hybrid peptide compounds having modified lysine residues

Abstract

Described herein are hybrid peptide compounds having modified lysine residues.

Description

Priority Declaration

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 609,335, filed December 12, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to hybrid peptide compounds having modified lysine residues. Background Technology

[0003] Peptide tyrosine-tyrosine (PYY) analogs and pharmaceutical compositions containing such analogs may have therapeutic uses for the treatment of metabolic diseases and conditions such as diabetes, obesity and type II diabetes, including associated comorbidities and conditions. Summary of the Invention

[0004] In one aspect, a peptide may include the following amino acid sequence: X3X4PEX7PX9X 10 X 11 AX 13 PEEX 17 X 18 RYYX 22 X 23 LRHYX 28 NX 30 X 31 TRQX 35 X 36 (SEQ ID: 39) in: X3 can be V, I, or P; X4 can be R, K, or P; X7 can be ,in It has the following structure: in Each Z 1 It can be independently composed of amino acid residues, sugar residues, and -C(O)-Z residues. 2 -O- or -C(O)-Z 2 -NH-; Each Z 2 It may be an alkylene linker with 2 to 8 carbon atoms, wherein one or two carbon atoms are optionally independently substituted by -NH2, -OH or -COOH, and wherein the alkylene linker may be straight-chain or branched and optionally include C. 3-8 cycloalkyl moiety; or each Z 2It can be independently -((CH2) a -O-(CH2) b ) c - where each a can be 1, 2 or 3 independently, each b can be 1, 2 or 3 independently, and c can be 1, 2 or 3; n can be 1, 2, 3, 4 or 5; R 1 Can be -Z 3 -R 2 or -C(O)-Z 3 -R 2 ; Z 3 It can be a straight-chain or branched, saturated or unsaturated 16 to 22 carbanion or alkenyl group; and R 2 It can be -P(O)(OH)2; X9 can be G or E; X 10 It can be E or K; X 11 It can be D or ,in It is either β-aspartic acid or d-aspartic acid; X 13 It can be A, C, K, M, N, P, R, S, T, W, Y, V, I, or P; X 17 It can be W or L; X 18 It can be N or Q; X 22 It can be A, D, E, F, I, L, M, or V; X 23 It can be D, S, or E; X 28 It can be I, L, or Aib; X 30 Can be E, L, W or ,in It can be tryptophan substituted with halogen, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide or heteroaryl, or tryptophan in which the cyclic CH is substituted with N; X 31 It can be V or L; X 35 Can be C, G, H, K, L, M, P, R, Q, T, or W, where It can be N(α)-methylarginine or β-homarginine; X 36 It can be Y or Z Z It can have the formula Ia, Ib, or Ic: in R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl groups, -OH, and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent; R d It can be H or methyl; R e It can be a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or Re It can be -COC(R) a (R) b )R c ; Ar can be a 5- or 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, or a 6-membered aryl group, wherein Ar can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; The C-terminal amino acid of the peptide may optionally be amidated; Or its pharmaceutically acceptable salt.

[0005] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 40), in: X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 It can be A, D, E, F, I, L, M, or V; X 30 It can be W W Tryptophan that has been substituted with a halogen or cyano group; X 35 Can be C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic.

[0006] In some embodiments, each Z 1 Can be selected independently from: , , , , , , and ; R 1 It can be -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k can be 16, 17, 18, 19, 20, 21 or 22.

[0007] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 41), in X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 It can be A, D, E, F, I, L, M, or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; X 35 Can be C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic; Each Z 1 Can be selected independently from: , , , , , , and ; R 1 It can be -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k can be 16, 17, 18, 19, 20, 21 or 22.

[0008] In some embodiments: X 13 It can be S or T; X 22 It can be I or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; and X 35 It can be R or β-homogeneous acid.

[0009] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 42), in: X7 can be K ; X 13 It can be S or T; X 22 It can be I or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; X 35 It can be R or β-high arginine; X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic; Each Z 1 Can be selected independently from: , , , , , , and ; R 1 -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k is 16, 17, 18, 19, 20, 21 or 22.

[0010] In some embodiments, a peptide may comprise an amino acid sequence selected from the group consisting of: PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRY(SEQ ID NO: 43); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRY(SEQ ID NO: 44); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRY(SEQ ID NO: 45); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRY(SEQ ID NO: 46); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 47); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 48); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 49); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 50); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Y(SEQ ID NO: 51); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Y(SEQ ID NO: 52); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Y(SEQ ID NO: 53); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Y(SEQ ID NO: 54); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 55) PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 56) PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 57) PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 58) PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRY(SEQ ID NO: 59); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRY(SEQ ID NO: 60); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRY(SEQ ID NO: 61); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRY(SEQ ID NO: 62); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 63) PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 64) PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 65) PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 66) PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Y(SEQ ID NO: 67); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Y(SEQ ID NO: 68); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Y(SEQ ID NO: 69); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQR Y(SEQ ID NO: 70); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 71) PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Z (SEQ ID NO: 72); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 73); and PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQR Z (SEQ ID NO: 74).

[0011] In some embodiments, each Z 1 Can be selected independently from: , and ; n can be 2 or 3; R 1 It can be -C(O)-Z 3 -R 2 ;and Z 3 It can be a straight-chain or branched, saturated 16 to 20 carboalkylene linker.

[0012] In some embodiments, R 1 It can be -C(O)-(CH2) k -P(O)(OH)2; and k can be 16, 17, 18, 19, 20, 21 or 22.

[0013] In some embodiments, It can have the following structure: Z can be: or ;and R 1 It can be -C(O)-(CH2) k -R 2 .

[0014] In some embodiments, R 1 It can be -C(O)-(CH2) k-R 2 .

[0015] In some embodiments, Z It can have the following formula: in R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent.

[0016] In some embodiments, Z It can have the following formula: in R a and R b Together with the carbon atoms they are attached to, they can form C atoms optionally substituted by 1 to 5 independent substituents selected from the following. 3-6 Cycloalkyl groups: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C1-3 Alkyl, -OH and -OC 1-3 Alkyl; and R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl.

[0017] In some embodiments, Z It can have the following structure in: Each R 3 It can be independently selected from halogen, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OC 1-3 Alkyl or -OC 1-3 Halogenated alkyl groups; i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0018] In some embodiments, Z It can have the following structure .

[0019] In some embodiments, Z It can have the formula Ib: in R d It can be H or methyl; R e It can be a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC1-3 alkyl; Or R e It can be -COC(R) a (R) b )R c ; R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent.

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

[0021] In some embodiments, W It can be 4-fluorotryptophan, 5-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6-cyanotryptophan, or 7-cyanotryptophan.

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

[0023] In another aspect, peptides can have the following structures: (SEQ ID NO: 24); Or its pharmaceutically acceptable salt.

[0024] In another aspect, peptides can have the following structures: (SEQ ID NO: 34); Or its pharmaceutically acceptable salt.

[0025] In another aspect, peptides can have the following structures: (SEQ ID NO: 11); Or its pharmaceutically acceptable salt.

[0026] In another aspect, peptides can have the following structures: (SEQ ID NO: 20); Or its pharmaceutically acceptable salt.

[0027] In another aspect, the pharmaceutical composition may comprise peptides as described herein and pharmaceutically acceptable carriers, diluents, or excipients.

[0028] In another aspect, methods for treating diabetes and related conditions, eating disorders, diabetic complications, cardiovascular disease, or sleep apnea may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0029] In another aspect, methods for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes may include administering a therapeutically effective amount of peptides as described herein to patients in need, thereby reducing food intake, reducing weight, suppressing appetite, and / or inducing satiety in the patient.

[0030] In another aspect, methods for treating or preventing bulimia, bulimia nervosa, or obesity induced by the use of antipsychotic drugs or steroids may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0031] In another aspect, methods for reducing gastric motility, delaying gastric emptying, or improving physical activity may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of this.

[0032] In another aspect, methods for treating or preventing comorbidities of obesity, osteoarthritis, or urinary incontinence may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0033] In another aspect, the use of peptides as described herein in the treatment of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular disease, or sleep apnea is provided.

[0034] In another aspect, the use of peptides as described herein for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes is provided.

[0035] In another aspect, the use of peptides as described herein in the treatment or prevention of bulimia nervosa, bulimia nervosa, or obesity induced by the administration of antipsychotic drugs or steroids is provided.

[0036] In another aspect, the peptides described herein are provided for use in reducing gastric motility, delaying gastric emptying, or improving physical activity.

[0037] In another aspect, the use of peptides as described herein in the treatment or prevention of comorbidities of obesity, osteoarthritis, or urinary incontinence is provided.

[0038] Other aspects, embodiments, and features will be apparent from the following description, the accompanying drawings, and the claims. Detailed Implementation

[0039] As used in this article, the term "PYY" (1-36) "PYY" refers to human peptide tyrosine-tyrosine (PYY) and contains amino acid residues 1-36 of human PYY. As used herein, the term "PYY" is... (3-36) "Refers to human PYY and contains amino acid residues 3-36 of human PYY (SEQ ID NO: 1). As used herein, the term "analyte" refers to a natural peptide or compound, such as natural PYY." (1-36) Or natural PYY (3-36) Variants, compounds, or derivatives of peptides, compounds, or derivatives. PYY (1-36) Or PYY (3-36)The “variants” refer to peptides, analogs, compounds, or derivatives in which PYY is formed. (1-36) Or PYY (3-36) One or more of the amino acids or molecular components are modified from their natural or original state. In a preferred embodiment, the peptide described herein is PYY. (3-36) Variants.

[0040] The peptides described herein are human PYY analogs that can be administered to patients as therapeutic agents to treat conditions or ailments. In preferred embodiments, the peptides can interact with NPY receptors to elicit a therapeutic response. Due to some modified substituents on the molecule, the compounds described herein can be considered heterozygous peptides, and for ease of reference, are sometimes referred to as peptides in this specification.

[0041] PYY is primarily released by L cells in the gastrointestinal tract, particularly the ileum and colon. Small amounts of PYY can be secreted by the upper digestive tract and can be found in certain localized areas of the brain. PYY exerts its biological effects by binding to neuropeptide Y (NPY) receptors, of which there are four subtypes: Y1, Y2, Y4, and Y5. These NPY receptors are present in various regions of the brain, central nervous system, intestine, and some blood vessels.

[0042] PYY has a C-terminal amide and it is primarily a 36-amino acid peptide (PYY). (1-36) It is released, and then converted into PYY by hydrolysis of its first two N-terminal amino acids (Tyr1-Pro2) by dipeptidyl peptidase-IV (DPP-IV). (3-36) As mentioned in this article, the amino acid position number refers to the position of amino acid residues in positions 1 to 36 of the reference PYY sequence.

[0043] Although PYY (1-36) Primarily activates the Y1, Y2, and Y5 isotypes with low selectivity, but PYY (3-36) It exhibits high selectivity for the Y2 isotype, while showing lower affinity for the Y1 and Y5 isotypes. Activation of the Y2 isotype has been shown to reduce appetite and food intake, while activation of the Y1 and Y5 isotypes has been shown to increase appetite and food intake.

[0044] PYY (1-36) The circulating plasma concentration of PYY is dominant during fasting. After feeding, typically within 15 minutes, the PYY level... (3-36) Plasma concentration exceeding PYY (1-36) PYY (3-36)Plasma concentrations typically peak within 60–90 minutes and remain elevated for several hours before dropping to baseline. It is believed that PYY (3-36) Through its selectivity for the Y2 subtype, it reduces appetite and gastric motility, thus exerting an anorexic effect, and may also affect insulin sensitivity and blood glucose. This makes PYY... (3-36) This makes it an attractive target for drugs used to treat various metabolic disorders, such as diabetes, obesity, and type 2 diabetes.

[0045] When applied exogenously, PYY is eliminated due to proteases and other in vivo clearance processes. (3-36) The presence of a half-life of less than 10 minutes in plasma naturally reduces its potency as an effective therapeutic agent due to the required treatment frequency. Therefore, there is an urgent need to identify PYYs with enhanced pharmacokinetic profiles, higher selectivity for NPY receptors (e.g., subtype Y2), or increased affinity. (3-36) analog.

[0046] Peptides can act as NPY receptor subtype Y2 agonists. In some embodiments, peptides can exhibit higher selectivity for NPY receptor subtype Y2 than for other NPY receptor subtypes (such as subtypes Y1, Y4, or Y5). In this regard, the potency of a peptide that is more selective for one receptor subtype than for another can be at least 2, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, or at least 100 times higher than the potency of the other receptor, as determined in vitro in receptor function assays.

[0047] In one embodiment, the peptide described herein can bind to the NPY receptor subtype Y2 with higher specificity than other subtypes Y1, Y4, and Y5. In a specific embodiment, the peptide binds to the NPY receptor subtype Y2 with higher specificity than PYY. (1-36) Or PYY (3-36) Higher specificity binding to NPY receptor subtype Y2. In other embodiments, the peptide fully activates NPY receptor subtype Y2. In yet another embodiment, the peptide herein binds to NPY receptor subtype Y2 with high potency. In a specific embodiment, the peptide binds to NPY receptor subtype Y2 with higher specificity than PYY receptor subtype Y2. (1-36) Or PYY (3-36) Greater potency binds to the NPY receptor subtype Y2.

[0048] In other embodiments, the peptides described herein exhibit similarities to PYY. (1-36) Or PYY (3-36) Compared to improved pharmacokinetic properties. In such embodiments, compared to PYY (1-36)Or PYY (3-36) In comparison, peptides have an increased half-life and / or reduced clearance. In other embodiments, the peptides described herein can, alone or in combination, lower blood glucose, reduce food intake or appetite, or reduce weight in vivo. In some embodiments, peptides can, alone or in combination, reduce blood glucose levels compared to PYY. (1-36) Or PYY (3-36) To a greater extent, it lowers blood sugar, reduces food intake or appetite, or helps with weight loss.

[0049] The peptides described herein are biologically active and highly potent against the human NPY receptor subtype Y2. In some embodiments, peptide activity and potency are determined by their efficacy in one or more human NPY receptor subtype Y2 receptor assays. In one embodiment, this efficacy is determined using a human NPY receptor subtype Y2 receptor activation assay.

[0050] The efficacy can be measured using the "half-maximum effective concentration" (EC50). 50 The half-maximum effective concentration (WMC) is the concentration at which a compound or molecule, using a dose-response curve as a reference, can elicit a biological response that is half or 50% of the baseline and maximum response.

[0051] The in vitro potency of the peptides described in this paper can be calculated as follows, where higher potency corresponds to lower EC50. 50 Value. In some embodiments, the peptides described herein bind efficiently to the NPY receptor subtype Y2.

[0052] In some embodiments, with PYY (3-36) In contrast, peptides may contain up to eight amino acid modifications and may have an optionally amidated C-terminal amino acid. Generally, throughout this application, when referring to a specific location of a PYY peptide, analogue, compound, variant, or derivative, the location referred to corresponds to PYY. (1-36) The specific location in [the document / reference]. Throughout this application, the term PYY peptide, analogue, compound, variant, or derivative refers to [the specific location of the peptide, analogue, compound, variant, or derivative corresponding to PYY]. (1-36) The presence of a specific amino acid at a certain position means that the natural (or original) amino acid at that position has been replaced by that specific amino acid or other modifications (if they are different). Therefore, human PPY can be referenced. (1-36) The identity and number of amino acid residues in the present document (e.g., modified numerical amino acid positions and the natural (or original) and final identity of the amino acid at those positions) are used to describe the PYY peptides, analogs, compounds, variants or derivatives described herein.

[0053] Amino acid residues can be identified equivalently by their full name, one-letter code, or three-letter code.

[0054] The peptide described in this article is human PYY. (3-36) Analogs, compounds or derivatives, wherein the analogues, compounds or derivatives are similar to PYY (3-36) In contrast, many amino acid residues have been modified. Such modifications may be independent or in combination and include amino acid substitution, insertion, or deletion. In some embodiments, such modifications may be independent or in combination and include non-natural or non-protein-derived amino acid substitution, insertion, or deletion. In some embodiments, such modifications may include non-amino acid modifications to amino acid functional groups, non-natural amino acid functional groups, or non-protein-derived amino acid functional groups, such as covalent linkage of substituents to such functional groups.

