), 1.46 - 1.39 (m, 2H), 1.32 - 1.25 (m, 22H).Methyl 17-(di-tert-butoxyphosphoryl)heptadecanoate

[0352] To a solution of methyl 17-bromoheptadecanoate (7.16 g, 2.0 equiv) in DMF (60 mL) was added NaH (1.47 g, 2.0 equiv, 60% w / w dispersion) after cooling to 0-5 °C. The reaction mixture was stirred at 0-5 °C for 0.5 hours, then methyl 17-bromoheptadecanoate (6.7 g, 18.44 mmol) in DMF (60 mL) was added. The reaction mixture was stirred at 20 °C for 15.5 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (500 mL) and then extracted with EtOAc (500 mL x 3). The combined organic extracts were washed with brine (30 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1) to give methyl 17-(di-tert-butoxyphosphoryl)heptadecanoate (8 g, 91% yield) as a colourless oil.1H NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 2.31 (t, J = 7.5 Hz, 2H), 1.68 - 1.56 (m, 6H), 1.50 (s, 19H), 1.26 (s, 23H).17-(di-tert-butoxyphosphoryl)heptadecanoic acid

[0353] To a solution of methyl 17-(di-tert-butoxyphosphoryl)heptadecanoate (8 g, 16.78 mmol) in THF (40 mL) and H2O (40 mL) was added LiOH.H2O (1.41 g, 33.57 mmol). The mixture was stirred at 20 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure to remove THF. The pH of the reaction mixture was adjusted to6 with HCl (1 M) and the aqueous phase was extracted with EtOAc (80 mL x 3). The combined organic extracts were concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1) to afford 17-(di-tert- butoxyphosphoryl)heptadecanoic acid (6.2 g, 80% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 2.34 (t, J = 7.5 Hz, 2H), 1.70 - 1.59 (m, 4H), 1.50 (s, 18H), 1.41 - 1.21 (m, 26H).[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylaniino)-6-(9H-fluoren- 9-ylmethoxycarbonylamino)hexanoate

[0354] To a slurry of chlorotrityl resin (1 mmol / g in resin, 6 g resin) in DCM (50 mL) was added DIPEA (10.4 mL, 10 equiv.) and N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysine (6.03 g, 2.0 equiv.). The reaction mixture was agitated by bubbling nitrogen for 16 hours at 20 °C. The resin was filtered and washed with MeOH (50 mL x 3), DMF (50 mL x 3) and DCM (50 mL x 3), and the resin was taken forward to next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-6-amino-2-(benzyloxycarbonylamino)hexanoate

[0355] A mixture of [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- (9H-fluoren-9-ylmethoxycarbonylamino)hexanoate (4.68 g, 6.01 mmol) in DMF (40 mL) and piperidine (10 mL) was agitated under nitrogen for 15 minutes at 20 °C. The resin was filtered and additional piperidine (10 mL) and DMF (40 mL) was added and the process was repeated. The resin was filtered, washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2*S)-2-(benzyloxycarbonylamino)-6- [ [2- [2- [2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetyl]amino]hexanoate

[0356] To a slurry of 1-(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecan-12-oic acid (4.64 g, 2.0 equiv.) in DMF (50 mL) was added HOBt (1.63 g, 2.0 equiv.), DIPEA (3.89 g, 5.0 equiv.) and HCTU (4.98 g, 2.0 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes, then added to [(2-chlorophenyl)-diphenylmethyl]-(2S)-6-amino-2-(benzyloxycarbonylamino)hexanoate (3.35 g, 6.01 mmol). The reaction mixture was agitated under nitrogen for 15.5 hours at 20 °C. At this point, test cleavage and LC-MS analysis of the cleaved product indicated that starting resin was completely consumed. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-6-[[2-[2-(2- aminoethoxy)ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoate

[0357] [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[2-[2-[2- (9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetyl]amino]hexanoate (5.56 g, 6.01 mmol) was suspended in piperidine (10 mL) and DMF (40 mL) was agitated for 15 minutes at 20 °C. The resin was filtered and the treatment with piperidine in DMF was repeated. The resin was filtered and washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [ [2- [2- [2- [[(4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo- pentanoyl] amino] ethoxy] ethoxy] acetyl] amino] hexanoate

[0358] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (5.11 g, 2.0 equiv.) in DMF (50 mL) was added HOBt (1.62 g, 2.0 equiv.), DIPEA (5.3 mL, 5.0 equiv.) and HCTU (4.96 g, 2.0 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes, then added to resin [(2-chlorophenyl)-diphenylmethyl] (2S)-6-[[2-[2-(2- aminoethoxy)ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoate (4.21 g, 6 mmol). The reaction mixture was agitated with nitrogen for 16 hours at 20 °C, whereupon test cleavage of the resin and analysis by LC-MS indicated complete consumption of starting resin. The reactionmixture was filtered and the resin was washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-6-[[2-[2-[2-[[(4S)-4-amino-5-tert-butoxy-5- oxo-pentanoyl] amino] ethoxy] ethoxy] acetyl] amino]-2-(benzyloxycarbonylamino)hexanoate

[0359] [(2-chlorophenyl)-diphenylmethyl](2S)-2-(benzyloxycarbonylamino)-6-[[2-[2-[2- [[(4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoate (6.66 g, 6.00 mmol) was suspended in piperidine (20 mL) and DMF (80 mL) and the reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and the treatment with piperidine in DMF was repeated. The resin was washed with DMF (100 mL x 3), DCM (100 mL x 3), and taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [ [2- [2- [2-[[(4S)-5-tert-butoxy-4-(17-ditert butoxyphosphorylheptadecanoylamino)-5-oxo- pentanoyl] amino] ethoxy] ethoxy] acetyl] amino] hexanoate

[0360] To a solution of 17-(di-tert-butoxyphosphoryl)heptadecanoic acid (4.16 g, 1.5 equiv.) in DMF (50 mL) was added HOBt (1.22 g, 1.5 equiv.), DIPEA (3.1 mL, 3.0 equiv.) and HCTU (3.72 g, 1.5 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes and then added to [(2- chlorophenyl)-diphenylmethyl]-(2S)-6-[[2-[2-[2-[[(4S)-4-amino-5-tert-butoxy-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoate (5.33 g, 6mmol). The reaction mixture was agitated with nitrogen for 16 hours at 20 °C, whereupon test cleavage of the resin and analysis by LC-MS indicated complete consumption of starting resin. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.(2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-38-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid

[0361] [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[2-[2-[2- [[(4S)-5-tert-butoxy-4-(17-di-tert-butoxyphosphorylheptadecanoylamino)-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoate (7.99 g, 6.00 mmol) in DCM (50 mL) and TFA (0.5 mL) was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and the treatment with TFA in DCM was repeated. The resin was then filtered and washed with DCM. (3x). The filtrate and washes were combined and diluted with water (50 mL). Saturated aqueousNaHCO3was added to neutralize TFA, and then the pH was adjusted to 5 with aqueous HCl (1 M). The organic phase was separated, washed with H2O (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S,2QS)-2- (((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-38-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid (6.3 g, 5,97 mmol, >99% yield) as a yellow oil. m / z (ESI, +ve ion) = 1055.7 [M+H]+.(2S, 20S)-2-amino-20-(tert-butoxycarbonyl)-38-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid

[0362] To a solution of (2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 38-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid (5.3 g, 5.02 mmol) in MeOH (53 mL) and HCl (0.1 M, 75.3 mL) was added Pd / C (5 g, 10 wt%) under an N2atmosphere. The suspension was degassed and purged with H2(50 psi)3 times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. On completion, the reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (7.5 mL) and H2O (50 mL). The filtrate and washes were combined, and the pH was adjusted to 7 with NaHCO3(1.5 equiv., 633 mg). The filtrate was concentrated under reduced pressure to afford crude (2S,20S)-2-amino-20-(tert-butoxycarbonyl)-38-(di-tert-butoxyphosphoryl)-8,17,22-trioxo- 10,13-dioxa-7,16,21-triazaoctatriacontanoic acid (4.63 g) as a yellow oil. The crude product was used in the next step without further purification, m / z (ESI, +ve ion) = 921.6 [M+H]+.(2S,20S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 38-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid

[0363] To a solution of (2S,20S)-2-amino-20-(tert-butoxycarbonyl)-38-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid (4.63 g, 5.03 mmol) in dioxane (25 mL) and H2O (25 mL) was added NaHCO3(4.22 g, 10.0 equiv.) and FMOC- OSU (1.86 g, 1.1 equiv.). The reaction mixture was stirred at 20 °C for 16 hours. On completion, the reaction mixture was adjusted to pH ~5 with HCl (1 M, 70 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue afforded was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate=l : 1 to 0: 1, to Ethyl acetate: Methanol = 10: 1) to give ACW-41 (2S,20S)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-38-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctatriacontanoic acid (4.24 g,72% yield, 98.2% purity) as a white solid, m / z (ESI, +ve ion) = 488.4 [1 / 2M+H]+.1H NMR (400 MHz, DM SO-d6) δ 12.69 - 12.40 (m, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.89 (br d, J = 7.5 Hz, 3H), 7.76 - 7.66 (m, 3H), 7.60 (br d, J = 7.7 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.36 - 7.28 (m, 2H), 4.31 - 4.18 (m, 3H), 4.09 - 3.99 (m, 1H), 3.92 - 3.92 (m, 1H), 3.92 - 3.87 (m, 1H), 3.85 (s, 2H), 3.60 - 3.49 (m, 4H), 3.43 - 3.37 (m, 2H), 3.32 - 3.28 (m, 2H), 3.23 - 3.15 (m, 2H), 3.09 (q, J = 6.6 Hz, 2H), 2.17 - 2.04 (m, 4H), 1.94 - 1.83 (m, 1H), 1.78 - 1.66 (m, 2H), 1.63 - 1.36 (m, 34H), 1.31 (br d, J = 6.7 Hz, 4H), 1.22 (s, 21H).Intermediate ACW-42[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoate

[0364] To a slurry of Cl-Trt Resin (1 mmol / g in resin, 6 g resin) in DCM (50 mL) was added DIPEA (7.75 g, 60.00 mmol) and N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysine (6.03 g, 12.00 mmol). The reaction mixture was agitated by bubbling nitrogen for 16 hours at 20 °C. The resin was filtered and washed with MeOH (50 mL x 3), DMF (50 mL x 3) and DCM (50 mL x 3) and taken forward to the next step, m / z (ESI, +ve ion) = 525.2 [M+H]+.[(2-chlorophenyl)-diphenylmethyl] (2S)-6-amino-2- (benzyloxycarbonylamino)hexanoate

[0365] A slurry of [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- (9H-fluoren-9-ylmethoxycarbonylamino)hexanoate (4.68 g, 6.01 mmol) in DMF (40 mL) and piperidine (10 mL) was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and the deprotection procedure was repeated. The resin was filtered, washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [ [ ( 2S)-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl] amino] hexanoate

[0366] To a solution of N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(tert-butoxycarbonyl)- L-lysine (5.64 g, 12.03 mmol) in DMF (50 mL) was added HOBt (1.63 g, 12.03 mmol), DIPEA (3.89 g, 30.07 mmol) and HCTU (4.98 g, 12.03 mmol). The reaction mixture was stirred at 20 °C for 30 minutes. The above solution was added to [(2-chlorophenyl)-diphenylmethyl] (2S)-6- amino-2-(benzyloxycarbonylamino)hexanoate (3.35 g, 6.01 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C and filtered. Test cleavage of an aliquot of the resin with 1 mL of 1%TFA in DCM for 1 minute, followed by dilution of the cleavage solution with MeOH and LCMS analysis showed that the starting resin was consumed completely. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-6-[[(2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (ACW-42-2B)

[0367] [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2- (tert-butoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl]amino]hexanoate (6.05 g, 6 mmol) was treated with 20% v / v piperidine in DMF (100 mL) with agitation for 15 minutes at 20 °C. The resin was filtered and the deprotection process was repeated. The resin was filtered, washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [ [ ( 2S)-2-(tert-butoxycarbonylamino)-6-[ [(4S)-5-tert-butoxy-4-(9H-fluoren-9- ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate

[0368] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (5.10 g, 11.99 mmol) in DMF (50 mL) was added HOBt (1.62 g, 11.99 mmol), DIPEA (3.88 g, 29.99 mmol) and HCTU (4.96 g, 11.99 mmol). The reaction mixture was stirred at 20 °C for 30 minutes, then added to [(2-chlorophenyl)diphenylmethyl] (2S)-6-[[(2S)-6-amino- 2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (4.71 g, 6.00 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C. At this time, test cleavage of the resin and analysis by LCMS showed reactant was consumed completely. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step. [(2-chlorophenyl)-diphenylmethyl]-(2S)-6-[ [(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5- oxo-pentanoyl] amino] -2-(tert-butoxycarbonylamino)hexanoyl] amino] -2- (benzyloxycarbonylamino)hexanoate

[0369] A slurry of [(2-chlorophenyl)-diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert-butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(9H-fluoren-9- ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate (7.15 g, 6.00 mmol) in 20% v / v piperidine in DMF (100 mL) was agitated for 15 minutes at 20 °C. The resinwas filtered and the deprotection process was repeated. The resin was filtered, washed with DMF (100 mL x 3), DCM (100 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert- butoxycarbonylami no)-6-[[(4S)-5-tert-butoxy-4-(17-di-tert- butoxyphosphorylheptadecanoylamino)-5-oxo- pentanoyl] amino] hexanoyl] amino] hexanoate

[0370] To a solution of 17-(di-tert-butoxyphosphoryl)heptadecanoic acid (4.16 g, 8.99 mmol) in DMF (80 mL) was added HOBt (1.22 g, 8.99 mmol), DIPEA (3.87 g, 29.98 mmol) and HCTU (3.72 g, 8.99 mmol). The reaction mixture was stirred at 15 °C for 30 minutes. The above solution was added to [(2-chlorophenyl)-diphenylmethyl] (2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5- oxo-pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (5.82 g, 6.00 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 15 °C. Test cleavage of a resin aliquot and analysis by LCMS at this time showed that unreacted starting resin remained. The resin was filtered. To additional 17-(di- tert-butoxyphosphoryl)heptadecanoic acid (1.39 g, 3.00 mmol) in DMF (80 mL) was added HOBt (405.1 mg, 3.00 mmol), DIPEA (1.55 g, 11.99 mmol) and HCTU (1.24 g, 3.00 mmol). The reaction mixture was stirred at 15 °C for 30 minutes, and added to starting resin (5.82 g, 6.00 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 15 °C. Test cleavage of an aliquot of resin showed that reactant was consumed completely. The reaction mixture was filtered and the resin was washed with (DMF 50 mL x 3), DCM (50 mL x 3), and then taken forward to the next step.N2-(( benzyloxy )carbonyl)-N6-(N6-((S)-5-(tert-b utoxy )-4-( 17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L-lysine