[0055] The term "amino acid" refers to a molecule consisting of an amino group and a carboxylic acid group, and optionally one or more additional groups commonly referred to as side chains. Amino acids can include standard, protein-derived, encoding, 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), aspartic acid (Asp; D), cysteine ​​(Cys; C), glutamine (Gln; Q), glutamic acid (Glu; E), glycine (Gly; G), histidine (His; H), isoleucine (Ile; 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 (Val; V). Amino acids may also include non-standard, non-protein-derived, non-coding, or non-natural amino acids, including those that are not present in nature or not encoded by the genetic code of natural DNA, or those that are not present in natural proteins or are not naturally produced in cells. Non-limiting examples of non-standard, non-protein-derived, non-coding, or non-natural amino acids include β-homarginine, cyanotryptophan (e.g., 7-cyanotryptophan, 6-cyanotryptophan, 5-cyanotryptophan, or 4-cyanotryptophan), tryptophan in which the CH ring is replaced by N, or azatryptophan (e.g., 4-azatryptophan, 5-azatryptophan, 6-azatryptophan, 7-azatryptophan), tryptophan substituted with halogen, methyl, trifluoromethyl, carboxylic acid, carboxamide, or heteroaryl groups, α-aminoisobutyric acid (Aib), or any D-isomer of a standard protein-derived amino acid.

[0056] Unless otherwise stated, the amino acids of peptides should be understood as L-isomers.

[0057] The term "amino acid modification" as used throughout this application refers to modifications of amino acids compared to PYY. This may result from amino acid substitution, insertion, deletion, or covalent linkage of substituents to amino acids in the peptide.

[0058] In some embodiments, one or more amino acids in the peptide may be substituted. In some embodiments, amino acids may be substituted by "conservative substitution," which is the substitution of one or more amino acids by another biologically or functionally similar amino acid. For example, conservative substitution may occur based on amino acid size, acidity, basicity, hydrophobicity, and aromaticity. In other embodiments, the peptide has amino acid substitutions in its sequence made of one or more non-standard, non-protein-derived, non-coding, or non-natural amino acids (such as amino acid mimics). In still other embodiments, the peptide has amino acid substitutions that may not be conserved substitutions but impart preferred functional, physical, or chemical properties to the peptide compared to natural or conservedly substituted amino acids.

[0059] In some embodiments, the peptide comprises one or more amino acids having covalently linked substituents. A "substituent" is a chemical group or portion connected to a side chain of a native or non-native amino acid via its functional group. In some embodiments, the substituent is covalently linked to the side chain via a direct bond or a chemical linker. In some embodiments, this corresponds to PYY. (1-36) The amino acid at position 7 (which is PYY) (3-36) The fifth amino acid in the formula may be covalently modified by a substituent. In some embodiments, the substituent is C. 16 -C 22 Fatty acids, diacids, acid phosphonates, or carboxyphosphonates. For example, in some specific embodiments, the amino acid at position 7 is lysine and the substituent may be an oxyethylene glycol fatty acid (C... 12 -C 20 () group. In other specific embodiments, the amino acid at position 36 may be amidated or otherwise substituted.

[0060] In some embodiments, with PYY (3-36) In contrast, one or more amino acids in a peptide can be deleted, either independently or in combination with one or more insertions or substitutions.

[0061] As used herein, the term "aliphatic" or "aliphatic group" means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units; or a monocyclic or bicyclic hydrocarbon (also referred to herein as a "carbocyclic" or "cycloaliphatic") that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single connection point to the rest of the molecule. Unless otherwise stated, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1 to 4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1 to 3 aliphatic carbon atoms, and in yet still other embodiments, an aliphatic group contains 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclic") means a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is not aromatic, having a single connection point to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0062] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., a carbon ring or heterocyclic ring, saturated or having one or more unsaturated units, sharing one or more atoms between the two rings of the ring system. Therefore, the term includes any permissible ring fusion, such as... Adjacent Fused or spirocyclic. As used herein, the term “heterocyclic” is a subset of “bicyclic”, requiring one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present at ring junctions and 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, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system having at least one bridge, i.e., a carbocyclic or heterocyclic ring, saturated or partially unsaturated.

[0063] The term "lower alkyl" refers to C 1-4 Straight-chain or branched alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and... Uncle Butyl.

[0064] The term "lower haloalkyl" refers to a C-aryl group that has been substituted with one or more halogen atoms. 1-4 Straight-chain or branched alkyl groups.

[0065] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or a substituted nitrogen in a heterocyclic ring, such as N (e.g., in 3,4-dihydro-2-) H -pyrrole group), NH (as in pyrrolidinyl group) or NR + (e.g., in N-substituted pyrrolidone groups).

[0066] As used herein, the term "unsaturated" means a portion having one or more unsaturated units.

[0067] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" consists of multiple methylene groups, i.e., -(CH2). n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The “substituted” alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0068] The term "alkenyl" refers to a divalent alkenyl group having at least one carbon-carbon double bond. Unless otherwise specified, the double bond may be... Cis or trans In some embodiments, the alkenyl group has a single carbon-carbon double bond. In some embodiments, the double bond is... Shun Mode In some embodiments, the double bond is trans The substituted alkenyl chain is a polymethylene group containing at least one double bond, in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group.

[0069] The term "ynynyl" refers to a divalent ynyl group having at least one carbon-carbon triple bond. The carbon-carbon triple bond can be located inside or at the end of the ynyl group, i.e., between two carbon atoms at either the end or inside of the chain or carbon atom. A substituted ynyl chain is a polymethylene group containing at least one triple bond, in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below with respect to the substituted aliphatic group. In some embodiments, the triple bond is at the terminal position and the ynyl hydrogen is optionally replaced by a substituent.

[0070] The term "halogen" refers to F, Cl, Br, or I.

[0071] The term "aryl" as used alone or as part of a larger portion (such as in "aralkyl", "aralkyloxy", or "aryloxyalkyl") refers to a monocyclic or bicyclic ring system 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 some embodiments, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc., which may have one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused with one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl, etc.

[0072] The terms "heteroaryl" and "heteroaryl-" used alone or as part of a larger group such as "heteroarylalkyl" or "heteroarylalkoxy" refer to a group that: has 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; has 6, 10, or 14 π electrons shared in the ring array; and has one to five heteroatoms in addition to a carbon atom. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaryl ring is fused with one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, wherein the group or connecting point is located on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4- H– Quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," and any term includes the optionally substituted ring. The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0073] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic portion that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above, in addition to a carbon atom. When used to refer to the ring atom of a heterocycle, the term “nitrogen” includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (e.g., in 3,4-dihydro-2-oxohydrogen ions). H - pyrrole group), NH (such as pyrrolidinyl) or + NR (e.g.) N– Substituted pyrrolidinyl group).

[0074] Heterocyclic rings can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure, and any ring atom can optionally be substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidyl, piperidinyl, pyrrololinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazine, dioxacyclohexyl, dioxopentyl, diazapyridine, oxonitrilepyridine, thiopyridine, morpholinyl, and quininyl. The terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which the heterocyclic ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinel, 3, H– Indole, benzodihydropiperanyl, phenanthridine, or tetrahydroquinolinyl. The heterocyclic group can be monocyclic or bicyclic. The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl and heterocyclic moieties are optionally substituted independently.

[0075] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to cover rings having multiple unsaturated positions, but is not intended to include aryl or heteroaryl moiety as defined herein.

[0076] As described herein, the peptides described herein may contain an "optionally substituted" portion. Generally, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogen atoms of the specified portion are replaced by a suitable substituent. Unless otherwise stated, the "optionally substituted" group may have a suitable substituent at each substituted position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents at each position may be either the same or different. Combinations of substituents may result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for the purposes disclosed herein.

[0077] Each optional substituent on the substituted carbon is a monovalent substituent, which is independently selected from: halogens; –(CH2). 0–4 R 1 ;–(CH2) 0–4 OR 1 ;-O(CH2) 0-4 R 1 ;–O–(CH2) 0–4 C(O)OR 1 ;–(CH2) 0–4 CH(OR 1 )2;–(CH2) 0– 4SR 1 ;–(CH2) 0–4 Ph, which can be R 1 Substitute; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be R 1 Replacement; –CH=CHPh, which can be replaced by R 1 Substitute; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which can be R 1 Substitution; –NO2; –CN; –N3; -(CH2) 0–4 N(R 1 )2;–(CH2) 0–4 N(R 1 )C(O)R 1 ;–N(R 1 )C(S)R 1 ;–(CH2) 0–4 N(R 1 )C(O)NR 1 2; -N(R) 1 )C(S)NR1 2;–(CH2) 0–4 N(R 1 )C(O)OR 1 ;–N(R 1 )N(R 1 )C(O)R 1 ;-N(R 1 )N(R 1 )C(O)NR 1 2;-N(R 1 )N(R 1 )C(O)OR 1 ;–(CH2) 0–4 C(O)R 1 ;–C(S)R 1 ;–(CH2) 0–4 C(O)OR 1 ;–(CH2) 0–4 C(O)SR 1 ;-(CH2) 0–4 C(O)OSiR 1 3;–(CH2) 0–4 OC(O)R 1 ;–OC(O)(CH2) 0–4 SR 1 –;SC(S)SR 1 ;–(CH2) 0–4 SC(O)R 1 ;–(CH2) 0–4 C(O)NR 1 2;–C(S)NR 1 2;–C(S)SR 1 ;–SC(S)SR 1 ,-(CH2) 0–4 OC(O)NR 1 2;-C(O)N(OR 1 )R 1 ;–C(O)C(O)R 1 ;–C(O)CH2C(O)R 1 ;–C(NOR 1 )R 1 ;-(CH2) 0–4 SSR 1 ;–(CH2) 0–4 S(O)2R 1 ;–(CH2) 0–4 S(O)2OR 1 ;–(CH2) 0–4 OS(O)2R 1 ;–S(O)2NR 12;-(CH2) 0–4 S(O)R 1 ;-N(R 1 S(O)2NR 1 2; –N(R) 1 )S(O)2R 1 ; –N(OR) 1 )R 1 ;–C(NH)NR 1 2; –P(O)2R 1 ;-P(O)R 1 2; -OP(O)R 1 2; –OP(O)(OR 1 )2; SiR 1 3; –(C 1–4 (linear or branched alkylene) O–N(R 1 )2; or –(C 1–4 (straight-chain or branched alkylene)C(O)O–N(R) 1 )2.

[0078] Each R 1 It can be hydrogen independently; C 1–6 Aliphatic group; –CH2Ph; –O(CH2) 0–1 Ph; -CH2- (5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated; partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independently occurring R 1 Together with one or more inserted atoms, it forms a ternary monocyclic or bicyclic ring with 3 to 12 saturated, partially unsaturated, or 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which can be R 1 The saturated carbon atoms are substituted with divalent substituents selected from =O and =S; or each R 1 Optionally substituted independently by a monovalent substituent selected from the following: halogen; –(CH2) 0–2 R 2 –(halogenated R) 2 ), –(CH2) 0–2 OH, –(CH2) 0–2 OR 2 –(CH2) 0–2 CH(OR 2 2;-O(halogenated R) 2 –CN, –N3, –(CH2) 0–2 C(O)R 2 –(CH2) 0–2 C(O)OH, –(CH2) 0–2C(O)OR 2 –(CH2) 0–2 SR 2 –(CH2) 0–2 SH, –(CH2) 0–2 NH2、–(CH2) 0–2 NHR 2 –(CH2) 0– 2NR 2 2, –NO2, –SiR 2 3. –OSiR 2 3. -C(O)SR 2 、 –(C 1–4 (straight-chain or branched alkylene)C(O)OR 2 Or –SSR 2 .

[0079] Each R 2 Can be independently selected from C 1-4 Aliphatic groups, -CH2Ph, –O(CH2) 0–1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R 2 The saturated carbon is either unsubstituted or, in the case of a preceding halogenation, substituted with only one or more halogens; or the optional substituents on the saturated carbon are independently selected from divalent substituents of: =O, =S, =NNR. 3 2、=NNHC(O)R 3 =NNHC(O)OR 3 =NNHS(O)2R 3 =NR 3 =NOR 3 、 –O(C(R) 3 2)) 2–3 O– or –S(C(R) 3 2)) 2–3 S–, or a divalent substituent of an ortho-substituted carbon bond to an "optionally substituted" group, is –O(CR). 3 2) 2–3 O–, where each independently occurring R 3 Selected from hydrogen, C 1–6 Aliphatic groups or unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl rings having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] When R 3 C 1–6 When the aliphatic group is present, R 3Optional halogenated, –R 2 -(halogenated R) 2 -OH, -OR 2 –O (halogenated R) 2 ), –CN, –C(O)OH, –C(O)OR 2 –NH2, –NHR 2 –NR 2 2 or –NO2 substitution, where each R 2 Can be selected independently from C 1–4 Aliphatic groups, –CH2Ph, –O(CH2) 0–1 Ph or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R 2 It is either unsubstituted or substituted by one or more halogens when there is a preceding halogen.

[0081] The optional substituents on the substituted nitrogen are independently –R 4 –NR 4 2. –C(O)R 4 –C(O)OR 4 –C(O)C(O)R 4 –C(O)CH2C(O)R 4 -S(O)2R 4 -S(O)2NR 4 2. –C(S)NR 4 2. –C(NH)NR 4 2 or –N(R) 4 )S(O)2R 4 ; where each R 4 Can be independently hydrogen, C 1–6 Aliphatic, unsubstituted -OPh or unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl rings having 0 to 4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or two independently occurring R... † Together with the inserted atoms, it forms an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0 to 4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; wherein when R † C 1–6 When the aliphatic group is present, R † Optional halogenated, –R 2 -(halogenated R) 2 -OH, -OR 2 –O (halogenated R) 2 ), –CN, –C(O)OH, –C(O)OR2 –NH2, –NHR 2 –NR 2 2 or –NO2 substitution, where each R 2 Selected independently from C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0 to 4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R 2 It is either unsubstituted or substituted by one or more halogens when there is a preceding halogen.

[0082] For therapeutic applications, including improving solubility, stability, or in vivo compatibility, the peptides described herein can preferably be formulated as pharmaceutically acceptable salts and by reaction with a variety of inorganic or organic acids or bases. The term "pharmaceutically acceptable salt" refers to a salt form of the peptide described herein that is considered safe for treating patients. The salt can be an acidic, basic, or 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 include, but are not limited to, sulfates, citrates, maleates, acetates, oxalates, hydrochlorides, hydrobromides, hydroiodates, nitrates, sulfates, hydrogen sulfates, phosphates, acid phosphates, isonicotinate, acetates, lactates, salicylates, citrates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrate, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, or pyrates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthylcarbamate)). Salts formed with free amino groups are also included, such as hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, or tartaric acid. It also includes salts that can form with free carboxyl groups, such as sodium, potassium, ammonium, sodium, lithium, calcium, iron hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, or procaine salts.

[0083] Pharmaceutically acceptable salts can be formed between one or more anionic groups of a peptide and an added cation, or between one or more cationic groups of a peptide and an added anion. The aforementioned anionic and cationic groups can be located in any component of the peptide (including, but not limited to, the peptide backbone, amino acid side chains, amino acid modifications or substituents, or peptide terminus modifications). Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N2 salts. + (C 1–4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate).

[0084] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformations)) of the structure; for example, R and S configurations, Z and E double bond isomers, and Z and E conformations for each asymmetric center. Thus, single stereochemical isomers and mixtures of enantiomers, diastereomers, and geometric isomers (or conformations) exist. Unless otherwise stated, all tautomers of peptides are within the scope of the compounds described herein. Furthermore, unless otherwise specified, the structures described herein are also intended to include compounds distinguished only by the presence of one or more isotopically enriched atoms. For example, structures having the structure of the present invention (including hydrogen replaced by deuterium or tritium, or carbon replaced by...) 13 C or 14 Compounds that are enriched by carbon substitution (C) fall within the scope of compounds described herein. Such compounds can be used, for example, as analytical tools, probes in bioassays, or as therapeutic agents as described herein.

[0085] The peptides described herein can be prepared using conventional peptide synthesis techniques. The peptides described herein can be purified using many methods known to those skilled in the art. These methods may include, but are not limited to, chromatography (e.g., reversed-phase high-performance liquid chromatography, rapid chromatography, ion exchange chromatography, hydrophilic interaction chromatography, hydrophobic interaction chromatography, gel filtration chromatography, and size exclusion chromatography), electrophoresis protocols, or extraction.

[0086] According to the embodiments described herein, the above protecting group (e.g., PG or PG) 1 The deprotection or addition of a protecting group, including the protecting groups and methods described in detail in the following literature: Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. In some embodiments, the protecting group is a suitable amino protecting group.

[0087] As used herein, the phrase “suitable amino protecting groups” is well known in the art and, when used with the nitrogen to which they are attached, includes, but is not limited to, aralkylamines, carbamates, allylamines, amides, and the like. Examples of monoprotecting groups of amines include tert-butoxycarbonyl (BOC), ethoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, benzyl (Bn), fluorenylmethoxycarbonyl (Fmoc), acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, benzoyl, and the like. Examples of biprotecting groups of amines include amines substituted with two substituents independently selected from those described above as monoprotecting groups, and further include cyclic imides such as phthalimides, maleimides, succinimides, 2,2,5,5-tetramethyl-1,2,5-azadisilacyclopentane, azides, and the like. It should be understood that when an amino protecting group is acidically hydrolyzed, its salt compound is formed. For example, when an amino protecting group is removed by treatment with an acid such as hydrochloric acid, the resulting amine compound will be formed in its hydrochloride salt form. Those skilled in the art will recognize that a variety of acids can be used to remove acid-labile amino protecting groups, and therefore a variety of salt forms are possible.

[0088] In some embodiments, deprotection includes hydrogenolysis, contact with an acid (e.g., HCl), contact with a base (e.g., piperidine, ammonia, K₂CO₃, or methylamine), or heating. According to the embodiments described herein, deprotection of the aforementioned protecting group (e.g., PG) includes the protecting groups and methods described in the following literature: Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. In some embodiments, the protecting group is a suitable amino protecting group. Deprotection can be performed in... The following text The deprotection is carried out in any solvent described. In some embodiments, deprotection is carried out in an alcohol selected from methanol, ethanol, propanol, butanol, pentanol, or hexanol. In some embodiments, deprotection is carried out in ethanol.

[0089] In any preparation method, the reaction can be carried out in a pure solution or in a solvent. A suitable medium is a solvent or solvent mixture that, in combination with the combined compounds, promotes the progress of the reaction. A suitable solvent can dissolve one or more reactant components, or alternatively, a suitable solvent can promote the agitation of a suspension of one or more reactant components. Examples of suitable solvents include protic solvents, halogenated hydrocarbons, ethers, esters, aromatic hydrocarbons, polar or nonpolar aprotic solvents, or any mixtures thereof. Such mixtures include, for example, mixtures of protic and aprotic solvents, such as benzene / methanol / water; benzene / water; DME / water, etc.

[0090] These and other suitable solvents of this kind are interchangeable, as is well known in the art; see, for example, "Advanced Organic Chemistry," Jerry March, 5th edition, John Wiley and Sons, NY. As used herein, the term “patient” means animal, preferably mammal, and most preferably human.

[0091] The term "pharmaceutically acceptable carrier, adjuvant, or catalyst" refers to a non-toxic carrier, adjuvant, or catalyst that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or catalysts that can 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, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0092] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the peptide described herein, which, when administered to a recipient, can directly or indirectly provide the peptide described herein or its active metabolites or residues.

[0093] Administration methods can be any known effective method for delivering compounds such as peptides or compositions described herein to the desired site or systemic location within the body. This includes parenteral administration of peptides or compositions, such as via intravenous, intramuscular, or subcutaneous injection, oral administration, inhalation, intranasal administration, intraperitoneal administration, intrathecal administration, transdermal administration, sublingual administration, rectal administration, buccal administration, sublingual administration, or transmucosal administration. In some embodiments, peptides described herein can be administered in a single dose or via a timed release method. In other embodiments, peptides described herein can be administered via an implantable device. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition can be administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions of 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are traditionally used as solvents or suspension media.

[0094] For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, can be used to prepare injectable formulations, as well as natural, pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0095] The pharmaceutically acceptable compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral administration, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are often also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Certain sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0096] Alternatively, pharmaceutically acceptable compositions can be administered rectally in suppository form. These can be prepared by mixing the pharmaceutical agent with a suitable, non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0097] The pharmaceutically acceptable compositions described herein can also be applied topically, particularly when the therapeutic target includes areas or organs easily accessible by topical application (including diseases of the eyes, skin, or lower intestine). Suitable topical formulations for each of these areas or organs are readily prepared.

[0098] Topical application to the lower intestine can be achieved in rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0099] For topical application, the pharmaceutically acceptable compositions provided may be formulated into suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for the topical application of the peptides described herein include, but are not limited to, mineral oils, liquid paraffin esters, leucoparaffin esters, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into suitable lotions or creams containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oils, sorbitan monostearate, polysorbate 60, cetyl esters, cetyl alcohol, 2-octyldodecanool, benzyl alcohol, and water.

[0100] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions can be prepared, and formulated as solutions in saline solutions, using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other commonly used solubilizers or dispersants, according to known techniques in pharmaceutical formulation.

[0101] Most preferably, the pharmaceutically acceptable composition is formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food.

[0102] The amount of a composition of compounds that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the provided compositions are formulated to allow administration of an inhibitory dose between 0.01 and 100 mg / kg body weight / day to patients receiving these compositions.

[0103] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the compound used, age, weight, general health status, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated.

[0104] The peptides described herein can be prepared to form pharmaceutical compositions for therapeutic applications. Formulations and preparation methods of such pharmaceutical compositions based on the previously described administration methods are known to those skilled in the art. The exact amount required varies from subject to subject, depending on the subject's species, age and general condition, severity of infection, specific drug, administration method, etc. The peptides described herein can be formulated in dose-unit form to facilitate administration and uniformity of dosage. As used herein, "dose-unit form" refers to physically discrete pharmaceutical units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions described herein will be determined by the attending physician within the bounds of reasonable medical judgment. For any specific patient or organism, a particular effective dose level depends on a variety of factors, including: the condition being treated and its severity; the activity of the specific compound used; the composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; duration of treatment; drugs used in combination with or in combination with the specific compound used; and similar factors well known in the medical field. As used herein, the term “patient” means animal, preferably mammal, and most preferably human.

[0105] The pharmaceutical compositions of the peptides described herein may also consist of pharmaceutically acceptable carriers, diluents, or excipients known to those skilled in the art. The pharmaceutically acceptable compositions described herein may be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as oral or nasal sprays, etc., depending on the severity of the infection being treated. In some embodiments, the peptides described herein may be administered orally or parenterally once or more daily at dose levels ranging from about 0.01 mg / kg to about 50 mg / kg, and preferably from about 1 mg / kg to about 25 mg / kg, according to the subject's body weight, to achieve the desired therapeutic effect.

[0106] 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 compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitol fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0107] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, for example, as solutions of 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are traditionally used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in injectable formulations.

[0108] Injectable formulations can be sterilized, for example, by filtration through a sterile filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[0109] To prolong the action of the peptides described herein, it is generally necessary to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystals or amorphous materials. The absorption rate of the compound then depends on its dissolution rate and, consequently, may depend on crystal size and morphology. Alternatively, delayed absorption of parenterally administered compounds can be achieved by dissolving or suspending the compound in an oil-based medium. Injectable long-acting formulations are prepared by forming microcapsule matrices of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The peptide release rate can be controlled depending on the compound-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include polyorthoesters and polyanhydrides. Long-acting injectable formulations are also prepared by encapsulating the compound in tissue-compatible liposomes or microemulsions.

[0110] 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 starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate; e) solution blockers such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of dosage forms such as capsules, tablets, and pills, the dosage form may also contain a buffer.

[0111] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk candy and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may optionally contain light-blocking agents and may also have compositions that release only one or more active ingredients, or preferentially release them in a portion of the intestine, optionally in a delayed manner. Examples of usable encapsulation compositions include polymers and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk candy and high molecular weight polyethylene glycol.

[0112] The active compound may also be in a microencapsulated form having one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules may be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also conventionally contain substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of dosage forms such as capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain a light-blocking agent and may also have a composition that releases only one or more active ingredients, or preferentially releases them in a portion of the intestine, optionally in a delayed manner. Examples of usable encapsulation compositions include polymers and waxes.

[0113] Dosage forms of the peptides described herein for external or transdermal application may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also considered as suitable dosage forms. Furthermore, the use of transdermal patches may offer the additional advantage of controlled delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. For example, for intramuscular or subcutaneous administration, injectable compositions can be prepared; for oral administration, tablets or capsules in immediate-release or delayed-release forms can be prepared; for inhalation, inhalers can be prepared; and for transdermal administration, creams, lotions, or skin patches can be prepared. In a specific embodiment, the pharmaceutical composition is administered subcutaneously. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0114] As described herein, the peptides exhibit potent biological activity through binding to the human NPY receptor, particularly the Y2 subtype. This receptor binding can be determined as described below.

[0115] As described in in vivo animal model experiments and clinical trials, the peptides described herein possess potent biological activity. In some embodiments, these experiments were performed using mouse models. In further embodiments, these experiments in mouse models demonstrated the biological activity and potency of the peptides herein by means of lowering blood glucose, reducing food intake, or reducing body weight, alone or in combination. This in vivo biological activity can be determined as described below. Activity and assays can be performed using PKPEK. 1 Comparison of PEEDASPEEWQRYYIELRHYLNWLTRQRY-NH2, where K 1 Lys-(oeg)-γ-Glu-C 18 Dioscortic acid (SEQ ID NO. 75), which is identified in this paper as compound Z.

[0116] In some embodiments, the peptides described herein may have an improved pharmacokinetic profile, such as with PYY. (1-36) Or PYY (3-36) Compared to an increased half-life or a decreased clearance rate, in some such embodiments, the peptide's half-life is greater than that of PYY. (1-36) Or PYY (3-36) The duration is approximately 5 hours to approximately 24 hours, particularly approximately 12 hours. This means that the peptides described in this article may not resemble PYY. (1-36) Or PYY (3-36)This allows for rapid removal through the body's clearance mechanisms, effectively increasing the amount of time the peptide remains in the body at therapeutic concentrations, and thus increasing the duration of the peptide's pharmacological effects.

[0117] The pharmacokinetic properties or profile of compounds such as the peptides described herein are typically 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 the body. Such studies can be performed using a variety of different animal models known in the art, including mice, rats, monkeys, dogs, or pigs, to measure the pharmacokinetic properties of the peptides described herein.

[0118] The pharmacokinetic properties and profile of peptides can be determined as described below.

[0119] The term "treatment" refers to the prevention (i.e., prophylaxis), reduction, alleviation, or cure of a disease, symptom, or condition. In some embodiments, the peptides or compositions described herein can be used as therapeutic agents for a variety of diseases, symptoms, or conditions. In some embodiments, the peptides or compositions described herein can be used as medicaments for a variety of diseases, symptoms, or conditions. These methods may include, but are not limited to, administering therapeutically effective amounts, frequencies, and durations of the peptides or compositions described herein to patients in need of treatment. It also describes various modes of administering these peptides or compositions to patients in need in a manner known to those skilled in the art.

[0120] In some embodiments, these methods may include administering the peptides or compositions once daily, every two days, three times a week, twice a week, once a week, once every two weeks, or once a month.

[0121] In some embodiments, the 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, juvenile-adult diabetes, gestational diabetes, or elevated HbA1C levels.

[0122] In another embodiment, the PYY analogue can be used to treat subjects with Prader-Willi syndrome, a rare and complex genetic condition associated with unsatisfactory hunger, hypotonia, short stature, cognitive deficits, and problem behaviors.

[0123] In another embodiment, the subject may have one or more forms or stages of obesity or obesity-related conditions, including being overweight.

[0124] In another embodiment, the subject may require treatment to improve β-cell function, including reducing β-cell apoptosis, increasing the number or quality of β-cells, or restoring β-cell glucose sensitivity.

[0125] In other embodiments, the subject may have an eating disorder, such as obesity, bulimia, or bulimia nervosa. In some embodiments, such a condition may be a result of a side effect of using another medication, such as an antipsychotic or steroid medication.

[0126] In another embodiment, the subject may need to reduce gastric activity or gastric emptying.

[0127] In another embodiment, the subject may have one or more lipid disorders, such as dyslipidemia, elevated serum lipids, elevated low-density lipoprotein, elevated very low-density lipoprotein, decreased high-density lipoprotein, elevated triglycerides, elevated cholesterol, elevated serum lipoprotein, or high apolipoprotein A production.

[0128] In another embodiment, the subject may have a metabolic disease.

[0129] In another embodiment, the subject may have cardiovascular disease.

[0130] In another embodiment, the subject may have sleep apnea.

[0131] In other embodiments, the subject may have comorbidities or complications that may accompany any of the aforementioned conditions, including but not limited to neuropathy, vascular disease, peripheral neuropathy, retinopathy, osteoarthritis, or urinary incontinence.

[0132] In some embodiments, the subject may have type 2 diabetes or obesity.

[0133] In some embodiments, the subject may have Predwell syndrome.

[0134] Improving the pharmacokinetic properties of PYY analogues could significantly impact their therapeutic potential in a variety of metabolic diseases, including diabetes and obesity. This could be achieved by replacing PYY with lysine residues linked to fatty acid phosphonates. (1-36) Modification of the lysine residue corresponding to K7 in PYY analogues can improve the pharmacokinetic profile, for example, by prolonging the circulating half-life and reducing the peak-to-trough ratio. This may result in a dose-dependent decrease in average food intake and increased weight loss, which can be further enhanced when used in combination with other PYY analogue modifications.

[0135] In one aspect, a peptide may include the following amino acid sequence: X3X4PEX7PX9X 10 X 11 AX 13 PEEX 17 X 18 RYYX 22 X 23 LRHYX 28 NX 30 X 31 TRQX 35 X 36 (SEQ ID: 39) in: X3 can be V, I, or P; X4 can be R, K, or P; X7 can be ,in It has the following structure: in Each Z 1 It can be independently composed of amino acid residues, sugar residues, and -C(O)-Z residues. 2 -O- or -C(O)-Z 2 -NH-; Each Z 2 It may be an alkylene linker with 2 to 8 carbon atoms, wherein one or two carbon atoms are optionally independently substituted by -NH2, -OH or -COOH, and wherein the alkylene linker may be straight-chain or branched and optionally include C. 3-8 cycloalkyl moiety; or each Z 2 It can be independently -((CH2) a -O-(CH2) b ) c - where each a can be 1, 2 or 3 independently, each b can be 1, 2 or 3 independently, and c can be 1, 2 or 3; n can be 1, 2, 3, 4 or 5; R 1 Can be -Z 3 -R 2 or -C(O)-Z 3 -R 2 ; Z 3 It can be a straight-chain or branched, saturated or unsaturated 16 to 22 carbanion or alkenyl group; and R 2 It can be -P(O)(OH)2; X9 can be G or E; X 10 It can be E or K; X 11 It can be D or ,in It is either β-aspartic acid or d-aspartic acid; X 13 It can be A, C, K, M, N, P, R, S, T, W, Y, V, I, or P; X 17 It can be W or L; X 18 It can be N or Q; X 22 It can be A, D, E, F, I, L, M, or V; X 23 It can be D, S, or E; X 28 It can be I, L, or Aib; X 30 Can be E, L, W or ,in It can be tryptophan substituted with halogen, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide or heteroaryl, or tryptophan in which the cyclic CH is substituted with N; X 31 It can be V or L; X 35 Can be C, G, H, K, L, M, P, R, Q, T, or W, where It can be N(α)-methylarginine or β-homarginine; X 36 It can be Y or Z Z It can have the formula Ia, Ib, or Ic: in R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3alkyl; R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent; R d It can be H or methyl; R e It can be a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R e It can be -COC(R) a (R) b )R c ; Ar can be a 5- or 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, or a 6-membered aryl group, wherein Ar can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; The C-terminal amino acid of the peptide may optionally be amidated; Or its pharmaceutically acceptable salt.