[0371] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [[(2S)-2-(tert-butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(17-di-tert- butoxyphosphorylheptadecanoylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate(8.49 g, 6.00 mmol) in DCM (100 mL) and TFA (1 mL) was agitated with nitrogen for 15 minutes at 20 °C to cleave the resin-bound compound. The resin was filtered and the cleavage process was repeated two more times. The resin was filtered and washed 3 times with DCM. The filtrates and washes were combined and neutralized with aqueous NaHCO3. The pH of the mixture was then adjusted to pH 5 with HCl (1 M). The organic phase was separated, washed with H2O (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford N2- ((benzyloxy)carbonyl)-N6-(N6-((S)-5-(tert-butoxy)-4-(17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (11 g, crude) as a yellow oil. m / z (ESI, +ve ion) = 1055.7 [M+H]+. N6-(N6-((S)-5-(tert-butoxy)-4-( 17-(di-tert-butoxyphosphoryl)heptadecanamido)-5- oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L-lysine

[0372] To a solution of N2-((benzyloxy)carbonyl)-N6-(N6-((S)-5-(tert-butoxy)-4-(17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (9 g, 7.91 mmol) in MeOH (90 mL) and HCI (0.1 M, 118.58 mL) was added Pd / C (4.5 g, 4.23 mmol, 10 wt%) under Ar atmosphere. The suspension was degassed and purged with H2two times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. After completion, the reaction mixture was filtered through a Celite pad and the filter cake was washed with MeOH (50 mL x 10) and H2O (50 mL x 3). The filtrate was adjusted to pH 7 with NaHCO3(1.5 equiv, 1 g), and concentrated under reduced pressure to afford N6-(N6-((S)-5-(tert-butoxy)-4-(17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (7.94 g, 7.91 mmol) as a colorless oil. The crude product was used in the next step without purification, m / z (ESI, +ve ion) = 1004.8 [M+H]+. N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(N6-((S)-5-(tert-butoxy)-4-(l 7-(di-tert- butoxyphosphoryl)heptadecanainido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)- L-lysine(ACW-42)

[0373] To a solution of N6-(N6-((S)-5-(tert-butoxy)-4-(17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (7.94 g, 7.91 mmol) in dioxane (40 mL) and H2O (40 mL) was added NaHCO3(6.64 g, 79.1 mmol) and FMOC-OSU (2.93 g, 8.7 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The pH of the reaction mixture was then adjusted to pH ~5 with HCl (1 M, 70 mL) and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1 : 1 to 0: 1, to Ethyl acetate: Methanol = 10: 1) to give a crude product, which was further purified by prep-HPLC (column: Welch Ultimate C18 250 x 70mm x 10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:50%-80% B over 20.0 minutes) to give ACW-42 N2-(((OH-fluoren-O- yl)methoxy)carbonyl)-N6-(N6-((S)-5-(tert-butoxy)-4-(17-(di-tert- butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (4.5 g) as a white solid, m / z (ESI, +ve ion) = 1226.5 [M+H]+.1H NMR (400 MHz, DMSO- d6) 6 8.12 (br d, J = 7.2 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.89 (d, 7.6 Hz, 2H), 7.77 (br t, J = 5.1Hz, 1H), 7.71 (br d, J = 7.3 Hz, 2H), 7.44 - 7.38 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.17 (m, 1H), 6.70 (br d, J = 7.9 Hz, 1H), 4.30 - 4.17 (m, 3H), 4.07 - 3.95 (m, 1H), 3.81 (quin, J = 6.8 Hz, 2H), 3.12 - 2.91 (m, 4H), 2.15 - 2.03 (m, 4H), 1.94 - 1.82 (m, 1H), 1.80 - 1.64 (m, 2H), 1.54 (br dd, J = 5.6, 9.0 Hz, 3H), 1.51 - 1.42 (m, 6H), 1.40 (s, 18H), 1.39 - 1.26 (m, 26H), 1.21 (br s, 24H).Intermediate ACW-43Methyl 19-bromononadecanoate

[0374] To a solution of 19-bromononadecanoic acid (15 g, 39.75 mmol) in DCM (250 mL) and DMF (31 μL) was added (COCl)2(3.5 mL, 1.0 equiv.) at 15 °C. The reaction mixture was stirred at 15 °C for 1.5 hours, then concentrated under reduced pressure at 40 °C to remove DCM and (COCl)2. The residue was redissolved in DCM (250 mL), cooled to 0-5 °C and MeOH (1.93 mL, 1.2 equiv.) was added. The reaction mixture was stirred at 15 °C for 2 hours. After completion, the reaction mixture was quenched by addition of saturated aqueous NaHCO3(500 mL) and then extracted with EtOAc (500 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford methyl 19-bromononadecanoate (23 g) as white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 3.67 (s, 3H), 3.42 (t, J= 6.9 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.86 (quin, J = 7.2 Hz, 2H), 1.68 - 1.59 (m, 2H), 1.50 - 1.38 (m, 2H), 1.34 - 1.22 (m, 27H).Methyl 19-( di-tert-but oxy phosphoryl (nonadecanoate

[0375] To a solution of methyl 19-bromononadecanoate (15.56 g, 39.75 mmol) in DMF (500 mL) that had been cooled to 0-5 °C was added NaH (3.18 g, 2.0 equiv., 60 wt%). After 30 minutes 2-tert-butoxyphosphonoyloxy-2-methylpropane (15.44 g, 79.50 mmol) was added. The mixture was allowed to warm to 20 °C and stirred for 16 hours. After completion, the reaction was quenched with saturated aqueous NH4CI solution (500 mL), and the aqueous phase was extracted with EtOAc (500 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the crude methyl 19-(di-tert-butoxyphosphoryl)nonadecanoate(18.43 g) as white solid.1HNMR (400 MHz, CHLOROFORM-d) δ = 3.67 (s, 3H), 2.31 (t, J= 7.6 Hz, 2H), 1.68 - 1.57 (m, 6H), 1.50 (s, 18H), 1.32 - 1.24 (m, 28H).19-(di-tert-butoxyphosphoryl)nonadecanoic acid

[0376] To a solution of methyl 19-di-tert-butoxyphosphorylnonadecanoate (18.43 g, 36.52 mmol) in THF (150 mL) and H2O (150 mL) was added LiOH.H2O (3.10 g, 2.0 equiv.). The reaction mixture was stirred at 20 °C for 16 hours. After completion, HCl (1M, 73.8 mL) was added. The reaction was quenched by H2O (100 mL) and then extracted with EtOAc (200 mL x 2). The combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to a residue, which was purified by silica gel chromatography to afford 19-(di-tert- butoxyphosphoryl)nonadecanoic acid (18.42 g) as white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 2.34 (t, J = 7.5 Hz, 2H), 1.70 - 1.60 (m, 4H), 1.59 - 1.54 (m, 1H), 1.50 (s, 18H), 1.39 - 1.23 (m, 29H).[(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysinate

[0377] To a slurry of Cl-Trt Resin (1 mmol / g in resin, 30 g resin) and DIPEA (52.3 mL, 10.0 equiv.) in DCM (600 mL) was added a solution of N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysine (22.62 g, 1.5 equiv.) in DCM (500 mL) at 15 °C, and then the reaction mixture was agitated at 15 °C for 16 hours. After completion, the reaction mixture was filtered and the resin was washed with MeOH (400 mL x 3), DMF (400 mL x 3), DCM (400 mL x 3), and then taken to the next step.[(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate

[0378] A slurry of [(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9- yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysinate (23.38 g, 30 mmol) in piperidine (30 mL) and DMF (120 mL) was agitated at 25 °C for 15 minutes and the reaction mixture was filtered. This procedure was repeated two more times to ensure complete Fmoc removal. The resin was washed with DMF (400 mL x 3), DCM (400 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)-1-(9H- fluoren-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oate

[0379] To a solution of 1-(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecan-12-oic acid(17.34 g, 1.5 equiv.) in DMF (100 mL) was added HOBt (6.08 g, 1.5 equiv.), HCTU (18.62 g, 1.5 equiv.) and DIPEA (15.7 mL, 3.0 equiv.). The reaction mixture was stirred at 25 °C for 30 minutes and then added to a solution of [(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L- lysinate (16.71 g, 30 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage and analysis by LCMS. showed that reactant [(2- chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate was consumed completely. The reaction mixture was filtered, and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N2- ((benzyloxy)carbonyl)-L-lysinate

[0380] A slurry of [(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)- 1 -(9H-fluoren-9-yl)-3, 12-di oxo-2, 7, 10-trioxa-4, 13 -diazanonadecan- 19-oate (27.73 g, 30 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated at 25 °C for 15 minutes and the reaction mixture was filtered. This procedure was repeated two more times to ensure complete Fmoc removal. The resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-27-(((benzyloxy)carbonyl)amino)-1-(9H- fluoren-9-yl)-3,12,21-trioxo-2,7,10,16,19-pentaoxa-4,13,22-triazaoctacosan-28-oate

[0381] To a solution of 1-(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecan-12-oic acid(28.91 g, 2.5 equiv.) in DMF (400 mL) was added HCTU (31.03 g, 2.5 equiv.), HOBt (10.13 g, 2.5 equiv.), DIPEA (31.4 mL, 6.0 equiv.) The reaction mixture was stirred at 25 °C for 30 minutes, and then added to a slurry of [(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2- aminoethoxy)ethoxy)acetyl)-N2-((benzyloxy)carbonyl)-L-lysinate (21.07 g, 30 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 3 hours, at which point test cleavage indicated that reactant [(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2- aminoethoxy)ethoxy)acetyl)-N2-((benzyloxy)carbonyl)-L-lysinate was consumed completely. Thereaction mixture was filtered, and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-1-amino-23-(((benzyloxy)carbonyl)amino)- 8,17-dioxo-3,6,12,15-tetraoxa-9,18-diazatetracosan-24-oate

[0382] A slurry of [(2-chlorophenyl)diphenylmethyl] (S)-27-(((benzyloxy)carbonyl)amino)- 1-(9H-fluoren-9-yl)-3,12,21-trioxo-2,7,10,16,19-pentaoxa-4,13,22-triazaoctacosan-28-oate (32.1 g, 30 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated at 25 °C for 15 minutes and the resin was filtered. This procedure was repeated two more times to ensure complete Fmoc removal. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step. l-(tert-butyl)-3()-[(2-chloi ophenyl)diphenylmethyl]-(2S,29S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-29-(((benzyloxy)carbonyl)amino)-5, 14, 23-trioxo-9, 12,18,21- tetraoxa-6, 15,24-triazatriacontanedioate

[0383] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (31.91 g, 1.5 equiv.) in DMF (400 mL) was added HCTU (31.03 g, 1.5equiv.), HOBt (10.13 g, 1.5 equiv.), DIPEA (26.1 mL, 3.0 equiv.)The reaction mixture was stirred at 25 °C for 30 minutes and then added to a slurry of [(2-chlorophenyl)diphenylmethyl] (S)-1- amino-23-(((benzyloxy)carbonyl)amino)-8, 17-dioxo-3,6, 12, 15-tetraoxa-9, 18-diazatetracosan-24- oate (25.4 g, 30 mmol) in DMF (400 mL). The reaction mixture was agitated at 25 °C for 2 hours at which point test cleavage indicated that reactant [(2-chlorophenyl)diphenylmethyl] (S)-1- amino-23-(((benzyloxy)carbonyl)amino)-8, 17-dioxo-3,6, 12, 15-tetraoxa-9, 18-diazatetracosan-24- oate was consumed completely. The reaction mixture was filtered, and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step. l-(tert-butyl)-30-[(2-chlorophenyl)diphenylmethyl]-(2S,29S )-2-amino-29- (((benzyloxy)carbonyl)amino)-5, 14, 23-trioxo-9, 12,18, 21-tetraoxa-6, 15,24- triazatriacontanedioate

[0384] A slurry of 1-(tert-butyl)-30-[(2-chlorophenyl)diphenylmethyl]-(2S,29S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-29-(((benzyloxy)carbonyl)amino)-5,14,23-trioxo- 9,12,18,21-tetraoxa-6,15,24-triazatriacontanedioate (18.82 g, 15 mmol) in piperidine (30 mL) and DMF (120 mL) was agitated at 25 °C for 15 minutes and the resin was filtered. This procedure was repeated two more times to ensure complete Fmoc removal. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step. 1-(tert-butyl) 30-[(2-chlorophenyl)diphenylmethyl] (2S,29S)-29-(((benzyloxy)carbonyl)amino)-2-(19-(di-tert-butoxyphosphoryl)nonadecanamido)-5,14,23- trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontanedioate

[0385] To a solution of 19-(di-tert-butoxyphosphoryl)nonadecanoic acid (19.87 g, 2.7 equiv.) in DMF (400 mL) was added HCTU (16.75 g, 2.7 equiv.), HOBt (5.47 g, 2.7 equiv.), DIPEA (18.3 mL, 7.0 equiv.)The reaction mixture was stirred at 25 °C for 30 minutes and then added to a slurry of 1-(tert-butyl)-30-[(2-chlorophenyl)diphenylmethyl]-(2S,29S)-2-amino-29-(((benzyloxy)carbonyl)amino)-5, 14, 23 -tri oxo-9, 12, 18,21 -tetraoxa-6, 15,24- tri azatri acontanedioate (15.49 g, 15 mmol) in DMF (400 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage and analysis by LCMS indicated that reactant was consumed completely. The reaction mixture was filtered, and the resin was washed with (DMF 500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.(2S,29S)-2-(((benzyloxy)carbonyl)amino)-29-(tert-butoxycarbonyl)-49-(di-tert- butoxyphosphoryl)-8, 17,26, 31-tetraoxo-10, 13,19, 22-tetraoxa-7, 16, 25,30- tetraazanonatetracontanoic acid

[0386] A slurry of 1-(tert-butyl) 30-[(2-chlorophenyl)diphenylmethyl] (2S,29S)-29- (((benzyloxy)carbonyl)amino)-2-(19-(di-tert-butoxyphosphoryl)nonadecanamido)-5, 14,23- trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontanedioate (22.58 g, 15.00 mmol) in TFA (4 mL) and DCM (396 mL) was agitated at 15 °C for 10 minutes and the reaction mixture was filtered. This procedure was repeated four times to ensure completion of the cleavage. The filtrates were combined and neutralized with a solution of NaHCO3(13.57 g) in H2O (100 mL), and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the desired crude phosphonate (32.4 g, ) as a brown oil.(2S,29S)-2-amino-29-(tert-butoxycarbonyl)-49-(di-tert-butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraazanonatetracontanoic acid