[0136] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 40), in: X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 It can be A, D, E, F, I, L, M, or V; X 30 It can be W W Tryptophan that has been substituted with a halogen or cyano group; X 35 Can be C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic.

[0137] In some embodiments, each Z 1 Can be selected independently from: , , , , , , and ; R 1 It can be -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k can be 16, 17, 18, 19, 20, 21 or 22.

[0138] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 41), in X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 It can be A, D, E, F, I, L, M, or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; X 35 Can be C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic; Each Z 1 Can be selected independently from: , , , , , , and ; R 1 It can be -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k can be 16, 17, 18, 19, 20, 21 or 22.

[0139] In some embodiments: X 13 It can be S or T; X 22 It can be I or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; and X35 It can be R or β-homogeneous acid.

[0140] In some embodiments, the peptide may include the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 42), in: X7 can be K ; X 13 It can be S or T; X 22 It can be I or V; X 30 It can be W or W W Tryptophan that has been substituted with a halogen or cyano group; X 35 It can be R or β-high arginine; X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic; Each Z 1 Can be selected independently from: , , , , , , and ; R 1 -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k is 16, 17, 18, 19, 20, 21 or 22.

[0141] In some embodiments, a peptide may comprise an amino acid sequence selected from the group consisting of: PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRY(SEQ ID NO: 43); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRY(SEQ ID NO: 44); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRY(SEQ ID NO: 45); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRY(SEQ ID NO: 46); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 47) PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 48) PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 49) PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 50) PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Y(SEQ ID NO: 51); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Y(SEQ ID NO: 52); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Y(SEQ ID NO: 53); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Y(SEQ ID NO: 54); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 55) PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 56) PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 57) PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 58) PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRY(SEQ ID NO: 59); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRY(SEQ ID NO: 60); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRY(SEQ ID NO: 61); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRY(SEQ ID NO: 62); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 63) PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 64) PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 65) PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 66); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Y(SEQ ID NO: 67); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Y(SEQ ID NO: 68); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Y(SEQ ID NO: 69); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQR Y(SEQ ID NO: 70); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 71); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Z (SEQ ID NO: 72); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 73); and PKPEK [[ID=7​​​​​​​​​1 Can be selected independently from: , and ; n can be 2 or 3; R 1 It can be -C(O)-Z 3 -R 2 ;and Z 3 It can be a straight-chain or branched, saturated 16 to 20 carboalkylene linker.

[0143] In some embodiments, R 1 It can be -C(O)-(CH2) k -P(O)(OH)2; and k can be 16, 17, 18, 19, 20, 21 or 22.

[0144] In some embodiments, It can have the following structure: Z can be: or ;and R 1 It can be -C(O)-(CH2) k -R 2 .

[0145] In some embodiments, R 1 It can be -C(O)-(CH2) k -R 2 .

[0146] In some embodiments, Z It can have the following formula: in R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R cIt can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent.

[0147] In some embodiments, Z It can have the following formula: in R a and R b Together with the carbon atoms they are attached to, they can form C atoms optionally substituted by 1 to 5 independent substituents selected from the following. 3-6 Cycloalkyl groups: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; and R c It can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl.

[0148] In some embodiments, Z It can have the following structure in: Each R 3 It can be independently selected from halogen, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OC 1-3 Alkyl or -OC 1-3 Halogenated alkyl groups; i can be 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

[0149] In some embodiments, Z It can have the following structure .

[0150] In some embodiments, Z It can have the formula Ib: in R d It can be H or methyl; R e It can be a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R e It can be -COC(R) a (R) b )R c ; R a Can be H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R b Can be H, C 1-3 Alkyl or C 1-3Alkenyl, wherein the alkyl or alkenyl group is optionally substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or R a and R b Together with the carbon atoms they are attached to, they can form: Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group may optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl; or A 6-membered aryl group, wherein the 6-membered aryl group may optionally be substituted by 1 to 5 substituents independently selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; R cIt can be phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c It may optionally be substituted by 1 to 5 independent substituents selected from the following: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It can be non-existent.

[0151] In some embodiments, Z It can have the formula Ic: in R d It can be H or methyl; and Ar can be a 5- or 6-membered heteroaryl group, or a 6-membered aryl group, having 1 to 3 ring atoms selected from O, N, and S, wherein Ar can optionally be substituted by 1 to 5 substituents independently selected from: halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 alkyl.

[0152] In some embodiments, W It can be 4-fluorotryptophan, 5-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6-cyanotryptophan, or 7-cyanotryptophan.

[0153] In some embodiments, W It can be 7-cyanotryptophan.

[0154] In some embodiments, the substituted lysine may have the structure K-ε-Lys-γ-Glu-C m+2 -phos (where m is 15, 16, 17, 18, 19, or 20): or K-(oeg) i -γ-Glu-C m+2 -phos (where m is 15, 16, 17, 18, 19 or 20, and i is 1, 2 or 3) In another aspect, peptides can have the following structures: (SEQ ID NO: 24); Or its pharmaceutically acceptable salt.

[0155] In another aspect, peptides can have the following structures: (SEQ ID NO: 34); Or its pharmaceutically acceptable salt.

[0156] In another aspect, peptides can have the following structures: (SEQ ID NO: 11); Or its pharmaceutically acceptable salt.

[0157] In another aspect, peptides can have the following structures: (SEQ ID NO: 20); Or its pharmaceutically acceptable salt.

[0158] In another aspect, the pharmaceutical composition may comprise peptides as described herein and pharmaceutically acceptable carriers, diluents, or excipients.

[0159] In another aspect, methods for treating diabetes and related conditions, eating disorders, diabetic complications, cardiovascular disease, or sleep apnea may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0160] In another aspect, methods for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes may include administering a therapeutically effective amount of peptides as described herein to patients in need, thereby reducing food intake, reducing weight, suppressing appetite, and / or inducing satiety in the patient.

[0161] In another aspect, methods for treating or preventing bulimia, bulimia nervosa, or obesity induced by the use of antipsychotic drugs or steroids may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0162] In another aspect, methods for reducing gastric motility, delaying gastric emptying, or improving physical activity may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of this.

[0163] In another aspect, methods for treating or preventing comorbidities of obesity, osteoarthritis, or urinary incontinence may include administering a therapeutically effective amount of a peptide as described herein to a patient in need of such treatment.

[0164] In another aspect, the use of peptides as described herein in the treatment of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular disease, or sleep apnea is provided.

[0165] In another aspect, the use of peptides as described herein for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes is provided.

[0166] In another aspect, the use of peptides as described herein in the treatment or prevention of bulimia nervosa, bulimia nervosa, or obesity induced by the administration of antipsychotic drugs or steroids is provided.

[0167] In another aspect, the peptides described herein are provided for use in reducing gastric motility, delaying gastric emptying, or improving physical activity.

[0168] In another aspect, the use of peptides as described herein in the treatment or prevention of comorbidities of obesity, osteoarthritis, or urinary incontinence is provided.

[0169] Exemplary compounds are listed in Table 1.

[0170] Table 1 Biological activity data for the exemplary compounds are listed in Table 2. Table 3 shows the elemental analysis and purity data for the exemplary compounds.

[0171] Table 3 To provide a fuller understanding of the invention described herein, the following examples are given. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0172] General Procedure Use the following general procedure to synthesize peptides.

[0173] General Program 1 (G1) Peptides were synthesized using microwave-assisted solid-phase peptide synthesis (SPPS) technology via the Fmoc / t-Bu strategy on a Liberty Blue microwave peptide synthesizer (CEM Corporation). Deprotection was performed using 20% ​​piperidine in 0.1 M Oxyma / DMF solution. Amino acid coupling was performed using a 5-fold excess of the 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 added at a scale of 0.05 or 0.1 mmol on Rink Amide ProTide Resin (LL) resin. N The end uses N -Boc protected amino acids.

[0174] General Procedure 2 (G2) Peptides containing the sequences Leu31-Thr32-Arg33-Gln34-Arg35 and non-natural C-terminal modifications were synthesized on Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Dap(mtt)-Rink amide resin using the Fmoc / t-Bu strategy on a Liberty Blue microwave peptide synthesizer (CEM Corporation). Deprotection was performed using 20% ​​piperidine in 0.1 M Oxyma / DMF solution. Amino acid coupling was performed using a 5-fold excess of the reagent. On Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Dap(mtt)-Rink amide resin, Fmoc-amino acid (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 applied at a scale of 0.05 or 0.1 mmol. Dap was deprotected and modified according to procedure F1 (see below). N The end uses N -Boc protected amino acids.

[0175] General Program 3 (G3) Peptides containing the sequence Leu31-Thr32-Arg33-Gln34-β-homoArg35 and non-natural C-terminal modifications were synthesized on a Liberty Blue microwave peptide synthesizer (CEM Corporation) using the Fmoc / t-Bu strategy and microwave-assisted solid-phase peptide synthesis (SPPS) on an amide resin. Deprotection was performed using 20% ​​piperidine in 0.1 M Oxyma / DMF solution. Amino acid coupling was performed using a 5-fold excess of the reagent. On Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β-homoArg(Pbf)-Dap(mtt)-Rink amide resin, 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 applied at a scale of 0.05 or 0.1 mmol. Dap was deprotected and modified according to procedure F1. N The end uses N -Boc protected amino acids.

[0176] Program S1 (When non-standard amino acids are present, PYY positions 7, 30, 35) The reaction was performed using 20% ​​piperidine in DMF solution (3 x 4 mL, 20 min cycles for a 0.05 mmol scale). N -Fmoc deprotection. Wash the resin with DMF (3 x 5 mL) and DCM (3 x 5 mL). Couple the specific amino acid (2 equivalents, 0.1 mmol) in DMF (1 mL) with DIC (4 equivalents, 0.4 mL, 0.5 M in DMF) and Oxyma (2 equivalents, 0.2 mL, 0.5 M in DMF) at 23 °C. After completion, wash the resin with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0177] For example, in some peptides, (2) is used at position 30. S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H-fluorene-9-yl)methoxy]carbonyl}amino)propionic acid is used to mount 7-cyanotryptophan, and in some peptides, an amino acid is used at position 7 ( S )-6-{[(2-{2-[( S )-4- Uncle -Butoxycarbonyl-4-(16- Uncle -Butoxycarbonylhexadecylcarbonylamino)butyrylamino]ethoxy}ethoxy)methyl]carbonylamino}-2-{[(9 H -fluorene-9-yl)methyl](oxycarbonylamino)}hexanoic acid, as further described below.

[0178] Program S2 Fmoc-Dap(mtt)-resin and Fmoc-Dap(ivDde)-resin Deprotection of 0.05 mmol Rink Amide ProTide Resin (LL) resin was performed using 20% ​​piperidine in DMF solution (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 specific amino acid (Fmoc-Dap(mtt)-OH or Fmoc-Dap(ivDde)-OH, 2 equivalents, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equivalents, 0.4 mL, 0.5 M in DMF) and Oxyma (2 equivalents, 0.2 mL, 0.5 M in DMF) at 23 °C. After completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0179] Program S3 (C-terminal modification) Peptide-MeNbz-G-Rink amide: Fmoc-MeDbz-G-Rink amides were prepared on a 0.1 mmol scale using S1. The remaining protected peptides were prepared using the procedure outlined in G1. DCM (10 mL) and 4-nitrobenzene chloroformate (200 mg, 1.0 mmol, 10 equivalences) were added to the resin-bound peptides and gently shaken at 23 °C for 1 h. 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 a second time with DCM (10 mL) and 4-nitrobenzene chloroformate (200 mg, 1.0 mmol, 10 equivalences) and gently shaken at 23 °C for 1 h. The solution was filtered, and the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The resin was then shaken with DIPEA (2 mL) in DMF (10 mL) at 23 °C for 1 h. The solution was filtered, and the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL) and dried to obtain activated peptide-MeNbz-G-Rink amide resin.

[0180] Adding a segment: A 2:1 CH3CN / DCM solution (1.5 mL) of a specific amine (10 equivalents) and Et3N (20 equivalents) was added to activated resin (0.0125 mmol scale). The slurry was heated to 50 °C and gently stirred for 18 hours. The slurry was filtered, washed with a minimal amount of 2:1 CH3CN / DCM, and concentrated to obtain crude protected peptides. The peptides were deprotected whole using program C1, and the crude material was purified using purification programs P1 and P2.

[0181] Fragment concatenation (PYY positions 7, 36) Program F1 -- mtt The Mtt group was deprotected using 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 (3 x 5 mL). An acid (2 equivalents, 0.1 mmol) (e.g., 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid) in DMF (1 mL) was coupled with DIC (4 equivalents, 0.4 mL, 0.5 M in DMF) and Oxyma (2 equivalents, 0.2 mL, 0.5 M in DMF) at 23 °C. After completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0182] Program F2 -- ivDde IvDde was deprotected using a 5% hydrazine DMF solution (3 x 5 mL, 30 min cycles for a 0.05 mmol scale). The resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL). The acid (2 equivalents, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equivalents, 0.4 mL, 0.5 M in DMF) and Oxyma (2 equivalents, 0.2 mL, 0.5 M in DMF) at 23 °C. After completion, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0183] Pyrolysis and post-processing conditions Program C1 Side-chain protecting groups were removed, accompanied by cleavage from the resin, and the reaction was carried out in a TFA / TIS / H2O / PhOH (88:2:5:5 v / v / v / v) solution (10 mL / 0.05 mmol) at room temperature for 3 hours. The peptide was precipitated using cold diethyl ether (30 mL / 0.05 mmol) and separated by centrifugation (3000 rpm, 10 min).

[0184] Purification conditions The crude peptide was repeatedly purified by RP-HPLC until a purity >95% was obtained. Purification conditions are listed below; suitable fractions were combined and lyophilized. The purity of the PYY analogue was checked by analytical RP-HPLC, and its identity was confirmed by LCMS.

[0185] Program P1: Program P2: Program P3: Program P4: Program P5: Analysis conditions The purity of the peptides was examined by analytical RP-HPLC, and identity was confirmed by LCMS under the following conditions.

[0186] Intermediate ACW-41 Methyl 17-bromoheptadecanoate (COCl)₂ (3.45 g, 1.0 equivalent) was added to a solution of 17-bromoheptadecanoic acid (9.5 g, 27.2 mmol) in DCM (100 mL) and DMF (19.9 mg) at 15 °C under N₂. The reaction mixture was stirred at 15 °C for 1.5 h, and 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 equivalent) was added. The reaction mixture was heated to 15 °C and stirred for 2 h. After completion, the reaction mixture was quenched by adding saturated sodium bicarbonate aqueous solution (100 mL) and then extracted with DCM (100 mL x 2). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain a white solid methyl 17-bromoheptadecanoate (7 g, yield 71%). 1 H 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).

[0187] 17-(II-) Uncle Methyl heptadecanoate (-butoxyphosphoryl) NaH (1.47 g, 2.0 equivalent, 60% w / w dispersion) was added to a solution of methyl 17-bromoheptadecanoate (7.16 g, 2.0 equivalent) in DMF (60 mL) after cooling to 0–5 °C. The reaction mixture was stirred at 0–5 °C for 0.5 h, followed by the addition of methyl 17-bromoheptadecanoate (6.7 g, 18.44 mmol) in DMF (60 mL). The reaction mixture was stirred at 20 °C for 15.5 h. After completion, the reaction was quenched with a saturated aqueous solution of ammonium chloride (500 mL) and 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 the residue, which was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 10:1 to 0:1) to give a colorless oily 17-(di- Uncle Methyl butoxyphosphoryl)heptadecanoate (8 g, yield 91%). 1 H 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).

[0188] 17-(II-) Uncle (-Butoxyphosphoryl)heptadecanoic acid To 17-(II-) Uncle Methyl heptadecanoate (8 g, 16.78 mmol) in a solution of THF (40 mL) and H2O (40 mL) was mixed with LiOH·H2O (1.41 g, 33.57 mmol). The mixture was stirred at 20 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to remove THF. The pH of the reaction mixture was adjusted to 6 with HCl (1 M), and the aqueous phase was extracted with EtOAc (80 mL × 3). The combined organic extracts were concentrated under reduced pressure to the residue, which was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 10:1 to 0:1) to obtain a white solid 17-(di- Uncle (-Butoxyphosphoryl)heptadecanoic acid (6.2 g, yield 80%). 1 H 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).

[0189] (2 S )-2-(benzyloxycarbonylamino)-6-(9 H fluorene-9-ylmethoxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester DIPEA (10.4 mL, 10 equivalents) and N6-(((9H-fluorene-9-yl)methoxy)carbonyl)-N2-((benzyloxy)carbonyl)-L-lysine (6.03 g, 2.0 equivalents) were added to a slurry of chlorotriphenylmethyl resin (1 mmol / g in resin, 6 g resin) in DCM (50 mL). The reaction mixture was stirred for 16 hours under nitrogen purging at 20 °C. The resin was filtered and washed with MeOH (50 mL × 3), DMF (50 mL × 3), and DCM (50 mL × 3), and the resin was used for the next step.

[0190] (2 S 6-amino-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester At 20℃, (2) S 4.68 g, 6.01 mmol) of 2-(benzyloxycarbonylamino)-6-(9H-fluorene-9-ylmethoxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (DMF) in DMF (40 mL) and piperidine (10 mL) was stirred under nitrogen for 15 minutes. The resin was filtered and additional piperidine (10 mL) and DMF (40 mL) were added, and the process was repeated. The resin was filtered, washed with DMF (50 mL × 3) and DCM (50 mL × 3), and then proceeded to the next step.

[0191] (2 S )-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-(9 H -fluorene-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetyl]amino]hexanoic acid[(2-chlorophenyl)-diphenylmethyl] ester HOBt (1.63 g, 2.0 equivalent), DIPEA (3.89 g, 5.0 equivalent), and HCTU (4.98 g, 2.0 equivalent) were added to a slurry of 1-(9H-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-carboxylic acid (4.64 g, 2.0 equivalent) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 30 minutes, and then added to (2 S The reaction mixture was added to 6-amino-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (3.35 g, 6.01 mmol). The reaction mixture was stirred at 20 °C for 15.5 h under nitrogen. At this point, pyrolysis was tested, and LC-MS analysis of the pyrolysis products indicated complete consumption of the starting resin. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0192] (2 S )-6-[[2-[2-(2-aminoethoxy)ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (2) S 2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[2-(9H-fluorene-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (5.56 g, 6.01 mmol) was suspended in piperidine (10 mL) and DMF (40 mL) and stirred at 20 °C for 15 min. The resin was filtered and the piperidine treatment in DMF was repeated. The resin was filtered and washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0193] (2 S )-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4-(9H-fluoren-9-ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester HOBt (1.62 g, 2.0 equivalent), DIPEA (5.3 mL, 5.0 equivalent), and HCTU (4.96 g, 2.0 equivalent) were added to a solution of (S)-4-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (5.11 g, 2.0 equivalent) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 30 minutes, and then added to the resin (2 S The reaction mixture was added to 6-[[2-[2-(2-aminoethoxy)ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (4.21 g, 6 mmol). The reaction mixture was stirred under nitrogen at 20 °C for 16 h, followed by resin pyrolysis testing and analysis by LC-MS indicating complete consumption of the starting resin. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0194] (2 S )-6-[[2-[2-[2-[[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (2) S 2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4-(9H-fluorene-9-ylmethoxycarbonylamino)-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (6.66 g, 6.00 mmol) was suspended in piperidine (20 mL) and DMF (80 mL) and the reaction mixture was stirred under nitrogen at 20 °C for 15 min. The resin was filtered and the piperidine treatment in DMF was repeated. The resin was washed with DMF (100 mL x 3) and DCM (100 mL x 3) and proceeded to the next step.

[0195] (2 S )-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[(4 S )-5- Uncle [-Butoxy-4-(17-di-tert-butoxyphosphorylheptadecanoylamino)-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid[(2-chlorophenyl)-diphenylmethyl] ester] To 17-(II-) Uncle HOBt (1.22 g, 1.5 equivalents), DIPEA (3.1 mL, 3.0 equivalents), and HCTU (3.72 g, 1.5 equivalents) were added to a solution of (2)-butoxyphosphoryl)heptadecanoic acid (4.16 g, 1.5 equivalents) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 30 minutes, and then added to (2) S 6-[[2-[2-[2-[[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (5.33 g, 6 mmol). The reaction mixture was stirred under nitrogen at 20 °C for 16 h, followed by resin pyrolysis testing and analysis by LC-MS indicating complete consumption of the starting resin. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0196] (2 S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle - (butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosanonic acid At 20°C, (2) DCM (50 mL) and TFA (0.5 mL) will be used in combination. S )-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[(4 S[(2-chlorophenyl)-diphenylmethyl] ester (7.99 g, 6.00 mmol) of 5-tert-butoxy-4-(17-di-tert-butoxyphosphorylheptadecanoylamino)-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (7.99 g, 6.00 mmol) was stirred under nitrogen for 15 min. The resin was filtered and reused for TFA treatment in DCM. The resin was then filtered and washed with DCM (3×). The filtrate and wash were combined and diluted with water (50 mL). Saturated NaHCO3 aqueous solution was added to neutralize the TFA, and then the pH was adjusted to 5 with HCl aqueous solution (1 M). The organic phase was separated, washed with H2O (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil (2 S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosananoic acid (6.3 g, 5.97 mmol, yield >99%). m / z (ESI, +ve ion) = 1055.7 [M+H) + .

[0197] (2 S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosanonic acid Under N2 atmosphere, towards (2) S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle(-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosananoic acid (5.3 g, 5.02 mmol) was added to a solution of MeOH (53 mL) and HCl (0.1 M, 75.3 mL) with Pd / C (5 g, 10 wt%). The suspension was degassed and purged three times with H2 (50 psi). The reaction mixture was stirred at 30 °C for 3 h with H2 (50 Psi). After completion, the reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (7.5 mL) and H2O (50 mL). The filtrate and washings were combined and the pH was adjusted to 7 with NaHCO3 (1.5 equivalent, 633 mg). The filtrate was concentrated under reduced pressure to obtain a yellow, oily crude (2 S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosananoic acid (4.63 g). The crude product can be used in the next step without further purification. m / z (ESI, +ve ion) = 921.6 [M+H) + .

[0198] (2 S 20 S )-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosanonic acid To (2) S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle(-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosananoic acid (4.63 g, 5.03 mmol) was added to a solution of dioxane (25 mL) and H₂O (25 mL) with NaHCO₃ (4.22 g, 10.0 equivalent) and FMOC-OSU (1.86 g, 1.1 equivalent). The reaction mixture was stirred at 20 °C for 16 hours. After completion, the reaction mixture was adjusted to pH 5 with HCl (1 M, 70 mL) and extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 0:1, to ethyl acetate: methanol = 10:1) to obtain a white solid ACW-41 (2 S 20 S )-2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-38-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazaoctacosananoic acid (4.24 g, yield 72%, purity 98.2%). m / z (ESI, +Ve ion) = 488.4 [1 / 2M+H] + . 1 H NMR (400 MHz, DMSO- 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).

[0199] Intermediate ACW-42 (2 S 2-(benzyloxycarbonylamino)-6-(9H-fluorene-9-ylmethoxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester DIPEA (7.75 g, 60.00 mmol) was added to the slurry of Cl-Trt resin (1 mmol / g in resin, 6 g resin) in DCM (50 mL). N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)-L-lysine (6.03 g, 12.00 mmol). The reaction mixture was stirred under nitrogen purging at 20 °C for 16 h. The resin was filtered off and washed with MeOH (50 mL × 3), DMF (50 mL × 3), and DCM (50 mL × 3) before proceeding to the next step. m / z (ESI, +ve ion) = 525.2 [M+H] + .

[0200] (2 S 6-amino-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester At 20℃, (2) SA slurry of 2-(benzyloxycarbonylamino)-6-(9H-fluorene-9-ylmethoxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (4.68 g, 6.01 mmol) in DMF (40 mL) and piperidine (10 mL) was agitated under nitrogen for 15 minutes. The resin was filtered and the deprotection procedure was repeated. The resin was filtered, washed with DMF (50 mL x 3) and DCM (50 mL x 3), and then proceeded to the next step.

[0201] (2 S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-(tert-butoxycarbonylamino)-6-(9H-fluoren-9-ylmethoxycarbonylamino)hexanoyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester Towards N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysine (5.64 g, 12.03 mmol) was added to a solution of HOBt (1.63 g, 12.03 mmol), DIPEA (3.89 g, 30.07 mmol), and HCTU (4.98 g, 12.03 mmol) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 30 minutes. The above solution was added to (2 S The reaction mixture was prepared in 6-amino-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (3.35 g, 6.01 mmol). The reaction mixture was stirred under nitrogen at 20 °C for 15.5 h and filtered. Aliquots of the resin were tested for lysis with 1 mL of 1% TFA in DCM for 1 min, followed by dilution of the lysis solution with MeOH and LCMS analysis showing complete consumption of the initial resin. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0202] (2 S )-6-[[(2 S )-6-amino-2-( Uncle [-Butoxycarbonylamino]hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)diphenylmethyl] ester (ACW-42-2B) At 20℃, while stirring, (2) S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-(9 H [-fluorene-9-ylmethoxycarbonylamino]hexanoyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (6.05 g, 6 mmol) was treated with 20% v / v piperidine in DMF (100 mL) for 15 min. The resin was filtered and the deprotection process was repeated. The resin was filtered, washed with DMF (50 mL x 3) and DCM (50 mL x 3), and then proceeded to the next step.

[0203] (2 S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4 S )-5- Uncle -butoxy-4-(9 H [-fluorene-9-ylmethoxycarbonylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester Towards( S )-4-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-5-( Uncle (-Butoxy)-5-oxovalerate (5.10 g, 11.99 mmol) was added to a solution of HOBt (1.62 g, 11.99 mmol), DIPEA (3.88 g, 29.99 mmol), and HCTU (4.96 g, 11.99 mmol) in DMF (50 mL). The reaction mixture was stirred at 20 °C for 30 minutes, and then added to (2 S )-6-[[(2 S[(2-chlorophenyl)diphenylmethyl] ester (4.71 g, 6.00 mmol) of 6-amino-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid. The reaction mixture was stirred under nitrogen at 20 °C for 15.5 h. At this point, resin cleavage tests and analysis by LCMS showed complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0204] (2 S )-6-[[(2 S )-6-[[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester At 20℃, (2) S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4 S )-5- Uncle -butoxy-4-(9 H [-fluorene-9-ylmethoxycarbonylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (7.15 g, 6.00 mmol) was stirred for 15 minutes in a slurry of 20% v / v piperidine in DMF (100 mL). The resin was filtered and the deprotection process was repeated. The resin was filtered, washed with DMF (100 mL x 3) and DCM (100 mL x 3), and then proceeded to the next step.

[0205] (2 S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-(tert-butoxycarbonylamino)-6-[[(4 S )-5-tert-butoxy-4-(17-di- Uncle [-Butoxyphosphorylheptadecanoylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid [(2-chlorophenyl)diphenylmethyl] ester To 17-(II-) Uncle(-Butoxyphosphoryl)heptadecanoic acid (4.16 g, 8.99 mmol) was added to a solution of HOBt (1.22 g, 8.99 mmol), DIPEA (3.87 g, 29.98 mmol), and HCTU (3.72 g, 8.99 mmol) in DMF (80 mL). The reaction mixture was stirred at 15 °C for 30 minutes. The above solution was added to (2... S )-6-[[(2 S )-6-[[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (5.82 g, 6.00 mmol). The reaction mixture was stirred under nitrogen at 15 °C for 15.5 h. At this time, the resin aliquots were tested for pyrolysis and analysis by LCMS showed that unreacted starting resin remained. The resin was filtered. 17-(di-)-[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]-2-(tert-butoxycarbonylamino)hexanoic acid [(2-chlorophenyl)-diphenylmethyl] ester (5.82 g, 6.00 mmol). Uncle HOBt (405.1 mg, 3.00 mmol), DIPEA (1.55 g, 11.99 mmol), and HCTU (1.24 g, 3.00 mmol) were added to (1.39 g, 3.00 mmol) butoxyphosphoryl heptadecanoic acid (1.39 g, 3.00 mmol). The reaction mixture was stirred at 15 °C for 30 min and then added to the starting resin (5.82 g, 6.00 mmol). The reaction mixture was stirred under nitrogen at 15 °C for 15.5 h. Cleavage tests on aliquots of the resin showed complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (50 mL x 3) and DCM (50 mL x 3) before proceeding to the next step.

[0206] N 2 -((benzyloxy)carbonyl)- N 6 -( N 6 -(( S )-5-(tert-butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-L-lysyl)-L-lysine At 20℃, (2) S)-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-(tert-butoxycarbonylamino)-6-[[(4 S )-5-tert-butoxy-4-(17-di- Uncle [(2-chlorophenyl)diphenylmethyl] ester (8.49 g, 6.00 mmol) was cleaved in a slurry of DCM (100 mL) and TFA (1 mL) under nitrogen for 15 min. The resin-bound compound was then filtered and the cleavage process was repeated twice. The resin was filtered and washed three times with DCM. The filtrate and washes were combined and neutralized with an aqueous solution of 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 obtain a yellow oily N2O. 2 -((benzyloxy)carbonyl)-N 6 -(N 6 -(( S )-5-(tert-butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N 2 -( Uncle (-Butoxycarbonyl)-L-lysyl)-L-lysine (11 g, crude product). m / z (ESI, +ve ion) = 1055.7 [M+H) + .

[0207] N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-L-lysyl)-L-lysine Under Ar atmosphere to N 2 -((benzyloxy)carbonyl)-N 6 -(N 6 -(( S )-5-(tert-butoxy)-4-(17-(di- Uncle-Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)-N 2 -( Uncle Pd / C (4.5 g, 4.23 mmol, 10 wt%) was added to a solution of (-butoxycarbonyl)-L-lysyl)-L-lysine (9 g, 7.91 mmol) in MeOH (90 mL) and HCl (0.1 M, 118.58 mL). The suspension was degassed and purged twice with H2. The reaction mixture was stirred at 30 °C under H2 (50 Psi) for 3 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat, 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 equivalent, 1 g) and concentrated under reduced pressure to obtain a colorless oil. N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-lysyl)-L-lysine (7.94 g, 7.91 mmol). The crude product can be used in the next step without purification. m / z (ESI, +ve ion) = 1004.8 [M+H) + .

[0208] N 2 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-L-lysyl)-L-lysine (ACW-42) Towards N 6 -( N6 -(( S )-5-( Uncle -butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-lysyl)-L-lysine (7.94 g, 7.91 mmol) was added to a solution of dioxane (40 mL) and H₂O (40 mL) along with 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 h. The pH of the reaction mixture was then adjusted to approximately 5 with HCl (1 M, 70 mL), and the aqueous phase was extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:1 to 0:1, to ethyl acetate: methanol = 10:1) to obtain a crude product, which was further purified by preparative HPLC (column: Welch Ultimate C18 250 × 70 mm × 10 μm; mobile phase: [H2O(10 mM NH4HCO3)-ACN]; gradient: 50%-80% B over 20.0 min) to obtain a white solid ACW-42. N 2 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(17-(di- Uncle -Butoxyphosphoryl)heptadecanamido)-5-oxopentanoyl)- N 2 -( Uncle (-Butoxycarbonyl)-L-lysyl)-L-lysine (4.5 g). m / z (ESI, +ve ion) = 1226.5 [M+H] + . 1 H NMR (400 MHz, DMSO- d6 ) δ 8.12 (br d, J=7.2 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.89 (d, J = 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).