[0387] To a solution of (2S,29S)-2-(((benzyloxy)carbonyl)amino)-29-(tert-butoxycarbonyl)- 49-(di-tert-butoxyphosphoryl)-8, 17,26, 31 -tetraoxo- 10, 13 , 19,22-tetraoxa-7, 16,25,30- tetraazanonatetracontanoic acid (27 g, 21.98 mmol) in MeOH (330 mL) was added Pd / C (15 g, 14.10 mmol, 10 wt%, 0.64 equiv.) and HCl (0.1 M, 329.7 mL). The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. After completion, the reaction mixture was filtered through a Celite pad and NaHCO3(2.77 g) was added, and the slurry was filtered. The filtrate was concentrated to afford the crude amine (30 g) as colorless oil. m / z (ESI, +ve ion) = 1094.8 [M+H]+.(2S,29S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-29-(tert-butoxycarbonyl)- 49-(di-tert-butoxyphosphoryl)-8, 17,26, 31-tetraoxo-10, 13,19, 22-tetraoxa-7, 16, 25,30- tetraazanonatetracontanoic acid(ACW-43)

[0388] To a solution of (2S,29S)-2-amino-29-(tert-butoxycarbonyl)-49-(di-tert- butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30- tetraazanonatetracontanoic acid (24.05 g, 21.98 mmol) in dioxane (30 mL) and H2O (30 mL) that had been pre-cooled to 0-5 °C was added FMOC-OSU (8.90 g, 1.2 equiv.) and Na2CO3(23.3 g, 10.0 equiv.). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. After completion, HCl (219 mL, 1 M) was added, and the aqueous phase was extracted with DCM (100 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by flash silica gel chromatography (Ethyl acetate : Methanol =1:0—3: 1) to afford the desired phosphonate ACW-43, (2S,29S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-29-(tert-butoxycarbonyl)-49-(di-tert-butoxyphosphoryl)- 8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraazanonatetracontanoic acid (13 g, 43% yield, 95.3% purity) as a white solid, m / z (ESI, +ve ion) = 1316.8 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (br d, J=7.34 Hz, 1 H) 8.07 - 8.13 (m, 1 H) 7.82 - 7.95 (m, 2 H) 7.58 - 7.78 (m, 3 H) 7.41 (t, J=7.34 Hz, 2 H) 7.28 - 7.36 (m, 2 H) 7.02 (br s, 1 H) 4.13 - 4.34 (m, 3 H) 4.02 (br d, J=4.16 Hz, 1 H) 3.84 (s, 2 H) 3.76 (br s, 1 H) 3.53 (br d, J=1.83 Hz, 4 H) 3.40 (br t, J=5.87 Hz, 3 H) 3.15 - 3.22 (m, 2 H) 3.01 - 3.12 (m, 2 H) 2.05 - 2.18 (m, 6 H) 1.82 - 1.95 (m, 1 H) 1.64 - 1.82 (m, 2 H) 1.51 - 1.63 (m, 2 H) 1.45 (br d, J=6.60 Hz, 5 H) 1.38 (d, J=2.69 Hz, 17 H) 1.26 (br s, 2 H) 1.21 (s, 22 H).Intermediate ACW-44[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoate

[0389] To a slurry of Cl-Trt Resin (1 mmol / g in resin, 70 g resin) in DCM (2 L) was addedDIPEA (121.9 mL, 10.0 equiv.) and N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysine (52.8 g, 1,5 equiv.). The reaction mixture was agitated bybubbling nitrogen for 16 hours at 20 °C. The resin was then filtered and washed with MeOH (800 mL, 3 x 30 minutes), DMF (800 mL, 3 x 2 minutes), and DCM (800 mL, 3 x 2 minutes), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-6-amino-2-(benzyloxycarbonylamino)hexanoate

[0390] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- (9H-fluoren-9-ylmethoxycarbonylamino)hexanoate (54.6 g, 70.00 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated with nitrogen for 15 minutes at 25 °C. The resin was filtered and the treatment with piperidine / DMF was repeated. The reaction mixture was filtered, and the resin was washed with DMF (1 L x 3), DCM (1 L x 3), and then was taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tertbutoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl] amino] hexanoate

[0391] To a solution of N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(tert-butoxycarbonyl)-L-lysine (49.20 g, 1.5 equiv.) in DMF (1 L) was added HOBt (14.19 g, 1.5 equiv.), DIPEA (61 mL, 5.0 equiv.) and HCTU (43.44 g, 1.5 equiv.). The reaction mixture was stirred at 25 °C for 30 minutes and then added to [(2-chlorophenyl)diphenylmethyl] (2S)-6-amino-2- (benzyloxycarbonylamino)hexanoate (39 g, 70 mmol). The reaction mixture was agitated withnitrogen for 15.5 hours at 25 °C, at which point test cleavage showed that reactant [(2- chlorophenyl)diphenylmethyl] (2S)-6-amino-2-(benzyloxycarbonylamino)hexanoate was consumed completely. The reaction mixture was filtered, and the resin was washed with DMF (800 mL x 3), DCM (800 mL x 3), and then taken forward to the next step. [(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate

[0392] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl]amino]hexanoate (6.05 g, 6 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and the treatment with piperidine / DMF was repeated two more times. The resin was washed with DMF (1 L x 3), DCM (1 L x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylami no)-6-[[(2S)-2-(tert- butoxycarbonylamino)-6-[ [(4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5- oxo-pentanoyl] amino] hexanoyl] amino] hexanoate

[0393] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (44.67 g, 1.5 equiv.) in DMF (800 mL) was added HOBt (14.19 g, 1.5 equiv.), DIPEA (61 mL, 5.0 equiv.) and HCTU (43.44 g, 1.5 equiv.). The reaction mixture wasstirred at 25 °C for 30 minutes and then added to [(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)- 6-amino-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (54.97 g, 69.99 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C, and a solution of additional (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (29.78 g, 1.0 equiv.) in DMF (800 mL) was added, followed by HOBt (9.46 g, 1.0 equiv.), DIPEA (36.6 mL, 3.0 equiv.) and HCTU (28.96 g, 1.0 equiv.) that had been stirred at 20 °C for 30 minutes. The reaction mixture was agitated with nitrogen for an additional 15.5 hours at 20 °C, at which point test cleavage showed complete consumption of reactant. The reaction mixture was filtered, and the resin was washed with DMF (800 mL x 3), DCM (800 mL x 3), and then taken forward to the next step. [(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5- oxo-pentanoyl] amino] -2-(tert-butoxycarbonylamino)hexanoyl] amino] -2-(benzyloxycarbonylamino)hexanoate

[0394] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [[(2S)-2-(tert-butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(9H-fluoren-9- ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate (20.87 g, 17.5 mmol) in piperidine (10 mL) and DMF (40 mL) was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and the treatment with piperidine / DMF was repeated. The resin was washed with DMF (0.5 L x 3), DCM (0.5 L x 3), and then taken forward to the next step. Tert- butyl-18-[[(1S)-4-[[(5S)-6-[[(5S)-5-(benzyloxycarbonylamino)-6-[(2- chlorophenyl)diphenylmethoxy]-6-oxo-hexyl]amino]-5-(tert-butoxycarbonylamino)-6-oxo- hexyl]amino]-1-tert-butoxycarbonyl-4-oxo-butyl]amino]-18-oxo-octadecanoate

[0395] To a solution of 18-(tert-butoxy)-18-oxooctadecanoic acid (12.97 g, 2.0 equiv.) in DMF (200 mL) was added HOBt (4.73 g, 2.0 equiv.), DIPEA (11.31 g, 5.0 equiv.) and HCTU (14.48 g, 2.0 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes, then added to [(2- chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5-oxo- pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (16.99 g, 17.50 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C, at which point test cleavage of an aliquot of resin and analysis by LCMS showed complete consumption of reactant. The reaction mixture was filtered, and the resin was washed with (DMF 500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.(23S,32S,39S)-39-(((benzyloxy)carbonyl)amino)-23-(tert-butoxycarbonyl)-32-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4, 21,26, 33-tetraoxo-3-oxa-22, 27, 34-triazatetracontan- 40-oic acid

[0396] To a slurry of tert-butyl-18-[[(lS)-4-[[(5S)-6-[[(5S)-5-(benzyloxycarbonylamino)-6- [(2-chlorophenyl)diphenylmethoxy]-6-oxo-hexyl]amino]-5-(tert-butoxycarbonylamino)-6-oxo- hexyl]amino]-1-tert-butoxycarbonyl-4-oxo-butyl]amino]-18-oxo-octadecanoate (23.16 g, 17.50 mmol) in DCM (300 mL) was added TFA (3 mL, 2.3 equiv.). The reaction mixture was agitated with nitrogen for 15 minutes at 20 °C. The resin was filtered and resubjected to these cleavage conditions two more times. The resin was filtered and washed with DCM (3x). The filtrates and washes were combined and neutralized by addition of aqueous NaHCO3(10.2 g, 6.9 equiv., in 100 mL of H2O). The reaction mixture was acidified to pH 5 with HCl (1 M). The organic phase was separated, washed with H2O (100 mL), dried (Na2SO4), and concentrated under reduced pressure to afford crude (23S,32S,39S)-39-(((benzyloxy)carbonyl)amino)-23-(tert-butoxycarbonyl)-32- ((tert-butoxycarbonyl)amino)-2,2-dimethyl-4,21,26,33-tetraoxo-3-oxa-22,27,34- triazatetracontan-40-oic acid (33 g) as a yellow oil. m / z (ESI, +ve ion) = 1046.8 [M+H]+.(23S,32S,39S)-39-amino-23-(tert-butoxycarbonyl)-32-((tert-butoxycarbonyl)amino)- 2,2-dimethyl-4,21,26,33-tetraoxo-3-oxa-22,27,34-triazatetracontan-40-oic acid

[0397] To a solution of (23S,32S,39S)-39-(((benzyloxy)carbonyl)amino)-23-(tert- butoxycarbonyl)-32-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4,21,26,33-tetraoxo-3-oxa- 22,27,34-triazatetracontan-40-oic acid (28 g, 26.76 mmol) in MeOH (250 mL) and HCI (0.1 M, 401.4 mL) was added Pd / C (5.60 g, 0.2 equiv., 10 wt%) under N2atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. After completion, the reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (100 mL x 10) and H2O (100 mL x 3). The filtrate and washes were combined, and neutralized with NaHCO3(1.5 equiv., 3.37 g), then concentrated under reduced pressure to afford (23S,32S,39S)-39-amino-23-(tert-butoxycarbonyl)-32-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4,21,26,33-tetraoxo-3-oxa-22,27,34-triazatetracontan-40- oic acid (24.41 g) as an oil. m / z (ESI, +ve ion) = 912.7 [M+H]+.(23S,32S,39S)-39-((((9H -fluoren-9-yl)methoxy)carbonyl)amino)-23-(tert- butoxycarbonyl)-32-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4, 21,26, 33-tetraoxo-3-oxa- 22,27,34-triazatetracontan-40-oic acid (ACW-44)

[0398] To a solution of (23S,32S,39S)-39-amino-23-(tert-butoxycarbonyl)-32-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4, 21,26, 33-tetraoxo-3-oxa-22, 27, 34-triazatetracontan-40- oic acid (24.41 g, 26.76 mmol) in dioxane (150 mL) and H2O (150 mL) was added NaHCO3(22.48 g, 10.0 equiv.) and FMOC-OSU (9.93 g, 1.1 equiv.). The reaction mixture was stirred at 25 °C for 16 hours. The pH of the solution was then adjusted to 5 with HCl (1 M, 70 mL) and the aqueous phase was extracted with EtOAc (500 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a. residue, which was purified by column chromatography (Petroleum ether: Ethyl acetate = 1 : 1 to 0: 1, to Ethyl acetate: Methanol = 10: 1). The product afforded wasfurther purified by prep-HPLC (column: Waters Xbridge BEH C18 250 x70mm x 10μm; mobile phase: [H2O ( 10mM NH4HCO3)-ACN]; gradient: 60%-90% B over 20,0 minutes) to afford ACW-44, (23S,32S,39S)-39-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 23-(tert-butoxycarbonyl)-32-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4, 21,26, 33-tetraoxo-3- oxa-22,27,34-triazatetracontan-40-oic acid (6.4 g) as a white solid, m / z (ESI, +ve ion) = 978.6 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.13 (br d, J = 7.5 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.80 - 7.66 (m, 3H), 7.44 - 7.28 (m, 4H), 7.24 - 7.13 (m, 1H), 6.75 - 6.64 (m, 1H), 4.28 - 4.18 (m, 3H), 4.07 - 3.98 (m, 1H), 3.85 - 3.74 (m, 2H), 3.01 - 2.92 (m, 3H), 2.19 - 2.05 (m, 7H), 1.93 - 1.52 (m, 6H), 1.46 (br s, 6H), 1.40 - 1.34 (m, 31H), 1.21 (br s, 27H).Intermediate ACW-45[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-(9H-fluoren- 9-ylmethoxycarbonylamino)hexanoate

[0399] To a slurry of Cl-Trt Resin (1 mmol / g in resin, 70 g resin) in DCM (2 L) was added DIPEA (121.9 mL, 10.0 equiv.) and N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysine (52.8 g, 1.5 equiv.). The reaction mixture was agitated by bubbling nitrogen for 16 hours at 20 °C. The resin was then filtered and washed with MeOH (800 mL × 3 × 30 minutes) DMF (800 mL × 3 × 2 minutes) and DCM (800 mL x 3 x 2 minutes) and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-6-amino-2- (benzyloxycarbonylamino)hexanoate

[0400] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- (9H-fluoren-9-ylmethoxycarbonylamino)hexanoate (54.55 g, 70.00 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated with nitrogen for 15 minutes at 25 °C and the resin was filtered. This process was repeated two more times for complete Fmoc removal. The resin was filtered and washed with DMF (1 L x 3), DCM (1 L x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert- butoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl] amino] hexanoate

[0401] To a solution of N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(tert-butoxycarbonyl)- L-lysine (49.2 g, 1.5 equiv.) in DMF (1 L) was added HOBt (14.19 g, 1.5 equiv.), DIPEA (61 mL, 5.0 equiv.) and HCTU (43.44 g, 1.5 equiv.). The reaction mixture was stirred at 25 °C for 30 minutes and then added to [(2-chlorophenyl)diphenylmethyl] (2S)-6-amino-2- (benzyloxycarbonylamino)hexanoate (38.99 g, 70 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 25 °C, at which point test cleavage and analysis by LCMS showed that reactant [(2-chlorophenyl)diphenylmethyl] (2S)-6-amino-2-(benzyloxycarbonylamino)hexanoate was consumed completely. The reaction mixture was filtered, and the resin was washed with DMF (800 mL x 3), DCM (800 mL x 3), and then taken forward to the next step. [(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate

[0402] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyl oxy carbonyl ami no)-6- [[(2S)-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9- ylmethoxycarbonylamino)hexanoyl]amino]hexanoate (6.05 g, 6 mmol) in piperidine (100 mL) and DMF (400 mL) was agitated with nitrogen for 15 minutes at 20 °C and the resin was filtered. The process was repeated two more times to ensure complete removal of the Fmoc group. The resin was filtered and washed with DMF (1 L x 3), DCM (1 L x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert- butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5- oxo-pentanoyl] amino] hexanoyl] amino] hexanoate

[0403] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (44.7 g, 1.5 equiv.) in DMF (800 mL) was added HOBt (14.2 g, 1.5 equiv.), DIPEA (61 mL, 5.0 equiv.) and HCTU (43.4 g, 1.5 equiv.). The reaction mixture was stirred at 20°C for 30 minutes and then added to [(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-amino-2- (tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (54.97 g, 70 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C, at which point test cleavage and analysis by LCMS showed that reactant remained. Additional (S)-4-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (29.8 g, 1.0 equiv.) was dissolved in DMF (800 mL) and HOBt (9.46 g, 1.0 equiv.), DIPEA (36.6 mL, 3.0 equiv.) and HCTU (29 g, 1.0 equiv.) were added. The reaction mixture was stirred at 20 °C for 30 minutes and added to resin-bound [(2-chlorophenyl)diphenylmethyl]-(2R)-6-[[(2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate. The reaction mixture was agitated with nitrogen for an additional 15.5 hours at 20 °C, at which point the reaction was deemed complete. The reaction mixture was filtered, and the resin was washed with DMF (800 mL x 3), DCM (800 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5- oxo-pentanoyl] amino] -2-(tert-but oxy ca rbony la m ino )hexa noyl] amino] -2- (benzyloxycarbonylamino)hexanoate

[0404] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [[(2S)-2-(tert-butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(9H-fluoren-9- ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate (20.87 g, 17.5 mmol) in piperidine (50 mL) and DMF (20 mL) was agitated with nitrogen for 15 minutes at 20 °C and the resin was filtered. This process was repeated to ensure complete Fmoc removal. The resin was filtered and washed with DMF (0.3 L x 3), DCM (0.3 L x 3), and then taken forward to the next step. tert- Butyl 20-[[(1S)-4-[[(5S)-6-[[(5S)-5-(benzyloxycarbonylamino)-6-[(2- chlorophenyl)diphenylmethoxy]-6-oxo-hexyl]amino]-5-(tert-butoxycarbonylamino)-6-oxo- hexyl]amino]-1-tert-butoxycarbonyl-4-oxo-butyl]amino]-20-oxo-icosanoate

[0405] To a solution of 20-( / erZ-butoxy)-20-oxoicosanoic acid (10.47 g, 1.5 equiv.) in DMF (300 mL) was added HOBt (3.55 g, 1.5 equiv.), DIPEA (15.2 mL, 5.0 equiv.) and HCTU (10.9 g, 1.5 equiv.). The reaction mixture was stirred at 20 °C for 30 minutes, and then added to [(2- chlorophenyl)diphenylmethyl] (2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5-oxo- pentanoyl]amino]-2-(ZerZ-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (16.99 g, 17.50 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 20 °C. At this point, test cleavage and analysis by LCMS showed remaining reactant. Additional 20-(tert-butoxy)-20-oxoicosanoic acid (4.88 g, 0.7 equiv.) wasdissolved in DMF (300 mL) and HOBt (1.66 g, 0.7 equiv.), DIPEA (6.1 mL, 2.0 equiv.) and HCTU (5.1 g, 0.7 equiv.) was added. The reaction mixture was stirred at 20 °C for 30 minutes and added to resin-bound reactant. The reaction mixture was agitated for a further 15.5 hours at 20 °C, at which point the reaction was deemed complete. The reaction mixture was filtered, and the resin was washed with (DMF 500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.(25S,34S,41S)-41-(((benzyloxy)carbonyl)amino)-25-(tert-butoxycarbonyl)-34-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4,23,28,35-tetraoxo-3-oxa-24,29,36- triazadotetracontan-42-oic acid

[0406] A slurry of tert-butyl 20-[[(1S)-4-[[(5S)-6-[[(5S)-5-(benzyloxycarbonylamino)-6-[(2- chlorophenyl)diphenylmetho.xy]-6-o.xo-he.xyl]amino]-5-(tert-buto.xycarbonylamino)-6-oxo- hexyl]amino]-1-tert-butoxycarbonyl-4-oxo-butyl]amino]-20-oxo-icosanoate (23.65 g, 17.50 mmol) in DCM (300 mL) and TFA (3 mL, 2.3 equiv.) was agitated with nitrogen for 15 minutes at 20 °C and the resin was filtered. This cleavage protocol was repeated two more times, and the resin was then washed with DCM (3 x). The filtrates and washes were combined and neutralized by addition of aqueous NaHCO3(10.2 g, 6.9 equiv. in 100 mL H2O). The aqueous phase was then acidified to pH 5 with HCl (1 M). The phases were separated, and the organic extract was washed with H2O (100 mL), dried (Na2SO4)and concentrated under reduced pressure to afford crude (25S,34S,41S)-41 -(((benzyloxy)carbonyl)amino)-25-(tert-butoxycarbonyl)-34-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4,23,28,35-tetraoxo-3-oxa-24,29,36-triazadotetracontan- 42-oic acid (22 g) as a yellow oil. m / z (ESI, +ve ion) = 1074.8 [M+H] .(25S,34S,41S)-41-amino-25-(tert-butoxycarbonyl)-34-((tert-butoxycarbonyl)amino)- 2,2-dimethyl-4,23,28,35-tetraoxo-3-oxa-24,29,36-triazadotetracontan-42-oic acid

[0407] To a solution of (25S,34S,41S)-41-(((benzyloxy)carbonyl)amino)-25-(tert- butoxycarbonyl)-34-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4, 23,28, 35-tetraoxo-3-oxa-24,29,36-triazadotetracontan-42-oic acid (15 g, 13.96 mmol) and HCl (0.1 M, 209.4 mL) in MeOH (150 mL) was added Pd / C (60.00 g, 4.0 equiv., 10 wt%) under an N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(50 Psi) at 30 °C for 2 hours. After completion, the reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (100 mL x 10) and H2O (100 mL x 3). The filtrate and washes were combined and neutralized with NaHCO3(1.5 equiv., 3.37 g). The slurry was filtered, and the filtrate was concentrated under reduced pressure to afford (25S,34S,41S)-41-amino-25-(tert- butoxycarbonyl)-34-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4, 23,28, 35-tetraoxo-3-oxa-24,29,36-triazadotetracontan-42-oic acid (3.13 g, 24% yield) as an oil. The crude product was used in the next step without further purification, m / z (ESI, +ve ion) = 940.8 [M+H]+.(25S,34S,41S)-41-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-25-(tert- butoxycarbonyl)-34-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4,23,28,35-tetraoxo-3-oxa-24,29,36-triazadotetracontan-42-oic acid

[0408] To a solution of (25S,34S,41S)-41-amino-25-(tert-butoxycarbonyl)-34-((tert- butoxycarbonyl)amino)-2,2-dimethyl-4,23,28,35-tetraoxo-3-oxa-24,29,36-triazadotetracontan- 42-oic acid (13.1 g, 13.96 mmol) in dioxane (100 mL) and H2O (100 mL) was added Na2CO3(14.8 g, 10.0 equiv.) and FMOC-OSU (5.2 g, 1.1 equiv.). The reaction mixture was stirred at 0-20 °C for 2 hours. The pH of the reaction mixture was then adjusted to pH ~5 with HCl (1 M, 100 mL) and the aqueous phase was extracted with EtOAc (100 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by column chromatography on silica gel eluted with Ethyl acetate: Methanol (80:20). The material afforded was further purified by preparative HPLC (column: Waters Xbridge BEH C18 250x70mmx 10μm;mobile phase: [H2O(10 mM NH4HCO3)-ACN];gradient:70%-90% B over 20.0 minutes) to afford ACW-45, (25S,34S,41S)-41-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- 25-(tert-butoxycarbonyl)-34-((tert-butoxycarbonyl)amino)-2,2-dimethyl-4,23,28,35-tetraoxo-3- oxa-24,29,36-triazadotetracontan-42-oic acid (6.9 g, ) as a white solid, m / z (ESI, +ve ion) = 1162.4. [M+H]+. Ti NMR (400 MHz, DMSO-d6) δ 8.17 - 8.07 (m, 1H), 7.96 - 7.86 (m, 3H), 7.79 (br s, 1H), 7.71 (br d, J = 7.2 Hz, 2H), 7.45 - 7.37 (m, 2H), 7.36 - 7.29 (m, 2H), 6.73 (br d, J = 8.2 Hz, 1H), 4.30 - 4.18 (m, 3H), 4.06 - 3.99 (m, 1H), 3.81 (br d, J = 4.4 Hz, 2H), 3.11 - 2.92 (m, 4H), 2.19 - 2.04 (m, 6H), 1.94 - 1.63 (m, 5H), 1.53 (br s, 3H), 1.46 (br s, 8H), 1.41 - 1.31 (m, 31H), 1.21 (br s, 27H).Intermediate ACW-46[(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tertbutoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(19-di-tert- butoxyphosphorylnonadecanoylamino)-5-oxo-pentanoyl] amino] hexanoyl] amino] hexanoate

[0409] To a solution of 19-(di-tert-butoxyphosphoryl)nonadecanoic acid (6.44 g, 1.5 equiv.) in DMF (200 mL) was added HOBt (1.77 g, 1.5 equiv.), DIPEA (7.6 mL, 5.0 equiv.) and HCTU (5.43 g, 1.5 equiv.). The reaction mixture was stirred at 15 °C for 30 minutes and then added to[(2-chlorophenyl)diphenylmethyl]-(2S)-6-[[(2S)-6-[[(4S)-4-amino-5-tert-butoxy-5-oxo- pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoate (8.49 g, 8.75 mmol). The reaction mixture was agitated with nitrogen for 15.5 hours at 15 °C, at which point test cleavage and analysis by LCMS indicated remaining compound starting material. A solution of additional 19-(di-tert- butoxyphosphoryl)nonadecanoic acid (2.15 g, 0.5 equiv.),HOBt (591 mg, 0.5 equiv ), DIPEA (3.0 mL, 2.0 equiv.) and HCTU (1.81 g, 0.5 equiv.) in DMF (200 mL) that had been stirred for 30 minutes was added. The reaction mixture was agitated with nitrogen for an additional 15.5 hours at 15 °C, at which point the reaction was deemed complete. The reaction mixture was filtered, and the resin was washed with (DMF 500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.(2S)-2-(benzyloxycarbonylamino)-6- [ [ ( 2S)-2-( tert-bu t oxy ca rbony la m ino )-6- [ [ ( 4S)-5- tert-butoxy-4-(19-di-tert-butoxyphosphorylnonadecanoylamino)-5-oxo- pentanoyl] amino] hexanoyl] amino] hexanoic acid

[0410] A slurry of [(2-chlorophenyl)diphenylmethyl] (2S)-2-(benzyloxycarbonylamino)-6- [[(2S)-2-(tert-butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(19-di-tert- butoxyphosphorylnonadecanoylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoate (12.62 g, 8.74 mmol) in DCM (400 mL) and TFA (4 mL) was agitated with nitrogen for 15 minutes at 20 °C and the resin was filtered. The cleavage process was repeated two more times, and the filtrates were combined. The resin was washed with DCM (3 x) and the washes were combined with the filtrates and neutralized with saturated aqueousNaHCO3. The aqueous phase was acidified to pH 5 using HCl (1 M) and extracted with DCM (100 mLx3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford crude (2S)-2-(benzyloxy carbonylamino)-6-[[(2S)-2-(tert-butoxy carbonylamino)-6-[[(4S)-5-tert-butoxy-4-(19- di-tert-butoxyphosphorylnonadecanoylamino)-5-oxo- pentanoyl]amino]hexanoyl]amino]hexanoic acid (10.2 g) as a yellow oil. m / z (ESI, +ve ion) =1166.8 [M+H]+,( N6-( N6-((S)-5-(tert-butoxy)-4-( 19-(di-tert-butoxyphosphoryl)nonadecanami do)-5- oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L-lysine

[0411] To a solution of (2S)-2-(benzyloxycarbonylamino)-6-[[(2S)-2-(tert- butoxycarbonylamino)-6-[[(4S)-5-tert-butoxy-4-(19-di-tert- butoxyphosphorylnonadecanoylamino)-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid (10 g, 8.57 mmol) in MeOH (100 mL) and HCI (0.1 M, 128.59 mL) was added Pd / C (5.0 g, 10 wt%) under N2. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. After completion, the reaction mixture was filtered through a Celite pad, and the filter cake was washed with MeOH (100 mL x 10) and H2O (100 mL x 3). The filtrate and washes were combined and neutralized with NaHCO3, then filtered. The filtrate was concentrated under reduced pressure to afford crude (N6-(N6-((S)-5-(tert-butoxy)- 4-(19-(di-tert-butoxyphosphoryl)nonadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L- lysyl)-L-lysine (8.85 g) as an oil. This crude product was used in the next step without further purification, m / z (ESI, +ve ion) = 1032.7 [M+H]+.N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-( N6-((S)-5-(tert-butoxy)-4-(l 9-(di-tert- butoxyphosphoryl)nonadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine(ACW-46)

[0412] To a solution of (N6-(N6-((S)-5-(tert-butoxy)-4-(19-(di-tert- butoxyphosphoryl)nonadecanamido)-5-oxopentanoyl)-N2-(tert- buto.xycarbonyl)-L-lysyl)-L- lysine (8.85 g, 8.57 mmol) in dioxane (50 mL) and H2O (50 mL) was added NaHCO3(7.20 g, 10.0 equiv.) and FMOC-OSU (3.18 g, 1.1 equiv.). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was acidified to pH ~5 with HCl (1 M, 80 mL) and extracted with EtOAc (200 mL x 3). The combined organic extracts were dried (Na2SO4)and concentrated under reduced pressure to a residue, which was purified by column chromatography (Petroleum ether: Ethyl acetate = 1 : 1 to 0: 1, to Ethyl acetate: Methanol = 4: 1) to afford ACW-46, N2-(((9H-fluoren-9- yl)methoxy)carbonyl)-N6-(N6-((S)-5-(tert-butoxy)-4-( 19-(di-tert- butoxyphosphoryl)nonadecanamido)-5-oxopentanoyl)-N2-(tert-butoxycarbonyl)-L-lysyl)-L- lysine (4.2 g) as a white solid, m / z (ESI, +ve ion) = 1254.8 [M+H]+.1H NMR (400 MHz, DMSO- d6) δ 12.71 - 12.34 (m, 1H), 8.04 (br d, J = 7.5 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.83 - 7.69 (m, 4H), 7.60 (br d, J = 7.9 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.35 - 7.29 (m, 2H), 6.71 (br d, J = 8.0 Hz, 1H), 4.30 - 4.19 (m, 3H), 4.09 - 3.99 (m, 1H), 3.92 - 3.77 (m, 2H), 3.09 - 2.93 (m, 4H), 2.15 - 2.03 (m, 4H), 1.94 - 1.83 (m, 1H), 1.79 - 1.66 (m, 2H), 1.62 - 1.27 (m, 54H), 1.22 (s, 27H).Intermediate ACW-47methyl 18-bromooctadecanoate