[0209] Intermediate ACW-43 methyl 19-bromononadecanoate (COCl)₂ (3.5 mL, 1.0 equivalence) was added to a solution of 19-bromononadecanoic acid (15 g, 39.75 mmol) in DCM (250 mL) and DMF (31 μL) at 15 °C. The reaction mixture was stirred at 15 °C for 1.5 h, and 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 equivalence) was added. The reaction mixture was stirred at 15 °C for 2 h. After completion, the reaction mixture was quenched by adding saturated aqueous NaHCO₃ solution (500 mL) and then extracted with EtOAc (500 mL x 2). The combined organic extracts were dried over (Na₂SO₄) and concentrated under reduced pressure to obtain methyl 19-bromononadecanoate (23 g) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 3.67 (s, 3H),3.42 (t, J = 6.9 Hz, 2H), 2.31 (t, J = 7.5 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).

[0210] 19-(II-) Uncle Methyl butoxyphosphoryl)nonadecanoate Add NaH (3.18 g, 2.0 equivalent, 60 wt%) to a solution of methyl 19-bromononadecanoate (15.56 g, 39.75 mmol) in DMF (500 mL) that has been cooled to 0–5 °C. After 30 minutes, add 2– Uncle 19-Butoxyphosphono-2-methylpropane (15.44 g, 79.50 mmol). The mixture was heated to 20 °C and stirred for 16 hours. After completion, the reaction was quenched with a saturated aqueous solution of NH4Cl (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 obtain a white solid crude 19-(di- Uncle methyl butoxyphosphoryl)nonadecanoate (18.43 g). 1H NMR (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).

[0211] 19-(II-) Uncle (-Butoxyphosphoryl)nonadecanoic acid To 19-2- Uncle methyl butoxyphosphoryl nonadecanoate (18.43 g, 36.52 mmol) was added to a solution of THF (150 mL) and H2O (150 mL) with LiOH·H2O (3.10 g, 2.0 equivalence). The reaction mixture was stirred at 20 °C for 16 h. After completion, HCl (1 M, 73.8 mL) was added. The reaction was quenched with 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 the residue, which was purified by silica gel chromatography to obtain a white solid 19-(di- Uncle (-Butoxyphosphoryl)nonadecanoic acid (18.42 g). 1 H 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).

[0212] N 6 -(((9H-fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester At 15°C, Cl-Trt resin (1 mmol / g in resin, 30 g resin) and DIPEA (52.3 mL, 10.0 equivalent) were added to a slurry in DCM (600 mL). N 6 -(((9 H-fluorene-9-yl)methoxy)carbonyl)- N 2 A solution of -((benzyloxy)carbonyl)-L-lysine (22.62 g, 1.5 equivalents) in DCM (500 mL) was prepared, and the reaction mixture was then stirred 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), and DCM (400 mL x 3), and then proceeded to the next step.

[0213] ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester Will N 6 -(((9H-fluorene-9-yl)methoxy)carbonyl)- N 2 The slurry of -((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester (23.38 g, 30 mmol) in piperidine (30 mL) and DMF (120 mL) was stirred at 25 °C for 15 minutes and the reaction mixture was filtered. This procedure was repeated twice to ensure complete removal of Fmoc. The resin was washed with DMF (400 mL x 3) and DCM (400 mL x 3) and then proceeded to the next step.

[0214] ( S )-18-(((benzyloxy)carbonyl)amino)-1-(9 H -fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oic acid [(2-chlorophenyl)diphenylmethyl] ester To 1-(9) HHOBt (6.08 g, 1.5 equivalence) (17.34 g, 1.5 equivalence) was added to a solution of ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester (16.71 g, 30 mmol) in DMF (100 mL). The reaction mixture was stirred at 25 °C for 30 min, and then added to a solution of ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester (16.71 g, 30 mmol) in DMF (300 mL). The reaction mixture was stirred at 25 °C for 2 h, at which point cleavage tests and analysis by LCMS showed that the reactant ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester was completely consumed. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0215] N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)- N 2 -((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester Will( S )-18-(((benzyloxy)carbonyl)amino)-1-(9 H The slurry of fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oic acid [(2-chlorophenyl)diphenylmethyl] ester (27.73 g, 30 mmol) in piperidine (100 mL) and DMF (400 mL) was stirred at 25 °C for 15 minutes and the reaction mixture was filtered. This procedure was repeated twice to ensure complete removal of Fmoc. The resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) and then proceeded to the next step.

[0216] ( S )-27-(((benzyloxy)carbonyl)amino)-1-(9 H -fluorene-9-yl)-3,12,21-trioxo-2,7,10,16,19-pentaoxa-4,13,22-triazaoctacosane-28-oic acid [(2-chlorophenyl)diphenylmethyl] ester To 1-(9)H 28.91 g (2.5 equivalents) of fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-carboxylic acid was added to a solution of fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-carboxylic acid in DMF (400 mL). HCTU (31.03 g, 2.5 equivalents), HOBt (10.13 g, 2.5 equivalents), and DIPEA (31.4 mL, 6.0 equivalents) were added. The reaction mixture was stirred at 25 °C for 30 minutes, and then added to... N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)- N 2 -((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester (21.07 g, 30 mmol) was added to a slurry of DMF (300 mL). The reaction mixture was stirred at 25 °C for 3 hours, during which time the cleavage indicator was tested. N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)- N 2 -((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester was completely consumed. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0217] ( S )-1-amino-23-(((benzyloxy)carbonyl)amino)-8,17-dioxo-3,6,12,15-tetraoxa-9,18-diazatocetane-24-acid [(2-chlorophenyl)diphenylmethyl] ester Will( S )-27-(((benzyloxy)carbonyl)amino)-1-(9 H A slurry of fluorene-9-yl)-3,12,21-trioxo-2,7,10,16,19-pentaoxa-4,13,22-triazaoctacosano-28-oic acid [(2-chlorophenyl)diphenylmethyl] ester (32.1 g, 30 mmol) in piperidine (100 mL) and DMF (400 mL) was stirred at 25 °C for 15 minutes and filtered through the resin. This procedure was repeated twice to ensure complete removal of Fmoc. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) before proceeding to the next step.

[0218] (2 S 29S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-29-(((benzyloxy)carbonyl)amino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle butyl)-30-[(2-chlorophenyl)diphenylmethyl] ester To (S)-4-((((9) H -fluorene-9-yl)methoxy)carbonyl)amino)-5-( Uncle HCTU (31.03 g, 1.5 equivalents), HOBt (10.13 g, 1.5 equivalents), and DIPEA (26.1 mL, 3.0 equivalents) were added to a solution of (-butoxy)-5-oxovalerate (31.91 g, 1.5 equivalents) in DMF (400 mL). The reaction mixture was stirred at 25 °C for 30 minutes and then added to ( S 1-Amino-23-(((benzyloxy)carbonyl)amino)-8,17-dioxo-3,6,12,15-tetraoxa-9,18-diazatocetane-24-acid [(2-chlorophenyl)diphenylmethyl] ester (25.4 g, 30 mmol) was added to a slurry of DMF (400 mL). The reaction mixture was stirred at 25 °C for 2 hours, during which time the pyrolysis indicator was tested. S The 1-amino-23-(((benzyloxy)carbonyl)amino)-8,17-dioxo-3,6,12,15-tetraoxa-9,18-diazatocetane-24-acid [(2-chlorophenyl)diphenylmethyl] ester was completely consumed. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0219] (2 S 29 S )-2-amino-29-(((benzyloxy)carbonyl)amino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle butyl)-30-[(2-chlorophenyl)diphenylmethyl] ester (2) S 29 S )-2-((((9 H-fluorene-9-yl)methoxy)carbonyl)amino)-29-(((benzyloxy)carbonyl)amino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle A slurry of (-butyl)-30-[(2-chlorophenyl)diphenylmethyl] ester (18.82 g, 15 mmol) in piperidine (30 mL) and DMF (120 mL) was stirred at 25 °C for 15 minutes and the resin was filtered off. This procedure was repeated twice to ensure complete removal of Fmoc. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) and then proceeded to the next step.

[0220] (2S,29S)-29-(((benzyloxy)carbonyl)amino)-2-(19-(di- Uncle -Butoxyphosphoryl)nonadecanylamino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle 30-Butyl)30-[(2-chlorophenyl)diphenylmethyl] ester To 19-(II-) Uncle (-Butoxyphosphoryl)nonadecanoic acid (19.87 g, 2.7 equivalents) was added to a solution of DMF (400 mL) with HCTU (16.75 g, 2.7 equivalents), HOBt (5.47 g, 2.7 equivalents), and DIPEA (18.3 mL, 7.0 equivalents). The reaction mixture was stirred at 25 °C for 30 minutes and then added to (2 S 29 S )-2-amino-29-(((benzyloxy)carbonyl)amino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle (-Butyl)-30-[(2-chlorophenyl)diphenylmethyl] ester (15.49 g, 15 mmol) was added to a slurry of DMF (400 mL). The reaction mixture was stirred at 25 °C for 2 h, at which point cleavage testing and analysis by LCMS indicated complete consumption of the reactants were performed. The reaction mixture was filtered, and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0221] (2 S 29 S )-2-(((benzyloxy)carbonyl)amino)-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle (-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonadecanoic acid (2S,29S)-29-(((benzyloxy)carbonyl)amino)-2-(19-(di- Uncle -Butoxyphosphoryl)nonadecanylamino)-5,14,23-trioxo-9,12,18,21-tetraoxa-6,15,24-triazatriacontivacosanoic acid 1-( Uncle 30-[(2-chlorophenyl)diphenylmethyl] ester (22.58 g, 15.00 mmol) in a slurry of TFA (4 mL) and DCM (396 mL) was stirred at 15 °C for 10 min and the reaction mixture was filtered. This procedure was repeated four times to ensure complete pyrolysis. 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 give the desired crude phosphonate (32.4 g) as a brown oil.

[0222] (2 S 29 S )-2-amino-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle (-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonadecanoic acid To (2) S 29 S )-2-(((benzyloxy)carbonyl)amino)-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle(-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonacosananoic acid (27 g, 21.98 mmol) was added to a solution of MeOH (330 mL) with Pd / C (15 g, 14.10 mmol, 10 wt%, 0.64 equivalents) and HCl (0.1 M, 329.7 mL). The suspension was degassed and purged three times with H2. The reaction mixture was stirred at 30 °C under H2 (50 Psi) for 3 hours. After completion, the reaction mixture was filtered through a diatomaceous earth mat, and NaHCO3 (2.77 g) was added, followed by filtration of the slurry. The filtrate was concentrated to obtain a colorless, oily crude amine (30 g). m / z (ESI, +ve ion) = 1094.8 [M+H] + .

[0223] (2 S 29 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle (-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonadecanoic acid (ACW-43) To the (2) that have been pre-cooled to 0-5℃ S 29 S )-2-amino-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle(-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonacosananoic acid (24.05 g, 21.98 mmol) was added to a solution of dioxane (30 mL) and H₂O (30 mL) along with FMOC-OSU (8.90 g, 1.2 equivalents) and Na₂CO₃ (23.3 g, 10.0 equivalents). The reaction mixture was heated to room 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 obtain a residue, which was then purified by rapid silica gel chromatography (ethyl acetate: methanol = 1:0 to 3:1) to obtain the desired phosphonate ACW-43, a white solid (2... S 29 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-29-( Uncle -Butoxycarbonyl)-49-(di- Uncle (-Butoxyphosphoryl)-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraaza-tetranonacosananoic acid (13 g, yield 43%, purity 95.3%). m / z (ESI, +Ve ion) = 1316.8 [M+H) + . 1H NMR (400 MHz, DMSO-d6) δppm 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 (brs, 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).

[0224] Intermediate ACW-46 (2 S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4S)-5- Uncle -butoxy-4-(19-di- Uncle [-Butoxyphosphorylnonadecanoylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid [(2-chlorophenyl)diphenylmethyl] ester To 19-(II-) Uncle (-Butoxyphosphoryl)nonadecanoic acid (6.44 g, 1.5 equivalents) was added to a solution of HOBt (1.77 g, 1.5 equivalents), DIPEA (7.6 mL, 5.0 equivalents), and HCTU (5.43 g, 1.5 equivalents) in DMF (200 mL). The reaction mixture was stirred at 15 °C for 30 minutes and then added to (2 S )-6-[[(2S )-6-[[(4 S )-4-amino-5- Uncle [-butoxy-5-oxo-pentanoyl]amino]-2-( Uncle [-Butoxycarbonylamino]hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)diphenylmethyl] ester (8.49 g, 8.75 mmol). The reaction mixture was stirred under nitrogen at 15 °C for 15.5 h, at which time cleavage tests and analysis by LCMS indicated the remaining starting material. Additional 19-(di-)butoxycarbonylamino]hexanoyl]amino]-2-(benzyloxycarbonylamino)hexanoic acid [(2-chlorophenyl)diphenylmethyl] ester (8.49 g, 8.75 mmol) was added. Uncle A solution of (-butoxyphosphoryl)nonadecanoic acid (2.15 g, 0.5 equivalent), HOBt (591 mg, 0.5 equivalent), DIPEA (3.0 mL, 2.0 equivalent), and HCTU (1.81 g, 0.5 equivalent) in DMF (200 mL) was prepared. The reaction mixture was stirred under nitrogen at 15 °C for 15.5 hours, at which point the reaction was considered complete. The reaction mixture was filtered, and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0225] (2 S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4 S )-5- Uncle -butoxy-4-(19-di- Uncle [-Butoxyphosphorylnonadecanoylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid At 20℃, (2) S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4S)-5- Uncle -butoxy-4-(19-di- Uncle[(2-chlorophenyl)diphenylmethyl] ester (12.62 g, 8.74 mmol) of slurry in DCM (400 mL) and TFA (4 mL) was agitated with nitrogen for 15 min and filtered through the resin. The pyrolysis process was repeated twice, and the filtrates were combined. The resin was washed with DCM (3×) and the washes were combined with the filtrate and neutralized with saturated NaHCO3 aqueous solution. The aqueous phase was acidified to pH 5 with HCl (1 M) and extracted with DCM (100 mL × 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to obtain a yellow oily crude (2) S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4 S )-5- Uncle -butoxy-4-(19-di- Uncle [-Butoxyphosphorylnonadecanoylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid (10.2 g). m / z (ESI, +ve ion) = 1166.8 [M+H] + .

[0226] ( N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(19-(di- Uncle -Butoxyphosphoryl)nonadecanamide)-5-oxopentanoyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysyl)- L -Lysine N2 downwards (2) S )-2-(benzyloxycarbonylamino)-6-[[(2 S )-2-( Uncle -butoxycarbonylamino)-6-[[(4 S )-5- Uncle -butoxy-4-(19-di- Uncle[-Butoxyphosphorylnonadecanoylamino]-5-oxo-pentanoyl]amino]hexanoyl]amino]hexanoic acid (10 g, 8.57 mmol) was added to a solution of MeOH (100 mL) and HCl (0.1 M, 128.59 mL) with Pd / C (5.0 g, 10 wt%). The suspension was degassed and purged three times with H2. The reaction mixture was stirred at 30 °C under H2 (50 Psi) for 3 hours. After completion, the reaction mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with MeOH (100 mL x 10) and H2O (100 mL x 3). The filtrate and washings were combined and neutralized with NaHCO3, then filtered. The filtrate was concentrated under reduced pressure to obtain an oily crude ( N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(19-(di- Uncle -Butoxyphosphoryl)nonadecanamide)-5-oxopentanoyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysyl)- L -Lysine (8.85 g). This crude product can be used in the next step without further purification. m / z (ESI, +ve ion) = 1032.7 [M+H] + .