[0413] To a solution of 18-bromooctadecanoic acid (22 g, 60.5 mmol) in DCM (220 mL) and anhydrous DMF (46.6 μL) was added (COCI)2(5.30 mL, 1.0 equiv.) at 20 °C under an N2atmosphere. The reaction mixture was stirred at 20 °C for 1.5 hours, then concentrated under reduced pressure at 40 °C. The residue was redissolved in DCM (220 mL) and cooled to 0-5 °C and MeOH ( 2.5 mL). The reaction mixture was allowed to warm to 20 °C and stirred for 2 hours. After completion, the reaction was quenched by addition of saturated aqueous NaHCO3(200 mL) and the aqueous phase was extracted with DCM (200 mL x 2). The combined organic extracts were dried (Na2SO4)and concentrated under reduced pressure to afford the desired bromoester (22.83 g, quantitative yield) as a white solid.1H NMR (400 MHz, CDCI3) δ = 3.68 (s, 3H), 3.42 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.6 Hz, 2H), 1.86 (quin, J = 7.2 Hz, 2H), 1.69 - 1.59 (m, 2H), 1.49 - 1.37 (m, 2H), 1.33 - 1.24 (m, 24H).Methyl 18-(di-tert-butoxyphosphoryl)octadecanoate

[0414] To a solution of 2-tert-butoxyphosphonoyloxy-2-methylpropane (23.5 g, 121 mmol) in DMF (300 mL) was added NaH (4.84 g, 1.0 equiv., 60 wt% dispersion). After 30 minutes, methyl 18-bromooctadecanoate (22.83 g, 60.49 mmol, 0.5 equiv.) was added. The reaction mixture was stirred at 15 °C for 16 hours. After completion, the reaction mixture was quenched with saturated aqueous NH4CI solution (500 mL), and extracted with EtOAc (500 mL x 2). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to afford thedesired crude phosphonate (40 g) as a white solid.1H NMR (400 MHz, CDCI3) δ = 3.65 (s, 3H), 2.29 (t, J = 7.6 Hz, 2H), 1.59 (br d, J = 14.7 Hz, 7H), 1.48 (s, 18H), 1.35 - 1.22 (m, 31H).18-(di-tert-butoxyphosphoryl)octadecanoic acid

[0415] To a solution of methyl 18-di-tert-butoxyphosphoryloctadecanoate (29.7 g, 60.5 mmol) in THF (50 mL) and H2O (50 mL) was added LiOH.H2O (5.08 g, 2.0 equiv.). The reaction mixture was stirred at 15 °C for 16 hours. After completion, HCl (1M, 120 mL) was added, followed by H2O (100 mL) and then extracted with EtOAc (200 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue obtained was purified by flash silica gel chromatography (Petroleum ether : Ethyl acetate =1:0~3: 1) to afford the desired carboxylic acid (28.2 g,98% yield) as a white solid.1H NMR (400 MHz, CDCI3) δ = 2.33 (t, J = 7.5 Hz, 2H), 1.70 - 1.60 (m, 4H), 1.59 - 1.53 (m, 2H), 1.49 (s, 18H), 1.39 - 1.21 (m, 28H).[(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2- ((benzyloxy)carbonyl)-L-lysinate

[0416] To a slurry of Cl-Trt Resin (0.64 mmol / g in resin, 48 g resin, 30.7 mmol) and DIPEA (52.3 mL, 9.8 equiv.) in DCM (500 mL) was added a solution of N6-(((9H-fluoren-9- yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysine (22.62 g, 1.5 equiv.) in DCM (500 mL) at 15 °C, and the reaction mixture was agitated at 15 °C for 16 hours under an inert atmosphere. The reaction mixture was then filtered, and the filter cake was washed with MeOH (400 mL x 3), DMF (400 mL x 3), DCM (400 mL x 3), and the resin was used directly to next step.[(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate

[0417] A mixture of [(2-chlorophenyl)diphenylmethyl] N6-(((OH-fluoren-O- yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysinate (23.4 g, 30 mmol) in piperidine (40 mL) and DMF (120 mL) was agitated at 25 °C for 15 minutes under N2atmosphere. The reaction mixture was filtered, and the filter cake was washed with DMF (300 mL x 1). This procedure was repeated two times to ensure completion of the Fmoc deprotection. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)-1-(9H- fluoren-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oate

[0418] A solution of 1 -(9H-fluoren-9-yl)-3-oxo-2,7,l 0-trioxa-4-azadodecan- 12-oic acid (17.3 g, 1.5 equiv.), HOBt (6.1 g, 1.5 equiv.), HCTU (18.6 g, 1.5 equiv.) and DIPEA (15.7 mL, 3.0 equiv) in DMF (100 mL) was stirred at 25 °C for 30 minutes. The reaction mixture was then added to a slurry of resin-bound [(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate (16.71 g, 30 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage of an aliquot of the resin and analysis by LCMS showed complete consumption of reactant. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N2- ((benzyloxy)carbonyl)-L-lysinate

[0419] A mixture of [(2-chlorophenyl)diphenylmethyl] (S)- 18-(((benzyloxy)carbonyl)amino)- 1-(9H-fluoren-9-yl)-3,12-di oxo-2, 7, 10-trioxa-4, 13 -diazanonadecan- 19-oate (27.73 g, 30 mmol,) in piperidine (60 mL) and DMF (240 mL) was agitated at 25 °C for 15 minutes. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 1). This procedure was repeated two times to ensure completion of the Fmoc deprotection. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step. 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15- diazahenicosanedioate

[0420] A mixture of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5- oxopentanoic acid (19.2 g, 45 mmol), HOBt (6.08 g, 1.0 equiv.), HCTU (18.62 g, 1.0 equiv.), and DIPEA (15.7 mL, 2.0 equiv.) ) in anhydrous DMF (150 mL) was agitated at 25 °C for 30 minutes. Then the mixture was added to a solution of [(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2- aminoethoxy)ethoxy)acetyl)-N2-((benzyloxy)carbonyl)-L-lysinate (21.07 g, 30 mmol) in DMF (300 mL). The mixture was agitated at 25 °C for 2 hours, at which point test cleavage of an aliquotof the resin and analysis by LCMS showed complete consumption of reactant. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0421] A slurry of 1 -(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12- dioxa-6,15-diazahenicosanedioate (11.10 g, 10 mmol,) in piperidine (20 mL) and DMF (100 mL) was agitated at 25 °C for 15 minutes. The reaction mixture was filtered and the filter cake was washed with DMF (300 mL x 1). This procedure was repeated two times to ensure completion of the Fmoc deprotection. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step.1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-20- (((benzyloxy)carbonyl)amino)-2-(18-(di-tert-butoxyphosphoryl)octadecanamido)-5,14- dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0422] A mixture of 18-(di-tert-butoxyphosphoryl)octadecanoic acid (7.15 g, 15.0 mmol),HOBt (2.03 g, 1.0 equiv.),HCTU (6.21 g, 1.0 equiv.),and DIPEA (5.23 mL, 2.0 equiv.,) in anhydrous DMF (200 mL) was stirred at 25 °C for 30 minutes. Then the mixture was added to a solution of 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate (8.87 g, 10 mmol) in DMF (200 mL). The reaction mixture was agitated at 25 °C for 2 hours at which point test cleavage of an aliquot of the resin and analysis by LCMS. showed complete consumption of reactant. The reaction mixture was filtered, and the resin was washed with DMF (300 mL x 3), DCM (300 mL x 3), and then taken forward to the next step.(2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-39-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonatriacontanoic acid

[0423] A mixture of l-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-20- (((benzyloxy)carbonyl)amino)-2-(18-(di-tert-butoxyphosphoryl)octadecanamido)-5,14-dioxo- 9,12-dioxa-6,15-diazahenicosanedioate (13.46 g, 10 mmol) in TFA (1 mL) and DCM (99 mL) was agitated at 15 °C for 10 minutes. This procedure was repeated ten times to ensure completion of the cleavage. The filtrates were combined and a solution of Sodium bicarbonate (13.6 g) in H2O (500 mL) was added, and the aqueous phase was extracted with DCM (300 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the crude desired product (10.45 g) as a yellow oil.(2S, 20S)-2-amino-20-(tert-butoxycarbonyl)-39-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazanonatriacontanoic acid

[0424] To a solution of (2S)-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4- (18-di-tert-butoxyphosphoryloctadecanoylamino)-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (10.45 g, 9.77 mmol) in MeOH (150 mL) and HCl (0.1 M, 156 mL) was added Pd / C (5 g, 4.70 mmol, 10 wt%) under an N2atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3hours. After completion, the reaction mixture was filtered through a Celite pad, NaHCO3(1.31 g) was added, and the filtrate was concentrated to afford the crude amino acid product (13 g). m / z (ESI, +ve ion) = 935.6 [M+H]+.(2S,20S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 39-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonatriacontanoic acid(ACW-47)

[0425] To a solution of (2S)-2-amino-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4-(18-ditert- butoxyphosphoryloctadecanoylamino)-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (9.14 g, 9.77 mmol) in dioxane (100 mL) and H2O (100 mL) that had been pre-cooled to 0-5 °C was added Na2CO3(10.36 g, 10.0 equiv.) and FMOC-OSU (3.63 g, 1.1 equiv.). The reaction mixture was allowed to warm to25 °C and stirred for 16hours. After reaction completion, HCl (1M, 97.7 mL) was added, followed by by H2O (100 mL) and the aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by flash silica gel chromatography (EtOAc : MeOH =1 :0-5: 1) to afford the desired product ACW-47, (2S,20S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-39-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazanonatriacontanoic acid (6.63 g,57% yield, 97.8% purity byHPLC) as a white solid, m / z (ESI, +ve ion) = 1057.7 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 8.04 (d, J = 7.4 Hz, 1H), 7.90 (br d, J = 7.4 Hz, 3H), 7.79 - 7.67 (m, 3H), 7.62 (br d, J = 8.0 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.38 - 7.28 (m, 2H), 4.33 - 4.19 (m, 3H), 4.05 (dt, J = 5.5, 8.1 Hz, 1H), 3.96 - 3.81 (m, 3H), 3.55 (br d, J = 2.7 Hz, 4H), 3.45 - 3.39 (m, 2H), 3.20 (br d, J = 5.8 Hz, 2H), 3.10 (br d, J = 6.4 Hz, 2H), 2.11 (td, J = 7.7, 18.1 Hz, 4H), 1.96 - 1.82 (m, 1H), 1.80 - 1.66 (m, 2H), 1.62 (br dd, J = 5.0, 9.1 Hz, 1H), 1.58 - 1.52 (m, 2H), 1.52 - 1.44 (m, 5H), 1.41 (s, 19H), 1.39 (s, 9H), 1.35 - 1.27 (m, 5H), 1.23 (s, 24H)Intermediate ACW-48[(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysinate

[0426] To a slurry of Cl-Trt Resin (0.64 mmol / g in resin, 48 g resin) and DIPEA (52.3 mL, 300.00 mmol) in DCM (500 mL) was added a solution of N6-(((9H-fluoren-9- yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysine (22.6 g, 45.00 mmol) in DCM (500 mL) at 15 °C, and then the reaction mixture was agitated at 15 °C for 16 hours. The reaction mixture was filtered and the resin was washed with MeOH (400 mL x 3), DMF (400 mL x 3), DCM (400 mL x 3), and the resin was taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] ((benzyloxy)carbonyl)-L-lysinate

[0427] A slurry of [(2-chlorophenyl)diphenylmethyl] N6-(((9H-fluoren-9- yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysinate (23.4 g, 30 mmol) in piperidine (40 mL) and DMF (120 mL) was agitated at 25 °C for 15 minutes. The resin was drained and washed with DMF (300 mL). This procedure was repeated two more times to ensure completion of the deprotection. The resin was washed with DMF (600 mL x 3), DCM (600 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)-1-(9H- fluoren-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oate

[0428] To a solution of 1-(9H-fluoren-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecan-12-oic acid (17.34 g, 1.5 equiv.) in DMF (100 mL) was added HOBt (6.08 g, 1.5 equiv ), HCTU (18.6 g, 1.5 equiv.) and DIPEA (15.7 mL, 3.0 equiv.) The reaction mixture was stirred at 25 °C for 30 minutes and then added to a slurry of [(2-chlorophenyl)diphenylmethyl]((benzyloxy)carbonyl)-L-lysinate (16.7 g, 30 mmol) in DMF (300 mL). The reaction mixture was agitated at 25°C for 2 hours, whereupon test cleavage of an aliquot of the resin and analysis by LCMS indicated complete consumption of reactant. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.[(2-chlorophenyl)diphenylmethyl] N6-(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N2- ((benzyloxy)carbonyl)-L-lysinate

[0429] A slurry of [(2-chlorophenyl)diphenylmethyl] (S)-18-(((benzyloxy)carbonyl)amino)- 1-(9H-fluoren-9-yl)-3,12-di oxo-2, 7, 10-trioxa-4, 13 -diazanonadecan- 19-oate (27.73 g, 30 mmol,) in piperidine (60 mL) and DMF (240 mL) was agitated at 25 °C for 15 minutes. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 1), and the treatment with piperidine in DMF was repeated two more times to ensure complete removal of the Fmoc protecting group. The resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step. 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15- diazahenicosanedioate

[0430] To a solution of (S)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)- 5-oxopentanoic acid (19.15 g, 1.5 equiv.) in DMF (150 mL) was added HOBt (6.08 g, 1.5 equiv.), HCTU (18.62 g, 1.5 equiv.) and DIPEA (15.7 mL, 3.0 equiv.). The reaction mixture was stirred at25 °C for 30 minutes, then added to a slurry of [(2-chlorophenyl)di phenylmethyl] N6-(2-(2-(2- aminoethoxy)ethoxy)acetyl)-N2-((benzyloxy)carbonyl)-L-lysinate (21.1 g, 30 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage of an aliquot of the resin indicated complete consumption of reactant. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step. l-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0431] A slurry of 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-((((9H- fluoren-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12- dioxa-6,15-diazahenicosanedioate (11.10 g, 10 mmol,) in piperidine (20 mL) and DMF (100 mL) was agitated at 25 °C for 15 minutes, then filtered and the resin was washed with DMF (200 mL x 1).This procedure was repeated two more times to ensure complete removal of the Fmoc protecting group. The resin was washed with DMF (300 mL x 3), DCM (300 mL x 3), and then taken forward to the next step. 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-20- (((benzyloxy)carbonyl)amino)-2-(19-(di-ter?-butoxyphosphoryl)nonadecanamido)-5,14- dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0432] To a solution of 19-(di-tert-butoxyphosphoryl)nonadecanoic acid (7.36 g, 1.5 equiv.) in DMF (300 mL) was added HOBt (2.03 g, 1.5 equiv.), HCTU (6.21 g, 1.5 equiv.) and DIPEA (5.2 mL, 3.0 equiv.) and the reaction mixture was stirred at 25 °C for 30 minutes, then added to a solution of 1 -(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate (8.87 g, 10 mmol) in DMF (300 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage of an aliquot of the resin indicated complete consumption of reactant. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 3), DCM (300 mL x 3), and then taken forward to the next step.(2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-40-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid

[0433] A slurry of 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-20- (((benzyloxy)carbonyl)amino)-2-(19-(di-tert-butoxyphosphoryl)nonadecanamido)-5,14-dioxo- 9,12-dioxa-6,15-diazahenicosanedioate (13.60 g, 10 mmol) in TFA (1 mL) and DCM (99 mL) was agitated at 15 °C for 10 minutes and filtered. This procedure was repeated ten times to ensure completion of the cleavage. The combined filtrates were diluted with a solution of NaHCO3(11.31 g) in H2O (500 mL), and then extracted with DCM (300 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the desired product (9.05 g, 84% yield) as a yellow oil.(2S,20S)-2-amino-20-(tert-buto xycarbonyl)-40-(di-tert-butoxyphosphoryl)-8,17.22- trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid

[0434] To a solution of (2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 40-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid (8 g, 7.38 mmol) in MeOH (110 mL) and HCl (0.1 M, 110.8 mL) was added Pd / C (10 wt%, 5 g) under an N2atmosphere. The suspension was degassed and purged with H2three times. The reaction mixture was stirred under H2(50 Psi) at 30 °C for 3 hours. After completion, the reaction mixture was filtered through a Celite pad; NaHCO3(935 mg) was added, and the filtrate was concentrated to afford the crude amino acid (13 g) as colorless oil. m / z (ESI, +ve ion) = 949.7 [M+H]+.(2S,20S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 40-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid (ACW-48)

[0435] To a solution of (2S,20S)-2-amino-20-(tert-butoxycarbonyl)-40-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid (7.01 g, 7.38 mmol) in dioxane (50 mL) and H2O (50 mL) was added Na2CO3(7.83 g, 10 equiv.) and FMOC- OSU (2.99 g, 1.2 equiv.). The reaction mixture was stirred at 25 °C for 16 hours. After completion, HCl (73.9 mL, 1M) was added. The reaction mixture was diluted with H2O (100 mL) and then extracted with EtOAc (100 mL x 2). The combined organic extracts was dried (Na2SO4), filtered and concentrated under reduced pressure to afford a residue, which was purified by flash silica gel chromatography (Ethyl acetate : Methanol =1 :0-5: 1) to afford the desired ACW-48, (2S,20S)-2- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-40-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracontanoic acid (5 g, 56% yield, 96.8% purity) as white solid, m / z (ESI, +ve ion) = 1171.7 [M+H]+. 'H NMR (400 MHz, DMSO- d6) δ = 12.81 - 12.31 (m, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.95 - 7.84 (m, 3H), 7.76 - 7.65 (m, 3H), 7.60 - 7.52 (m, 1H), 7.45 - 7.37 (m, 2H), 7.36 - 7.28 (m, 2H), 4.30 - 4.18 (m, 3H), 4.04 (dt, J = 5.5, 8.3 Hz, 1H), 3.93 - 3.81 (m, 3H), 3.54 (br d, J = 2.7 Hz, 4H), 3.43 - 3.36 (m, 2H), 3.22 - 3.14 (m, 2H), 3.08 (q, J = 6.6 Hz, 2H), 2.10 (td, J = 7.6, 18.4 Hz, 4H), 1.94 - 1.82 (m, 1H), 1.79 - 1.65 (m, 2H), 1.64 - 1.51 (m, 2H), 1.51 - 1.41 (m, 6H), 1.40 (s, 18H), 1.37 (s, 10H), 1.30 (br d, J = 5.5 Hz, 4H), 1.21 (s, 26H).Intermediate ACW-49l-(tert-butyl)-21-[(2-chlor ophenyl)diphenylmethyl] (2S,20S)-20-(((benzyloxy)carbonyl)amino)-2-(20-(di-tert-butoxyphosphoryl)icosanamido)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate

[0436] A solution of 20-(di-tert-butoxyphosphoryl)icosanoic acid (7.57 g, 15.00 mmol), HCTU (6.21 g, 15.00 mmol), HOBt (2.03 g, 15.00 mmol), and DIPEA (3.88 g, 30.00 mmol) in DMF (100 mL) was stirred at 25 °C for 30 minutes and the reaction mixture was then added to a slurry of 1-(tert-butyl) 21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-2-amino-20- (((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazahenicosanedioate (9.19 g, 10 mmol) in DMF (100 mL). The reaction mixture was agitated at 25 °C for 2 hours, at which point test cleavage of an aliquot of resin and analysis by LCMS indicated complete consumption of starting material. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3), DCM (500 mL x 3), and then taken forward to the next step.(2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-41-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazahentetracontanoic acid

[0437] A slurry of 1-(tert-butyl)-21-[(2-chlorophenyl)diphenylmethyl] (2S,20S)-20- (((benzyloxy)carbonyl)amino)-2-(20-(di-tert-butoxyphosphoryl)icosanamido)-5,14-dioxo-9,12- dioxa-6,15-diazahenicosanedioate (68.20 g, 55 mmol) in TFA (3 mL) and DCM (300 mL) was shaken at 15 °C for 10 minutes under an N2atmosphere. This procedure was repeated three times to ensure completion of the cleavage. The reaction mixture was filtered and the filtrates were combined. Saturated aqueous NaHCO3was added to neutralize the filtrate, and then the pH was adjusted to 5 with 1M HCl. The aqueous phase was extracted with DCM (100 mL x 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the crude desired product (8.3 g) as a yellow oil.(2S, 20S)-2-amino-20-(tert-butoxycarbonyl)-41-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazahentetracontanoic acid

[0438] To a solution of (2S,20S)-2-(((benzyloxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 41 -(di -tert-butoxyphosphoryl )-8, 17,22-trioxo- 10, 13 -dioxa-7, 16,21 -triazahentetracontanoic acid (6 g, 5.47 mmol) in MeOH (80 mL) was added Pd / C (3 g, 10 wt%) and HCl (0.1 M, 82 mL) under an N2atmosphere. The suspension was degassed and purged with H23 times. The reaction mixture was then stirred under H2(50 Psi) at 30 °C for 2 hours. After completion, the reaction mixture was filtered through a Celite pad. Sodium bicarbonate (0.69 g) was added to the filtrate for neutralization and the reaction mixture was concentrated to afford the crude product (5.72 g), which was taken forward to the next step without further purification, m / z (ESI, +ve ion) = 963.7 [M+H]+.(2S.20S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)- 41-(di-tert-butoxyphosphoryl)-8,17,22-trioxo- 10, 13-dioxa-7, 16,21-triazahentetracontanoic acid(ACW-49)

[0439] To a solution of (2S,20S)-2-amino-20-(tert-butoxycarbonyl)-41-(di-tert- butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazahentetracontanoic acid (5.27 g, 5.47 mmol) in dioxane (20 mL) and H2O (20 mL) that had been pre-cooled to 0-5 °C was added FMOC- OSU (2.03 g, 6.02 mmol) and NaHCO3(4.60 g, 54.71 mmol). The reaction mixture was allowed to warm to 25 °C and stirred for 2 hours. After completion, HCl (1 M) was added to adjust the pH to 5, and the aqueous phase was extracted with DCM (100 mL x 2). The combined organic extracts were dried over (Na2SO4), filtered and concentrated under reduced pressure. The residue afforded was purified by flash silica gel chromatography (Ethyl acetate: Methanol = 1 :0~3: 1) to afford the desired protected amino acid ACW-49, (2S,20S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-20-(tert-butoxycarbonyl)-41-(di-tert-butoxyphosphoryl)-8, 17,22- trioxo-10,13-dioxa-7,16,21-triazahentetracontanoic acid (3.6 g). m / z (ESI, +ve ion) = 1185.7 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.03 (br d, J = 7.6 Hz, 1H), 7.89 (br d, J = 7.5 Hz, 3H), 7.75 - 7.66 (m, 3H), 7.60 (br d, J= 7.6 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.36 - 7.27 (m, 2H), 4.32 - 4.17 (m, 3H), 4.08 - 4.00 (m, 1H), 3.94 - 3.82 (m, 3H), 3.54 (br d, J = 2.4 Hz, 4H), 3.40 (br t, J = 5.7 Hz, 2H), 3.23 - 3.14 (m, 2H), 3.09 (q, J = 6.4 Hz, 2H), 2.16 - 2.04 (m, 4H), 1.88 (dt, J =7.5, 13.2 Hz, 2H), 1.79 - 1.67 (m, 3H), 1.53 (br d, J = 8.4 Hz, 4H), 1.49 - 1.36 (m, 31H), 1.31 (br d, J = 6.8 Hz, 4H), 1.22 (br s, 27H).Intermediate ACW-51Tert-butyl 18-hydroxyoctadecanoate

[0440] A solution of 18-tert-butoxy-18-oxo-octadecanoic acid (10 g, 27 mmol) in THF (100 mL) was cooled to 0-5 °C, and BH3-Me2S (10 M, 3.5 mL, 1.3 equiv.) was added under nitrogen. Vigorous gas evolution occurred over the first few mL of addition. After the addition, the reaction mixture was allowed to slowly warm to 25°C and stirred 16 hours, at which point the reaction was deemed complete. The reaction mixture was cooled to 0-5 °C and quenched with saturated aqueous sodium carbonate solution (100 mL), and the aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 20: 1 to 5: 1) to afford tert-butyl 18-hydroxyoctadecanoate (9.5 g, 99% yield) as a white solid. 1HNMR (400 MHz, METHANOL-d4) δ 3.54 (t, J = 6.6 Hz, 2H), 2.21 (t, J = 7.3 Hz, 2H), 1.55 (td, J = 7.2, 14.6 Hz, 4H), 1.45 (s, 9H), 1.29 (br s, 26H).(2R, 3R,4S,5R, 6R)-2-(acetoxymethyl)-6-((18-(tert-butoxy)-18- oxooctadecyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0441] This reaction was set up in a glovebox, with 4 batches carried out in parallel. To a solution of tert-butyl 18-hydroxyoctadecanoate (2 g, 5.61 mmol) in toluene (15 mL) was added HgO (971.9 mg, 0.8 equiv.), dibromomercury (1.62 g, 0.8 equiv.), [(2R,3R,4S,5R,6R)-3,4,5- triacetoxy-6-bromo-tetrahydropyran-2-yl] methyl acetate (2.31 g, 1.0 equiv.) and 4A molecular sieves with vigorous stirring. The reaction mixture was stirred at 25 °C for 16 hours under Ar, at which point the reaction was deemed complete. The 4 batches were combined and filtered throughCelite. The filtrate was treated with Cu(II)triflate (80 mg) and stirred for 1 hour. The reaction mixture was diluted with water and the phases were separated. The organic phase was concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1) to afford (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6- ((18-(tert-butoxy)-18-oxooctadecyl) oxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate (7.7 g, 50% yield) as a colorless oil.1H NMR (400 MHz, METHANOL-d4) δ ppm 5.21 - 5.31 (m, 1 H) 5.01 (t, J = 9.72 Hz, 1 H) 4.90 - 4.92 (m, 1 H) 4.64 (d, J = 8.07 Hz, 1 H) 4.28 (dd, J = 12.35, 4.65 Hz, 1 H) 4.06 - 4.17 (m, 1 H) 3.79 - 3.91 (m, 2 H) 3.52 (dt, J = 9.69, 6.65 Hz, 1 H) 2.21 (t, J = 7.27 Hz, 2 H) 2.01 (dd, J = 19.56, 16.63 Hz, 12 H) 1.50 - 1.62 (m, 4 H) 1.45 (s, 9 H) 1.29 (s, 26 H). tert- Butyl 18-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-tetrahydro- 2H-pyran-2-yl)oxy) octadecanoate

[0442] To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((18-(tert-butoxy)-18- oxooctadecyl) oxy) tetrahydro-2H-pyran-3,4,5-triyl triacetate (7.7 g, 11.21 mmol) in MeOH (40 mL) was added NaOMe (42 μL, 2 mol%, 30% w / v). The reaction mixture was stirred at 25 °C for 1 hour, at which point the reaction was deemed complete. The reaction mixture was neutralized with AcOH and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 5: 1 to 0: 1) to afford tert-butyl 18- (((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro -2H-pyran-2-yl) oxy) octadecenoate (4.32 g, 74% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ ppm 4.24 (d, J = 7.88 Hz, 1 H) 3.84 - 3.94 (m, 2 H) 3.63 - 3.73 (m, 1 H) 3.53 (dt, J = 9.47, 6.77 Hz, 1 H) 3.35 (s, 1 H) 3,25 - 3.29 (m, 2 H) 3.13 - 3.20 (m, 1 H) 2.21 (t, J = 7.38 Hz, 2 H) 1.50 - 1.69 (m, 4 H) 1.44 (s, 9 H) 1.36 - 1.41 (m, 2 H) 1.29 (s, 24 H).(2S,3S,4S,5R,6R)-6-((18-(tert-butoxy)-18-oxooctadecyl) oxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid(ACW-51)

[0443] To a solution of 18-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) octadecenoate (4.32 g, 8.33 mmol) in dioxane (72 mL) that had been cooled to 10 °C was added TEMPO (13.1 mg, 1 mol%) and KBr (99.1 mg, 10 mol%). Dropping funnels containing saturated aqueous sodium carbonate (26 mL) and aqueous NaOCl (19.3 mL of a 7% wt / v solution, 2.6 equiv.) were attached to the flask. The sodium carbonatesolution was started on a rapid drip and the NaOCl was added at a slow drip (ca. 1 drop / second). The pH was checked and more sodium carbonate solution was added as necessary to maintain a pH~10. The temperature was maintained at 10-15°C throughout. The reaction mixture was stirred at 10-15 °C for 16 hours, at which point analysis by LCMS showed that the reaction was incomplete. Additional NaOCl (19.2 mL, 2.6 equiv.) and saturated aqueous sodium carbonate (5 mL) was added. The pH was checked and more was added as necessary to maintain apH~10. The reaction mixture was stirred at 25 °C for an additional 24 hours at which point the reaction was deemed complete. The reaction was quenched with MeOH (0.6 mL) and acidified to pH 3 with 6 N HCl. The aqueous phase mixture was extracted with ethyl acetate (300 mL x 2). The combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: I to O: l) to afford intermediate ACW-51 (2S,3S,4S,5R,6R)-6-((18-(tert-butoxy)-18-oxooctadecyl) oxy)- 3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (5.3 g, 52% yield) as a white solid, m / z (ESI, -ve ion) = 531.4 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ ppm 4.31 (d, J = 7.70 Hz, 1 H) 3.85 (dt, J = 9.51, 6.74 Hz, 1 H) 3.78 (d, J = 9.78 Hz, 1 H) 3.48 - 3.59 (m, 2 H) 3.37 (br t, J = 9.11 Hz, 1 H) 3.22 (dd, J = 9.17, 7.83 Hz, 1 H) 2.21 (t, J = 7.34 Hz, 2 H) 1.59 (td, J = 14.70, 6.91 Hz, 4 H) 1.44 (s, 9 H) 1.26 - 1.41 (m, 26 H).Intermediate ACW-52tert-butyl 20-hydroxyicosanoate