[0227] N 2 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(19-(di- Uncle -Butoxyphosphoryl)nonadecanamide)-5-oxopentanoyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysyl)- L -Lysine (ACW-46) Towards( N 6 -( N6 -(( S )-5-( Uncle -butoxy)-4-(19-(di- Uncle -Butoxyphosphoryl)nonadecanamide)-5-oxopentanoyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysyl)- L -Lysine (8.85 g, 8.57 mmol) was added to a solution of dioxane (50 mL) and H2O (50 mL) with NaHCO3 (7.20 g, 10.0 equivalent) and FMOC-OSU (3.18 g, 1.1 equivalent). 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 × 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to the residue, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:1 to 0:1, to ethyl acetate: methanol = 4:1) to obtain a white solid ACW-46, i.e. N 2 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 6 -( N 6 -(( S )-5-( Uncle -butoxy)-4-(19-(di- Uncle -Butoxyphosphoryl)nonadecanamide)-5-oxopentanoyl)- N 2 -( Uncle -butoxycarbonyl)- L -Lysyl)- L -Lysine (4.2 g). m / z (ESI, +VE ion) = 1254.8 [M+H] + . 1 H 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= 7.9Hz, 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).

[0228] Intermediate ACW-47 methyl 18-bromooctadecanoate (COCl)₂ (5.30 mL, 1.0 equivalent) was added to a solution of 18-bromooctadecanoic acid (22 g, 60.5 mmol) in DCM (220 mL) and anhydrous DMF (46.6 μL) at 20 °C under a nitrogen atmosphere. The reaction mixture was stirred at 20 °C for 1.5 h and then concentrated under reduced pressure at 40 °C. The residue was redissolved in DCM (220 mL) and cooled to 0–5 °C with MeOH (2.5 mL). The reaction mixture was heated to 20 °C and stirred for 2 h. After completion, the reaction was quenched by adding a saturated aqueous solution of 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 obtain the desired bromide ester (22.83 g, quantitative yield) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0229] 18-(II-) Uncle Methyl octadecanoate (-butoxyphosphoryl) To 2- Uncle 2-Butoxyphosphono-2-methylpropane (23.5 g, 121 mmol) was dissolved in DMF (300 mL) and then NaH (4.84 g, 1.0 equivalent, 60 wt% dispersion) was added. After 30 minutes, methyl 18-bromooctadecanoate (22.83 g, 60.49 mmol, 0.5 equivalent) was added. The reaction mixture was stirred at 15 °C for 16 hours. After completion, the reaction mixture was quenched with saturated NH4Cl aqueous 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 obtain the desired crude phosphonate (40 g) as a white solid. 1 H NMR (400 MHz, CDCl3) 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).

[0230] 18-(II-) Uncle (-Butoxyphosphoryl)octadecanoic acid To 18-two- Uncle Methyl butoxyphosphoryl octadecanoate (29.7 g, 60.5 mmol) was added to a solution of THF (50 mL) and H₂O (50 mL) with LiOH·H₂O (5.08 g, 2.0 equivalents). The reaction mixture was stirred at 15 °C for 16 h. After completion, HCl (1 M, 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 resulting residue was purified by rapid silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 3:1) to give the desired carboxylic acid as a white solid (28.2 g, 98% yield). 1 H NMR (400 MHz, CDCl3) 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).

[0231] N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- L -Lysine [(2-chlorophenyl)diphenylmethyl] ester At 15°C, Cl-Trt resin (0.64 mmol / g in resin, 48 g resin, 30.7 mmol) and DIPEA (52.3 mL, 9.8 equivalents) were added to a slurry in DCM (500 mL). N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- L A solution of lysine (22.62 g, 1.5 equivalents) in DCM (500 mL) was prepared, and the reaction mixture was stirred 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), and DCM (400 mL x 3), and the resin was used directly for the next step.

[0232] ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester Under N2 atmosphere N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- LA mixture of lysine [(2-chlorophenyl)diphenylmethyl] ester (23.4 g, 30 mmol) in piperidine (40 mL) and DMF (120 mL) was stirred at 25 °C for 15 min. The reaction mixture was filtered, and the filter cake was washed with DMF (300 mL x 1). This procedure was repeated twice to ensure that Fmoc deprotection was complete. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) before proceeding to the next step.

[0233] ( S )-18-(((benzyloxy)carbonyl)amino)-1-(9H-fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-acid [(2-chlorophenyl)diphenylmethyl] ester 1-(9) H A solution of (-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-carboxylic acid (17.3 g, 1.5 equivalents), HOBt (6.1 g, 1.5 equivalents), HCTU (18.6 g, 1.5 equivalents), and DIPEA (15.7 mL, 3.0 equivalents) in DMF (100 mL) was stirred at 25 °C for 30 min. The reaction mixture was then added to a resin-bound slurry of ((benzyloxy)carbonyl)-L-lysine [(2-chlorophenyl)diphenylmethyl] ester (16.71 g, 30 mmol) in DMF (300 mL). The reaction mixture was stirred at 25 °C for 2 h, at which point test cleavage of resin aliquots and analysis by LCMS showed complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0234] N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)- N 2 -((benzyloxy)carbonyl)- L -Lysine [(2-chlorophenyl)diphenylmethyl] ester Will( S18-(((benzyloxy)carbonyl)amino)-1-(9H-fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oic acid [(2-chlorophenyl)diphenylmethyl] ester (27.73 g, 30 mmol) in piperidine (60 mL) and DMF (240 mL) were stirred at 25 °C for 15 min. The reaction mixture was filtered, and the resin was washed with DMF (300 mL x 1). This procedure was repeated twice to ensure that Fmoc deprotection was complete. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) and then proceeded to the next step.

[0235] (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester Will( S )-4-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-5-( Uncle A mixture of (-butoxy)-5-oxovaleric acid (19.2 g, 45 mmol), HOBt (6.08 g, 1.0 equivalent), HCTU (18.62 g, 1.0 equivalent), and DIPEA (15.7 mL, 2.0 equivalent) in anhydrous DMF (150 mL) was stirred at 25 °C for 30 minutes. The mixture was then added to... N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)- N 2 -((benzyloxy)carbonyl)- L 21.07 g, 30 mmol of lysine [(2-chlorophenyl)diphenylmethyl] ester was added to a solution of DMF (300 mL). The mixture was stirred at 25 °C for 2 hours, at which point cleavage tests of aliquots of resin and analysis by LCMS showed complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0236] (2S,20S)-2-amino-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester (2) S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle A slurry of 21-[(2-chlorophenyl)diphenylmethyl] ester (11.10 g, 10 mmol) in piperidine (20 mL) and DMF (100 mL) was stirred at 25 °C for 15 min. The reaction mixture was filtered, and the filter cake was washed with DMF (300 mL x 1). This procedure was repeated twice to ensure that Fmoc deprotection was complete. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) and then proceeded to the next step.

[0237] (2 S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(18-(di- Uncle (-Butoxyphosphoryl)octadecanoylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester 18-(two- Uncle A mixture of (2S,20S)-2-amino-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle21-[(2-chlorophenyl)diphenylmethyl] ester (8.87 g, 10 mmol) was added to a solution of DMF (200 mL). The reaction mixture was stirred at 25 °C for 2 hours, at which point the resin aliquots were tested for cleavage and analysis by LCMS showed complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 3) and DCM (300 mL x 3) before proceeding to the next step.

[0238] (2 S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-39-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonadecanoic acid (2) S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(18-(di- Uncle (-Butoxyphosphoryl)octadecanoylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (13.46 g, 10 mmol) was mixed with TFA (1 mL) and DCM (99 mL) and stirred at 15 °C for 10 min. This procedure was repeated ten times to ensure complete lysis. 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 obtain a yellow, oily crude product (10.45 g).

[0239] (2 S 20 S )-2-amino-20-(tert-butoxycarbonyl)-39-(di-tert-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonadecanoic acid Under N2 atmosphere, towards (2) S )-2-(benzyloxycarbonylamino)-6-[[2-[2-[2-[(4 S )-5-tert-butoxy-4-(18-di- Uncle [-Butoxyphosphoryloctadecylamino]-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (10.45 g, 9.77 mmol) was added to a solution of MeOH (150 mL) and HCl (0.1 M, 156 mL) with Pd / C (5 g, 4.70 mmol, 10 wt%). The suspension was degassed and purged three times with H2. The reaction mixture was stirred at 30 °C under H2 (50 Psi) for 3 hours. After completion, the reaction mixture was filtered through a diatomaceous earth mat, NaHCO3 (1.31 g) was added, and the filtrate was concentrated to obtain crude amino acid product (13 g). m / z (ESI, +ve ion) = 935.6 [M+H] + .

[0240] (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-39-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonadecanoic acid (ACW-47) To the (2) that have been pre-cooled to 0-5℃ S )-2-amino-6-[[2-[2-[2-[[(4S)-5-tert-butoxy-4-(18-di) Uncle [-Butoxyphosphoryloctadecylamino]-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]hexanoic acid (9.14 g, 9.77 mmol) was added to a solution of dioxane (100 mL) and H2O (100 mL) with Na2CO3 (10.36 g, 10.0 equivalent) and FMOC-OSU (3.63 g, 1.1 equivalent). The reaction mixture was heated to 25 °C and stirred for 16 hours. After the reaction was complete, HCl (1 M, 97.7 mL) was added, followed by H2O (100 mL), and the aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by rapid silica gel chromatography (EtOAc:MeOH = 1:0 to 5:1) to obtain the desired product ACW-47 as a white solid, i.e. (2 S 20S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-39-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazanonadecanoic acid (6.63 g, yield 57%, purity 97.8% by HPLC). m / z (ESI, +Ve ion) = 1057.7 [M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.04 (d, J = 7.4 Hz, 1H), 7.90 (br d, J = 7.4Hz, 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).

[0241] Intermediate ACW-48 N 6 -(((9H-fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- L-Lysine [(2-chlorophenyl)diphenylmethyl] ester At 15°C, slurries containing Cl-Trt resin (0.64 mmol / g in resin, 48 g resin) and DIPEA (52.3 mL, 300.00 mmol) in DCM (500 mL) were added. N 6 -(((9 H -fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- L A solution of lysine (22.6 g, 45.00 mmol) in DCM (500 mL) was added, and the reaction mixture was stirred 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), and DCM (400 mL x 3), and the resin was then proceeded to the next step.

[0242] ((benzyloxy)carbonyl)- L -Lysine [(2-chlorophenyl)diphenylmethyl] ester Will N 6 -(((9H-fluorene-9-yl)methoxy)carbonyl)- N 2 -((benzyloxy)carbonyl)- L 23.4 g, 30 mmol of lysine [(2-chlorophenyl)diphenylmethyl] ester (40 mL) was stirred at 25 °C for 15 min in a slurry of piperidine (40 mL) and DMF (120 mL). The resin was drained and washed with DMF (300 mL). This procedure was repeated twice to ensure deprotection was complete. The resin was washed with DMF (600 mL x 3) and DCM (600 mL x 3) before proceeding to the next step.

[0243] ( S )-18-(((benzyloxy)carbonyl)amino)-1-(9 H -fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oic acid [(2-chlorophenyl)diphenylmethyl] ester To 1-(9) H(-fluorene-9-yl)-3-oxo-2,7,10-trioxa-4-azadodecane-12-carboxylic acid (17.34 g, 1.5 equivalents) was added to a solution of ((benzyloxy)carbonyl)- L 16.7 g, 30 mmol of lysine [(2-chlorophenyl)diphenylmethyl] ester was added to a slurry of DMF (300 mL). The reaction mixture was stirred at 25 °C for 2 h, followed by testing of resin aliquots for pyrolysis and analysis by LCMS indicating complete consumption of the reactants. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0244] N 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N 2 -((benzyloxy)carbonyl)- L -Lysine [(2-chlorophenyl)diphenylmethyl] ester Will( S )-18-(((benzyloxy)carbonyl)amino)-1-(9 H A slurry of fluorene-9-yl)-3,12-dioxo-2,7,10-trioxa-4,13-diazanonadecan-19-oic acid [(2-chlorophenyl)diphenylmethyl] ester (27.73 g, 30 mmol) in piperidine (60 mL) and DMF (240 mL) was stirred at 25 °C for 15 min. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 1), and the piperidine treatment in DMF was repeated twice to ensure complete removal of the Fmoc protecting group. The resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) and then proceeded to the next step.

[0245] (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester Towards( S )-4-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-5-( Uncle HOBt (6.08 g, 1.5 equivalents), HCTU (18.62 g, 1.5 equivalents), and DIPEA (15.7 mL, 3.0 equivalents) were added to a solution of (-butoxy)-5-oxovalerate (19.15 g, 1.5 equivalents) in DMF (150 mL). The reaction mixture was stirred at 25 °C for 30 minutes, and then added to N. 6 -(2-(2-(2-aminoethoxy)ethoxy)acetyl)-N 2 -((benzyloxy)carbonyl)- L -Lysine [(2-chlorophenyl)diphenylmethyl] ester (21.1 g, 30 mmol) was added to a slurry of DMF (300 mL). The reaction mixture was stirred at 25 °C for 2 hours, at which point the test cleavage indicator reactants in the resin aliquots were completely consumed. The reaction mixture was filtered and the resin was washed with DMF (500 mL x 3) and DCM (500 mL x 3) before proceeding to the next step.

[0246] (2 S 20 S )-2-amino-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester (2) S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( UncleA slurry of 21-[(2-chlorophenyl)diphenylmethyl] ester (11.10 g, 10 mmol) in piperidine (20 mL) and DMF (100 mL) was stirred at 25 °C for 15 min, then filtered and the resin was washed with DMF (200 mL x 1). This procedure was repeated twice to ensure complete removal of the Fmoc protecting group. The resin was washed with DMF (300 mL x 3) and DCM (300 mL x 3) before proceeding to the next step.

[0247] (2 S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(19-(di- Uncle (-Butoxyphosphoryl)nonadecanylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (-butyl) ester To 19-(II-) Uncle (-Butoxyphosphoryl)nonadecanoic acid (7.36 g, 1.5 equivalents) was added to a solution of DMF (300 mL) with HOBt (2.03 g, 1.5 equivalents), HCTU (6.21 g, 1.5 equivalents) and DIPEA (5.2 mL, 3.0 equivalents). The reaction mixture was stirred at 25 °C for 30 minutes, and then added to (2 S 20 S )-2-amino-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (8.87 g, 10 mmol) was added to a solution of DMF (300 mL). The reaction mixture was stirred at 25 °C for 2 hours, at which point the test cleavage indicator reactants in the resin aliquots were completely consumed. The reaction mixture was filtered and the resin was washed with DMF (300 mL x 3) and DCM (300 mL x 3) before proceeding to the next step.

[0248] (2 S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle(-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatoracoacetic acid (2) S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(19-(di- Uncle (-Butoxyphosphoryl)nonadecanylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (13.60 g, 10 mmol) in a slurry of TFA (1 mL) and DCM (99 mL) was stirred at 15 °C for 10 min and filtered. This procedure was repeated ten times to ensure complete lysis. 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 provide the desired compound as a yellow oil (9.05 g, 84% yield).

[0249] (2 S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatoracoacetic acid Under N2 atmosphere, towards (2) S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle(-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazattrachianoic acid (8 g, 7.38 mmol) was added to a solution of MeOH (110 mL) and HCl (0.1 M, 110.8 mL) with Pd / C (10 wt%, 5 g). The suspension was degassed and purged three times with H2. The reaction mixture was stirred at 30 °C under H2 (50 Psi) for 3 hours. After completion, the reaction mixture was filtered through a diatomaceous earth mat; NaHCO3 (935 mg) was added, and the filtrate was concentrated to obtain a colorless, oily crude amino acid (13 g). m / z (ESI, +Ve ion) = 949.7 [M+H) + .