[0444] A solution of 20-tert-butoxy-20-oxo-icosanoic acid (10 g, 25.09 mmol) in THF (100 mL) was cooled to 0-5 °C, and BH3-Me2S (10 M, 3.26 mL, 1.3 equiv.) was added under nitrogen.Vigorous gas evolution occurred over the first few mL of addition. After addition, the reaction mixture was allowed to warm to 25 °C and was stirred 16 hours, at which point the reaction was deemed complete. The reaction mixture was cooled to 0-5 °C and quenched with saturated aqueous sodium carbonate solution (50 mL) and H2O (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were concentrated under reduced pressure to a residue, which was purified by column chromatography (SiCL, Petroleum ether: Ethyl acetate = 5: 1 to 3: 1) to afford tert-butyl 20-hydroxyicosanoate (9 g, 93% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ ppm 3.54 (t, J = 6.60 Hz, 2 H) 2.21 (t, J = 7.34 Hz, 2 H) 1.48 - 1.63 (m, 4 H) 1.44 (s, 9 H) 1.29 (s, 30 H).(2R,3R, 4S.5R.6R)-2-(acetoxymethyl)-6-((20-(tert-butoxy)-20- oxoicosyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (ACW-52-3)

[0445] This reaction needed to be set up in a glovebox, and 5 batches were carried out in parallel. To a solution of tert-butyl 20-hydroxyicosanoate (2 g, 5.20 mmol) in toluene (15 mL) was added HgO (901 mg, 0.8 equiv.), dibromomercury (1.50 g, 0.8 equiv.), [(2R,3R,4S,5R,6R)-3,4,5- triacetoxy-6-bromo-tetrahydropyran-2-yl] methyl acetate (2.14 g, 1.0 equiv.) and 4A molecular sieve with vigorous stirring. The reaction mixture was stirred at 25 °C for 16 hours, at which point the reaction was deemed complete. The 5 reaction batches were combined and filtered through Celite. The filtrate was treated with Cu (Il)triflate (200 mg) and stirred for 1 hour. The reaction mixture was then washed with water and the organic phase was concentrated under reduced pressure to a residue, which was purified by column chromatography ( Si O2, Petroleum ether: Ethyl acetate = 100: 1 to 3: 1) to afford (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((20-(tert-butoxy)-20- oxoicosyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9.1 g, 49% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ ppm 5.19 - 5.30 (m, 1 H) 5.01 (t, .7 = 9.72 Hz, 1 H) 4.89 - 4.91 (m, 1 H) 4.65 (d, J = 8.07 Hz, 1 H) 4.28 (dd, J = 12.35, 4.52 Hz, 1 H) 4.13 (dd, J = 12.35, 2.20 Hz, 1 H) 3.80 - 3.91 (m, 2 H) 3.52 (dt, J = 9.66, 6.60 Hz, 1 H) 2.21 (t, J = 7.34 Hz, 2 H) 2.01 (dd, J = 19.56, 16.63 Hz, 12 H) 1.52 - 1.62 (m, 4 H) 1.45 (s, 9 H) 1.29 (s, 30 H). tert-Butyl 20-(((2R.3R.4S.5S.6R)-3.4.5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yl)oxy)icosanoate

[0446] To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((20-(tert-butoxy)-20- oxoicosyl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9.1 g, 12.73 mmol) in MeOH (60 mL)was added NaOMe (48 μL, 2 mol%, 30% w / v solution). The reaction mixture was stirred at 25 °C for 1 hour, at which point the reaction was deemed complete. The reaction mixture was neutralized using AcOH and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2. Petroleum ether: Ethyl acetate = 10: 1 to 0: 1) to afford tert-butyl 20- (((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)icosanoate (6.35 g, 91% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) δ ppm 4.24 (d, J = 7.70 Hz, 1 H) 3.82 - 3.95 (m, 2 H) 3.66 (dd, J = 11.92, 5.32 Hz, 1 H) 3.53 (dt, J = 9.41, 6.85 Hz, 1 H) 3.33 - 3.38 (m, 1 H) 3.22 - 3.29 (m, 2 H) 3.13 - 3.20 (m, 1 H) 2.21 (t, J = 7.34 Hz, 2 H) 1.52 - 1.67 (m, 4 H) 1.45 (s, 9 H) 1.29 (s, 30 H).(2S,3S,4»S,5R,6R)-6-((20-(tert-butoxy)-20-oxoicosyl)oxy)-3,4,5-trihydroxytetrahydro- 2H-pyran-2-carboxylic acid(ACW-52)

[0447] A solution of tert-butyl 20-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)icosanoate (10.7 g, 19.57 mmol) in dioxane (180 mL) was cooled to 10 °C and TEMPO (30.8 mg, 1 mol%) and KBr (232.9 mg, 10 mol%) were added. Dropping funnels containing saturated aqueous sodium carbonate (64 mL) and NaOCl (45.2 mL, 7% wt / v, 2.6 equiv.) were attached to the flask. The sodium carbonate solution was started on a rapid drip and the NaOCl solution was added at a slow drip (ca. 1 drop / second). The pH was checked and more sodium carbonate solution was added as necessary to maintain pH~10. The temperature was maintained at 10-15 °C. Once the addition was complete, the mixture was allowed to warm to 25 °C and stirred for 24 hours, at which point LCMS analysis showed that the reaction was not complete. Additional saturated aqueous sodium carbonate (10 mL) and NaOCl solution (7% wt / v, 15 mL, 0.9 equiv.) were added. The reaction mixture was stirred at 25 °C for an additional 16 hours, at which point the reaction was deemed complete. The reaction mixture was quenched with MeOH (2 mL) and adjusted to pH 3 with 6 N HCl. The aqueous phase was extracted with ethyl acetate (400 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to a residue, which was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 10: 1 to 0: 1) to afford the desired carboxylic acid. Further purification by preparative HPLC (column: Phenomenex Titan C18 Bulk 250 x 70mm, 10μm; mobile phase: [H2O (10mM NH4HCO3j-MeCN]; gradient:55%-85% MeCNover 20.0 min) to afford intermediate ACW-52, (2S,3S,4S,5R,6R)-6-((20-(tert-butoxy)-20- oxoicosyl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (5.1 g, 46% yield) as a white solid, m / z (ESI, -ve ion) = 559.4 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ ppm 4.30 (d, J = 7.82 Hz, 1 H) 3.86 (dt, J = 9.54, 6.79 Hz, 1 H) 3,77 (d, J = 9.66 Hz, 1 H) 3.48 - 3.58 (m, 2 H) 3.37 (t, .7= 9.11 Hz, 1 H) 3.18 - 3.25 (m, 1 H) 2.21 (t, J = 7.34 Hz, 2 H) 1.52 - 1.67 (m, 4 H) 1.44 (s, 9 H) 1.35 - 1.41 (m, 2 H) 1.29 (s, 28 H).Synthesis of Specific CompoundsCompound 1

[0448] Compound 1 was synthesized according to procedure G3 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG3: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(6-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0449] Fractions with a purity of >95 % at 214 nm were pooled and lyophilized to give the title peptide, 9.8 mg, LCMS (ESI) m / z [M+4]4+calculated for C237H351FN60O66: 1279.1, found 1279.4, HPLC purity at 214 nm: 94.9 %.Compound 2

[0450] Compound 2 was synthesized according to procedure G3 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG3: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(5-cyano-1H-indol-3-yl)-2-({ [(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0451] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 1.57 mg, LCMS (ESI) m / z [M+4]4+calculated for C237H35IFN60O66: 1279.1, found 1279.4, HPLC purity at 214 nm: 99.7 %.Compound 3

[0452] Compound 3 was synthesized according to procedure G3 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG3: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(4-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0453] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 6.9 mg, LCMS (ESI) m / z [M+4]4+calculated for C237H351FN60O66: 1279.1, found 1279.4, HPLC purity at 214 nm: 97.7 %.Compound 4

[0454] Compound 4 was synthesized according to procedure G2 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG2: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(6-cyano-1H-indol-3-yl)-2-({ [(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0455] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 3.77 mg, LCMS (ESI) m / z [M+4]4+calculated for C236H349FN60O66: 1275.6, found 1275.8, HPLC purity at 214 nm: 95.4 %.Compound 5

[0456] Compound 5 was synthesized according to procedure G2 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG2: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(5-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0457] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 4.8 mg, LCMS (ESI) m / z [M+4]4+calculated for C236H349FN60O66: 1275.6, found 1275.8, HPLC purity at 214 nm: 94.8 %.Compound 6

[0458] Compound 6 was synthesized according to procedure G2 with the following modifications:F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG2: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(4-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidC1, P1, P2 unmodified

[0459] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 3.98 mg, LCMS (ESI) m / z [M+4]4+calculated for C236H349FN60O66: 1275.6, found 1275.8, HPLC purity at 214 nm: 96.6 %.Compound 16

[0460] The peptide was prepared according to Procedure G1, with positions 7 and 30 being added using Procedure S1, and in all cases using the appropriate reagents to access the desired structure.G2: X1= (S)-6-[(S)-5-{(S)-4-tert-butoxycarbonyl-4-[16-(di-tert- butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert- butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9H-fluoren-9- yl)methyl](oxycarbonylamino)}hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid

[0461] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0462] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 4.2 mg, LCMS (ESI) m / z [M+4]4+calculated for C231H347N60O65P: 1259.1, found 1259.3, HPLC purity at 214 nm: 98.4 %.Compound 17

[0463] From Procedure G3, previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β- homoArg(Pbf)-Dap(mtt)-Rink Amide Resin (228 mg, 0.05 mmol) was subjected to selective mtt deprotection and C-terminal modification according to Procedure F1. The peptide was extended using Procedure G1 with the appropriate reagents to access the desired structure. For positions 7 and 30, Procedure S1 was used with the appropriate reagents to access the desired structure.F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG3: X1= (S)-6-[(S)-5-{(S)-4-tert-butoxycarbonyl-4-[16-(di-tert- butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert- butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9H-fluoren-9- yl)methyl](oxycarbonylamino)}hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid

[0464] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0465] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 1.2 mg, LCMS (ESI) m / z [M+4]4+calculated for C236H349FN60O66: 1275.6, found 1275.8, HPLC purity at 214 nm: 95.3 %.Compound 18

[0466] From Procedure G3, previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β- homoArg(Pbf)-Dap(mtt)-Rink Amide Resin (228 mg, 0.05 mmol) was subjected to selective mtt deprotection and C-terminal modification according to Procedure F1. The peptide was extended using Procedure G1 with the appropriate reagents to access the desired structure. For positions 7 and 30, Procedure S1 was used with the appropriate reagents to access the desired structure.F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG3: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fIuoren-9- yl)methoxy]carbonyl}amino)propanoic acid

[0467] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0468] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 8.5 mg, LCMS (ESI) m / z [M+4]4+calculated for C238H353FN60O66: 1282.7, found 1282.8, HPLC purity at 214 nm: 97.1 %.Compound 19

[0469] From Procedure G2, previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)- Arg(Pbf)-Dap(mtt)-Rink Amide Resin (228 mg, 0.05 mmol) was subjected to selective mtt deprotection and C-terminal modification according to Procedure F1. The peptide was extended using Procedure G1 with the appropriate reagents to access the desired structure. For positions 7 and 30, Procedure S1 was used with the appropriate reagents to access the desired structure.F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG2: X1= (S)-6-[(S)-5-{(S)-4-tert-butoxycarbonyl-4-[16-(di-tert- butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9H-fluoren-9- yl)methyl](oxycarbonylamino)}hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid

[0470] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0471] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 5.8 mg, LCMS (ESI) m / z [M+4]4+calculated for C235H347FN60O66: 1272.1, found 1272.2, HPLC purity at 214 nm: 96.3 %.Compound 20

[0472] From Procedure G2, previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)- Arg(Pbf)-Dap(mtt)-Rink Amide Resin (228 mg, 0.05 mmol) was subjected to selective mtt deprotection and C-terminal modification according to Procedure F1. The peptide was extended using Procedure G1 with the appropriate reagents to access the desired structure. For positions 7 and 30, Procedure S1 was used with the appropriate reagents to access the desired structure.F1: 1 -(3 -fluorophenyl)cyclopropane-1-carboxylic acidG1: X1= (S)-6-[(S)-5-{(S)-4-tert-butoxycarbonyl-4-[16-(di-tert- butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert- butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9H-fluoren-9- yl)methyl](oxycarbonylamino)}hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid

[0473] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0474] Fractions with an acceptable purity (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 3.5 mg, LCMS (ESI) m / z [M+4]4+calculated for C237H351FN60O66: 1279.1, found 1279.2, HPLC purity at 214 nm: 92.9 %.Compound 23

[0475] From Procedure G2, previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)- Arg(Pbf)-Dap(mtt)-Rink Amide Resin (228 mg, 0.05 mmol) was subjected to selective mtt deprotection and C-terminal modification according to Procedure F1. The peptide was extended using Procedure G1 with the appropriate reagents to access the desired structure. For positions 7 and 30, Procedure S1 was used with the appropriate reagents to access the desired structure.G1: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy}ethoxy)acetamido]-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-3-(7-cyano-1H-indol-3-yl)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acidX5= Fmoc-β-homo-Arg(Pbf)-OH

[0476] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fractions were pooled and lyophilized and purified a second time using Procedure P2.

[0477] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were lyophilized to give the title peptide, 6.5mg, LCMS (ESI) m / z [M+4]4+calculated for C233H347N59O66: 1257.9, found 1258.2, HPLC purity at 214 nm: 98.5 %.Compound 24

[0478] Compound 24 was synthesized according to procedure G1 with the following modifications:G1: X1= (S)-6-[(S)-5-{(S)-4-tert-butoxycarbonyl-4-[16-(di-tert- butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert- butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9H-fluoren-9- yl)methyl](oxycarbonylamino)}hexanoic acidX4= (2S)-2-({ [(9H-fl uoren-9-yl )m ethoxy ]carbonyl } amino)-3 -(7 -fluoro-1H-indol-3 - yl)propanoic acidC1, P1, P2 unmodified

[0479] Fractions with a purity of >95 % (analytical HPLC) at 214 nm were pooled and lyophilized to give the title peptide, 3.0 mg, LCMS (ESI) m / z [M+4]4+calculated for C231H347N60O65P: 1259.1, found 1259.6, HPLC purity at 214 nm: 98.8 %.Compound 26

[0480] The peptide was prepared according to Procedure G1, with positions 7 and 30 being added using Procedure S1, and in all cases using the appropriate reagents to access the desired structure.G1: X1= (2S)-6-[2-(2-{2-[(4S)-5-(tert-butoxy)-4-[18-(tert-butoxy)-18-oxooctadecanamido]-5- oxopentanamido]ethoxy }ethoxy)acetamido]-2-({ [(9H-fluoren-9- yl)methoxy]carbonyl}amino)hexanoic acidX4= (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-(7-fluoro-1H-indol-3- yl)propanoic acid

[0481] Side chain protecting group removal concomitant with cleavage from the resin was carried out using Procedure C1. The crude peptide was iteratively purified by RP-HPLC using Procedure P1. Suitable fr...

Claims

CLAIMSWe claim:

1. A peptide comprising an amino acid sequence of:X3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID: 143) wherein:X3is V, l or P; X4is R, K or P; X7is A, K or K*, wherein K* has the structure:wherein each Z1, independently, is an amino acid residue, sugar residue, -C(O)-Z2-O-, or -C(O)- Z2-NH-; each Z2, independently, is a 2-8 carbon alkylene linker wherein 1 or 2 carbon atoms are optionally independently substituted by -NH2, -OH, or -COOH and wherein the alkylene linker is straight or branched and optionally includes a C3-8cycloalkyl moiety; or each Z2, independently, is -((CH2)a-O-(CH2)b)c-, wherein each a is independently 1, 2, or 3, each b is independently 1, 2, or 3, and c is 1, 2, or 3; n is 1, 2, 3, 4, or 5;R1is -Z3-R2or -C(O)-Z3-R2;Z3is a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2is -C(O)OH or -P(O)(OH)2;X9is G or E;X10is E or K;X11is D or D*, wherein D* is beta-aspartic acid, or D-aspartic acid;X13is A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17is W or L;X18is N or Q; X22is A, D, E, F, I, L, M, or V; X23is D, S or E; X28is I, L, or Aib;X30is W* wherein W* is tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31is V or L; X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine; X36is Y or Z*, wherein Z* has Formula la, lb, or Ic:whereinRais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdis H or methyl;Reis a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Reis -C0C(Ra)(Rb)Rc;Ar is a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, wherein Ar is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; wherein the C-terminal amino acid of the peptide is optionally amidated; or a pharmaceutically acceptable salt thereof2. The peptide according to claim 1, comprising an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 144), wherein: X7can be K*;X13is A, C, K, M, N, P, R, S, T, W, or Y; X22is A, D, E, F, I, L, M, or V;X30is W*, wherein W* is a halo- or cyano-substituted tryptophan;X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Y or Z*, where Z* has Formula la, lb, or Ic.

3. The peptide according to any one of claims 1-2, wherein: each Z1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

4. The peptide according to any one of claims 1-3, comprising an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 145), wherein: X7can be K*;X13is A, C, K, M, N, P, R, S, T, W, or Y;X22is A, D, E, F, I, L, M, or V;X30is W*, wherein W* is a halo- or cyano-substituted tryptophan;X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine; andX36can be Y or Z*, where Z* has Formula la, lb, or Ic; each Z1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

5. The peptide according to any one of claims 1-4, wherein:X13is S or T;X22is I or V; andX35is R or beta-homo-arginine.

6. The peptide according to any one of claims 1-5, comprising an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 146), wherein: X7can be K*;X13is S or T;X22is I or V;X35is R or beta-homo-arginine; each Z1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

7. The peptide according to any one of claims 1-6, wherein the amino acid sequence is selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 147);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 148);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRY (SEQ ID NO: 149);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRY (SEQ ID NO: 150);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 151);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 152);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 153);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 154);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 155);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 156);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Y (SEQ ID NO: 157);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Y (SEQ ID NO: 158);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 159);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 160);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 161); and PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 162).

8. The peptide according to any one of claims 1-7, wherein R2is -C(O)OH.

9. The peptide according to any one of claims 1-8, wherein R2is -P(O)(OH)2.

10. The peptide according to any one of claims 1-9, wherein:K* has the structure:wherein Z is:

11. The peptide according to claim 10, wherein R1is -C(O)-(CH2)k-R2.

12. The peptide according to any one of claims 1-11, wherein:Z* has the formula la:whereinRais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

13. The peptide according to claim 12, wherein:Z* has the formula la:whereinRaand Rbtaken together with the carbon to which they are attached form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl; andRcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

14. The peptide according to claim 13, wherein:Z* has the structurewherein: each R3, independently, is selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl; i is 1, 2, 3, or 4; and j is 0, 1, 2 or 3.

15. The peptide according to claim 14, wherein:Z* has the structure16. The peptide according to any one of claims 1-11, wherein:Z* has the formula lb:whereinRdis H or methyl;Reis a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Reis -C0C(Ra)(Rh)Rc;Rais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

17. The peptide according to any one of claims 1-11, wherein:Z* has the formula Ic:whereinRdis H or methyl; andAr is a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, wherein Ar is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

18. The peptide according to any one of claims 1-17, wherein W* is 4- fluorotryptophan, 5 -fluor otry ptophan, 6-fluorotryptophan, 7-fluorotry ptophan, 4- cyanotryptophan, 5 -cyanotryptophan, 6-cyanotryptophan, or 7-cyanotryptophan.

19. The peptide according to claim 18, wherein W* is 7-cyanotryptophan.

20. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

21. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

22. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

23. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

24. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

25. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

26. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

27. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

28. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

29. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

30. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

31. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

32. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

33. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

34. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

35. A peptide comprising an amino acid sequence of:X3X4PEX7PX9X10X11AX13PEEX17X18RYYX22X23LRHYX28NX30X31TRQX35X36(SEQ ID: 469) wherein:X3is V, l or P; X4is R, K or P; X7is K*, wherein K* has the structure:wherein each J1, independently, is an amino acid residue, sugar residue, -C(O)-J2-O-, or -C(O)-J2- NH-; each J2, independently, is a 2-8 carbon alkylene linker wherein 1 or 2 carbon atoms are optionally independently substituted by -NH2, -OH, or -COOH and wherein the alkylene linker is straight or branched and optionally includes a C3-8cycloalkyl moiety; or each J2, independently,is -((CH2)a-O-(CH2)b)c-, wherein each a is independently 1, 2, or 3, each b is independently 1, 2, or 3, and c is 1, 2, or 3; n is 1, 2, 3, 4, or 5;R1is -J3-R2or -C(O)-J3-R2;J3is a straight or branched, saturated or unsaturated 16-22 carbon alkylene or alkenylene linker; andR2is -C(O)OH or -P(O)(OH)2;X9is G or E;X10is E or K;X11is D or D*, wherein D* is beta-aspartic acid, or D-aspartic acid;X13is A, C, K, M, N, P, R, S, T, W, Y, V, I or P;X17is W or L;X18is N or Q;X22is A, D, E, F, I, L, M, or V;X23is D, S or E;X28is I, L, or Aib;X30is E, L, W, or W*, wherein W* is tryptophan substituted by halo, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl, or tryptophan in which a ring C-H is substituted by N;X31is V or L;X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine;X36is Z*, wherein Z* has Formula la, lb, or Ic:whereinRais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group;Rdis H or methyl;Reis a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Reis -C0C(Ra)(Rh)Rc;Ar is a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, wherein Ar is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or a pharmaceutically acceptable salt thereof.

36. The peptide according to claim 35, comprising an amino acid sequence of: PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 470), wherein: X7can be K*;X13is A, C, K, M, N, P, R, S, T, W, or Y;X22is A, D, E, F, I, L, M, or V;X30is W*, wherein W* is a halo- or cyano-substituted tryptophan;X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic.

37. The peptide according to any one of claims 34-35, wherein: each J1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22.

38. The peptide according to any one of claims 34-38, comprising an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 471), wherein: X7can be K*;X13is A, C, K, M, N, P, R, S, T, W, or Y;X22is A, D, E, F, I, L, M, or V;X30is W or W*, wherein W* is a halo- or cyano-substituted tryptophan;X35is C, G, H, K, L, M, P, R, R*, Q, T, or W, wherein R* is N(alpha)-methylarginine or beta-homo-arginine; and X36can be Z*, where Z* has Formula la, lb, or Ic; each Z1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; and k is 16, 17, 18, 19, 20, 21, or 22;.

39. The peptide according to any one of claims 34-38, wherein:X13is S or T;X22is I or V;X30is W or W*, wherein W* is a halo- or cyano-substituted tryptophan; andX35is R or beta-homo-arginine.

40. The peptide according to any one of claims 34-39, comprising an amino acid sequence of:PKPEX7PEEDAX13PEEWQRYYX22ELRHYLNX30LTRQX35X36(SEQ ID NO: 472), wherein: X7can be K*;X13is S or T;X22is I or V;X30is W or W*, wherein W* is a halo- or cyano-substituted tryptophan;X35is R or beta-homo-arginine; X36can be Z*, where Z* has Formula la, lb, or Ic; each J1independently is selected from:R1is -(CH2)k-R2or -C(O)-(CH2)k-R2; k is 16, 17, 18, 19, 20, 21, or 22; or a pharmaceutically acceptable salt thereof.

41. The peptide according to any one of claims 34-40, wherein the amino acid sequence is selected from the group consisting of:PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 473);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 474);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQRZ* (SEQ ID NO: 475);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQRZ* (SEQ ID NO: 476);PKPEK*PEEDASPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 477);PKPEK*PEEDASPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 478);PKPEK*PEEDATPEEWQRYYIELRHYLNWLTRQR*Z* (SEQ ID NO: 479);PKPEK*PEEDATPEEWQRYYVELRHYLNWLTRQR*Z* (SEQ ID NO: 480);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 481);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 482);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQRZ* (SEQ ID NO: 483);PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQRZ* (SEQ ID NO: 484);PKPEK*PEEDASPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 485);PKPEK*PEEDASPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 486);PKPEK*PEEDATPEEWQRYYIELRHYLNW*LTRQR*Z* (SEQ ID NO: 487); and PKPEK*PEEDATPEEWQRYYVELRHYLNW*LTRQR*Z* (SEQ ID NO: 488).

42. The peptide according to any one of claims 34-41, wherein: each J1independently is selected from:n is 2 or 3;R1is -C(O)-J3-R2; andJ3is a straight or branched, saturated 16-20 carbon alkylene linker.

43. The peptide according to any one of claims 34-42, wherein:R1is -C(O)-(CH2)k-P(O)(OH)2; and k is 16, 17, 18, 19, 20, 21, or 22.

44. The peptide according to any one of claims 34-43, wherein:K* has the structure:wherein J is:R1is -C(O)-(CH2)k-R2.

45. The peptide according to claim 44, wherein R1is -C(O)-(CH2)k-R2.

46. The peptide according to any one of claims 34-44, wherein:Z* has the formula la:whereinRais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, - C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituentsindependently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

47. The peptide according to claim 46, wherein:Z* has the formula la:whereinRaand Rbtaken together with the carbon to which they are attached form a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl; andRcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

48. The peptide according to claim 47, wherein:Z* has the structurewherein: each R3, independently, is selected from halo, cyano, amino, nitro, C1-3alkyl, C1-3haloalkyl, -OH, -O-C1-3alkyl, or -O-C1-3haloalkyl; i is 1, 2, 3, or 4; andj is 0, 1, 2 or 3.

49. The peptide according to claim 48, wherein:Z* has the structure50. The peptide according to any one of claims 34-44, wherein:Z* has the formula lb:whereinRdis H or methyl;Reis a 9-10 membered heterocyclic group having 1-5 ring atoms selected from O, N and S, and is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Reis -C0C(Ra)(Rb)Rc;Rais H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;Rbis H, C1-3alkyl, or C1-3alkenyl, wherein alkyl or alkenyl is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH- C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Raand Rbtaken together with the carbon to which they are attached form:(i) a C3-6cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(ii) a 5-6 membered heterocyclic group having 1-3 ring atoms selected from O, N andS, wherein the 5-6 membered heterocyclic group is optionally substituted by 1 to5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl,-C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl;(iii) a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N andS, wherein the 5-6 membered heteroaryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or(iv) a 6 membered aryl group, wherein the 6 membered aryl group is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, -NHC(O)-C1-3alkyl, -OH, and -O- C1-3alkyl;Rcis phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-6 membered cycloalkyl, C1-3alkyl, or -O-C1-3alkyl, wherein Rcis optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl; or Rcis absent when Raand Rbtaken together with the carbon to which they are attached form a 5-6 membered heteroaryl group or a 6 membered aryl group.

51. The peptide according to any one of claims 34-44, wherein: Z* has the formula Ic:whereinRdis H or methyl; andAr is a 5-6 membered heteroaryl group having 1-3 ring atoms selected from O, N and S, or a 6 membered aryl group, wherein Ar is optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, oxo, CF3, C1-3alkyl, -C(O)NH-C1-3alkyl, - NHC(O)-C1-3alkyl, -OH, and -O-C1-3alkyl.

52. The peptide according to any one of claims 34-51, wherein W* is 4- fluorotryptophan, 5 -fluorotryptophan, 6-fluorotryptophan, 7 -fluorotry ptophan, 4- cyanotryptophan, 5 -cyanotryptophan, 6-cyanotryptophan, or 7-cyanotryptophan.

53. The peptide according to claim 52, wherein W* is 7-cyanotryptophan.

54. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

55. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

56. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

57. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

58. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

59. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

60. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

61. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

62. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

63. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

64. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

65. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

66. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

67. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

68. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

69. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

70. A peptide having the structure:or a pharmaceutically acceptable salt thereof.

71. A peptide having the structure :or a pharmaceutically acceptable salt thereof.

72. A pharmaceutical composition comprising a peptide according to any one of claims 1-71 and a pharmaceutically acceptable carrier, diluent, or excipient.

73. A method of treating diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea, comprising administering a therapeutically effective amount of a peptide according to any one of claims 1-71 to a patient in need thereof.

74. A method of improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression, comprising administering a therapeutically effective amount of a peptide according to any one of claims 1-71 to a patient in need thereof, thereby decreasing food intake, reducing body weight, suppressing appetite, and / or inducing satiety in the patient.

75. A method of treating or preventing binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid, comprising administering a therapeutically effective amount of a peptide according to any one of claims 1-34 to a patient in need thereof.

76. A method of reducing of gastric motility, delaying gastric emptying, or increasing physical mobility, comprising administering a therapeutically effective amount of a peptide according to any one of claims 1-71 to a patient in need thereof.

77. A method of treating or preventing comorbidities to obesity, osteoarthritis, or urine incontinence, comprising administering a therapeutically effective amount of a peptide according to any one of claims 1-71 to a patient in need thereof.

78. Use of a peptide according to any one of claims 1-71 in the treatment of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases, or sleep apnea.

79. Use of a peptide according to any one of claims 1-71 for improving lipid parameters, improving β-cell function, or delaying or preventing diabetic disease progression.

80. Use of a peptide according to any one of claims 1-71 in the treatment or prevention of binge eating disorder, bulimia nervosa, or obesity induced by administration of an antipsychotic or a steroid.

81. Use of a peptide according to any one of claims 1-71 for reducing of gastric motility, delaying gastric emptying, or increasing physical mobility.

82. Use of a peptide according to any one of claims 1-71 in the treatment or prevention of comorbidities to obesity, osteoarthritis, or urine incontinence.