[0250] (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatoracoacetic acid (ACW-48) To (2) S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle (-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracosanic acid (7.01 g, 7.38 mmol) was added to a solution of dioxane (50 mL) and H2O (50 mL) with Na2CO3 (7.83 g, 10 equivalents) and FMOC-OSU (2.99 g, 1.2 equivalents). The reaction mixture was stirred at 25 °C for 16 hours. After completion, HCl (73.9 mL, 1 M) was added. The reaction mixture was diluted with H2O (100 mL) and then extracted with EtOAc (100 mL x 2). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a residue, which was purified by rapid silica gel chromatography (ethyl acetate:methanol = 1:0 to 5:1) to obtain a white solid, the desired ACW-48, i.e. (2 S 20 S )-2-((((9 H-fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-40-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazattrachianoic acid (5 g, yield 56%, purity 96.8%). m / z (ESI, +Ve ion) = 1171.7 [M+H) + . 1 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).

[0251] Intermediate ACW-49 (2 S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(20-(di- Uncle (-Butoxyphosphoryl)eicosanoylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle butyl)-21-[(2-chlorophenyl)diphenylmethyl] ester 20-(two-) Uncle A solution of (2S,20S)-2-amino-20-(((benzyloxy)carbonyl)amino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle 21-[(2-chlorophenyl)diphenylmethyl] ester (9.19 g, 10 mmol) was added to a slurry of DMF (100 mL). The reaction mixture was stirred at 25 °C for 2 hours, at which point the test cleavage of resin aliquots and analysis by LCMS indicated complete consumption of the starting material. The reaction mixture was filtered and the resin was washed with DMF (500 mL × 3) and DCM (500 mL × 3) before proceeding to the next step.

[0252] (2 S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetraloic acid (2) under N2 atmosphere S 20 S )-20-(((benzyloxy)carbonyl)amino)-2-(20-(di- Uncle (-Butoxyphosphoryl)eicosanoylamino)-5,14-dioxo-9,12-dioxa-6,15-diazaeicosanoic acid 1-( Uncle(-Butyl)-21-[(2-chlorophenyl)diphenylmethyl] ester (68.20 g, 55 mmol) was slurried in TFA (3 mL) and DCM (300 mL) and shaken at 15 °C for 10 min. This procedure was repeated three times to ensure complete lysis. The reaction mixture was filtered and the filtrates were combined. The filtrate was neutralized with saturated NaHCO3 aqueous solution and then the pH was adjusted to 5 with 1 M HCl. The aqueous phase was extracted with DCM (100 mL × 3). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to obtain the desired crude product (8.3 g) as a yellow oil.

[0253] (2 S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetraloic acid Under N2 atmosphere, towards (2) S 20 S )-2-(((benzyloxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracosanonic acid (6 g, 5.47 mmol) was added to a solution of MeOH (80 mL) with Pd / C (3 g, 10 wt%) and HCl (0.1 M, 82 mL). The suspension was degassed and purged three times with H2. The reaction mixture was then stirred at 30 °C for 2 hours under H2 (50 Psi). After completion, the reaction mixture was filtered through a diatomaceous earth mat. Sodium bicarbonate (0.69 g) was added to the filtrate for neutralization, and the reaction mixture was concentrated to obtain a crude product (5.72 g), which could be used for the next step without further purification. m / z (ESI, +ve ions) = 963.7 [M+H] + .

[0254] (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle(-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetraloic acid (ACW-49) To the (2) that have been pre-cooled to 0-5℃ S 20 S )-2-amino-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle (-butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracosanonic acid (5.27 g, 5.47 mmol) was added to a solution of dioxane (20 mL) and H2O (20 mL) along with FMOC-OSU (2.03 g, 6.02 mmol) and NaHCO3 (4.60 g, 54.71 mmol). The reaction mixture was heated to 25 °C and stirred for 2 hours. After this, the pH was adjusted to 5 with HCl (1 M), and the aqueous phase was extracted with DCM (100 mL × 2). The combined organic extracts were dried over (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid silica gel chromatography (ethyl acetate: methanol = 1:0 to 3:1) to obtain the desired protected amino acid ACW-49, i.e., (2 S 20 S )-2-((((9 H -fluorene-9-yl)methoxy)carbonyl)amino)-20-( Uncle -Butoxycarbonyl)-41-(di- Uncle (-Butoxyphosphoryl)-8,17,22-trioxo-10,13-dioxa-7,16,21-triazatetracosanonic acid (3.6 g). m / z (ESI, +Ve ion) = 1185.7 [M+H] + . 1 H 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 = 5.7Hz, 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).

[0255] Synthesis of specific compounds Compound 7 Following procedure F1: the previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Dap(mtt)-Rink amide resin (228 mg, 0.05 mmol) was selectively deprotected with mtt using HFIP:TIS:DCM (15:1:34 v / v / v) (3 x 5 mL, 15 min cycles). The resin was then washed with DCM (3 x 5 mL) and DMF (3 x 5 mL). 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid (18 mg, 2 equivalents, 0.1 mmol) in DMF (1 mL) was coupled with DIC (4 equivalents, 0.2 mmol, 0.4 mL, 0.5 M in DMF) and Oxyma (2 equivalents, 0.2 mL, 0.1 mmol, 0.5 M in DMF) at 23 °C. After coupling, the resin was washed with DMF (3 x 5 mL) and DCM (3 x 5 mL).

[0256] Following procedure G2: The remaining peptides were synthesized at a scale of 0.05 mmol using a Fmoc / t-Bu strategy on a Liberty Blue microwave peptide synthesizer (CEM Corporation) via microwave-assisted solid-phase peptide synthesis (SPPS). Deprotection was performed using 20% ​​piperidine in 0.1 M Oxyma / DMF solution. Amino acid coupling was performed using a 5-fold excess of the reagent. Fmoc-amino acids (0.2 M solution in DMF), DIC (0.5 M solution in DMF), and Oxyma (0.5 M solution in DMF) were used at a scale of 0.05 mmol. [The remaining peptides were then analyzed at position X.] 1 and X 4 The following modified amino acids are used: S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-(tert-butoxycarbonylamino)pentylcarbonylamino]-2-[(9 H -fluorene-9-yl)methoxycarbonylamino]hexanoic acid, (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid. In N The terminal uses Boc-Tyr(tBu)-OH.

[0257] Following procedure C1: simultaneous cleavage of the resin and removal of side-chain protecting groups were performed at room temperature in a TFA / TIS / H2O / PhOH (88:2:5:5 v / v / v / v) solution (10 mL / 0.05 mmol) for 3 hours. The peptide was precipitated using cold diethyl ether (30 mL / 0.05 mmol) and separated by centrifugation (3000 rpm, 10 min).

[0258] Following procedure P1: The crude peptide was repeatedly purified by RP-HPLC using a Phenomenex Aeris 5 µm Peptide XB-C18 250 x 21.2 mm column packed with AXIA under the following conditions: Solvent A = H2O containing 0.1% TFA, Solvent B = MeCN containing 0.1% TFA, flow rate = 25 mL / min, over a 30-55% A / B gradient for 25 minutes.

[0259] Following procedure P2: Combine suitable fractions and freeze-dry them for a second purification under the following conditions: Phenomenex Aeris 5 μm peptide XB-C18 250 x 21.2 mm column packed with AXIA and the following conditions: solvent A = H2O, solvent B = MeCN containing 20 mM NH4HCO3, flow rate = 25 mL / min, through a 25-45% A / B gradient for 25 minutes.

[0260] Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 3.23 mg, LCMS (ESI) m / z [M+4]. 4+ C 235 H 351 FN 61 O 65 Calculated value of P: 1280.4, measured value: 1280.9, HPLC purity at 214 nm: 95.1%.

[0261] Compound 10 (SEQ ID NO: 11) Peptides were prepared according to procedure G1, and positions 7 and 30 were added using procedure S1, with appropriate reagents used in all cases to obtain the desired structure.

[0262] G2:X 1 = ( S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9 H [-fluorene-9-yl]methyl](oxycarbonylamino)hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid The side-chain protecting groups were removed and the peptide was cleaved from the resin using program C1. The crude peptide was then repeatedly purified by RP-HPLC using program P1. The appropriate fractions were combined, lyophilized, and purified again using program P2.

[0263] The fraction with a purity >95% (analytical HPLC) at 214 nm was lyophilized to obtain the title peptide, 4.2 mg, LCMS (ESI) m / z [M+4]. 4+ C 231 H 347 N 60 O 65 Calculated value of P: 1259.1, measured value: 1259.3, HPLC purity at 214 nm: 98.4%.

[0264] Compound 17 Compound 17 was synthesized according to procedure G1 with the following modifications: G1:X 1 = ( S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9 H [-fluorene-9-yl]methyl](oxycarbonylamino)hexanoic acid X 4 = (2 S )-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)-3-(7-fluoro-1 H -Indole-3-yl)propionic acid C1, P1, and P2 are unmodified. Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 3.0 mg, LCMS (ESI) m / z [M+4]. 4+ C 231 H 347 N 60 O 65 Calculated value of P: 1259.1, measured value: 1259.6, HPLC purity at 214 nm: 98.8%.

[0265] Compound 18 Compound 18 was synthesized according to procedure G1 with the following modifications: G1:X 1 = ( S )-6-[( S )-5-{( S)-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9 H [-fluorene-9-yl]methyl](oxycarbonylamino)hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid X 5 = Fmoc-β-homo-Arg(Pbf)-OH C1, P1, and P2 are unmodified. Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 1.1 mg, LCMS (ESI) m / z [M+4]. 4+ Calculated value.

[0266] Compound 19 (SEQ ID NO: 20) According to procedure G2, the previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Dap(mtt)-Rink amide resin (228 mg, 0.05 mmol) underwent selective mtt deprotection and C-terminal modification according to procedure F1. The peptide was extended using appropriate reagents with procedure G1 to obtain the desired structure. For positions 7 and 30, the desired structure was obtained using procedure S1 and appropriate reagents.

[0267] F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G2:X 1 = ( S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9 H [-fluorene-9-yl]methyl](oxycarbonylamino)hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H-indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid The side-chain protecting groups were removed and cleaved from the resin using program C1. The crude peptide was then repeatedly purified by RP-HPLC using program P1. The appropriate fractions were combined, lyophilized, and purified again using program P2.

[0268] The fraction with acceptable purity (analytical HPLC) at 214 nm was lyophilized to obtain the title peptide, 1.6 mg, LCMS (ESI) m / z [M+4]. 4+ C 235 H 351 FN 61 O 65 Calculated value of P: 1280.4, measured value: 1280.9, HPLC purity at 214 nm: 94.7%.

[0269] Compound 23 (SEQ ID NO: 24) According to procedure G3, the previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β-homoArg(Pbf)-Dap(mtt)-Rink amide resin (228 mg, 0.05 mmol) underwent selective mtt deprotection and C-terminal modification according to procedure F1. The peptide was then extended using appropriate reagents with procedure G1 to obtain the desired structure. For positions 7 and 30, the desired structures were obtained using procedure S1 and appropriate reagents.

[0270] F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G2:X 1 = ( S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-[(tert-butyl)(oxycarbonylamino)]pentylcarbonylamino]-2-{[(9 H [-fluorene-9-yl]methyl](oxycarbonylamino)hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid The side-chain protecting groups were removed and cleaved from the resin using program C1. The crude peptide was then repeatedly purified by RP-HPLC using program P1. The appropriate fractions were combined, lyophilized, and purified again using program P2.

[0271] The fraction with a purity >95% (analytical HPLC) at 214 nm was lyophilized to obtain the title peptide, 2.4 mg, LCMS (ESI) m / z [M+4]. 4+ C 236 H 353 FN 61 O 65 Calculated value of P: 1283.9, measured value: 1284.3, HPLC purity at 214 nm: 98.3%.

[0272] Compound 29 Compound 29 was synthesized according to procedure G2 with the following modifications: F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G2:X 1 = ( S )-6-({[2-(2-{( S )-4-tert-butoxycarbonyl-4-[17-(di-tert-butoxyphosphoryl)heptadecylcarbonylamino]butyrylamino}ethoxy)ethoxy]methyl}carbonylamino)-2-[(9 H -fluorene-9-yl)methoxycarbonylamino]hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid C1, P1, and P2 are unmodified. Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 4.99 mg, LCMS (ESI) m / z [M+4]. 4+ C 236 H 352 FN 60 O 67 Calculated value of P: 1288.1, measured value: 1288.5, HPLC purity at 214 nm: 95.6%.

[0273] Compound 31 Compound 31 was synthesized according to procedure G2 with the following modifications: F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G2:X 1 = ( S )-6-[( S )-5-{( S )-4-tert-butoxycarbonyl-4-[18-(di-tert-butoxyphosphoryl)octadecylcarbonylamino]butyrylamino}-1-(tert-butoxycarbonylamino)pentylcarbonylamino]-2-[(9 H -fluorene-9-yl)methoxycarbonylamino]hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid C1, P1, and P2 are unmodified. Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 5.43 mg, LCMS (ESI) m / z [M+4]. 4+ C 237 H 355 FN 61 O 65 Calculated value of P: 1287.4, measured value: 1287.8, HPLC purity at 214 nm: 95.5%.

[0274] Compound 33 (SEQ ID NO: 34) According to procedure G3, the previously prepared Fmoc-Leu-Thr(tBu)-Arg(Pbf)-Gln(Trt)-β-homoArg(Pbf)-Dap(mtt)-Rink amide resin (228 mg, 0.05 mmol) underwent selective mtt deprotection and C-terminal modification according to procedure F1. The peptide was then extended using appropriate reagents with procedure G1 to obtain the desired structure. For positions 7 and 30, the desired structures were obtained using procedure S1 and appropriate reagents. N F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G3:X 1 = ( S )-6-[( S )-5-{( S)-4-tert-butoxycarbonyl-4-[16-(di-tert-butoxyphosphoryl)hexadecylcarbonylamino]butyrylamino}-1-(tert-butoxycarbonylamino)pentylcarbonylamino]-2-[(9 H -fluorene-9-yl)methoxycarbonylamino]hexanoic acid X 4 = (2 S )-3-(7-cyano-1 H -indol-3-yl)-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)propionic acid The side-chain protecting groups were removed and cleaved from the resin using program C1. The crude peptide was then repeatedly purified by RP-HPLC using program P2. The suitable fractions were then combined, lyophilized, and purified again using program P2.

[0275] The fraction with a purity >95% (analytical HPLC) at 214 nm was lyophilized to obtain the title peptide, 3.5 mg, LCMS (ESI) m / z [M+4]. 4+ C 236 H 353 FN 61 O 65 Calculated value of P: 1283.9, measured value: 1284.3, HPLC purity at 214 nm: 99.1%.

[0276] Compound 37 Compound 37 was synthesized according to procedure G2 with the following modifications: F1: 1-(3-fluorophenyl)cyclopropane-1-carboxylic acid G2:X 1 = ( S )-6-{( S )-5-[( S )-4-tert-butoxycarbonyl-4-(18-tert-butoxycarbonyloctadecylcarbonylamino)butyrylamino]-1-(tert-butoxycarbonylamino)pentylcarbonylamino}-2-[(9 H -fluorene-9-yl)methoxycarbonylamino]hexanoic acid X 4 = (2 S )-2-({[(9 H -fluorene-9-yl)methoxy]carbonyl}amino)-3-(7-fluoro-1 H -Indole-3-yl)propionic acid C1, P1, and P2 are unmodified. Fractions with a purity >95% (analytical HPLC) at 214 nm were combined and lyophilized to obtain the title peptide, 24.5 mg, LCMS (ESI) m / z [M+4]. 4+ C 235 H 350 FN 60 O 67 Calculated value of P: 1284.6, measured value: 1285.1, HPLC purity at 214 nm: 95.8%.

[0277] Biological program The exemplary peptides described herein were measured.

[0278] General Method Cells were maintained in cell-specific medium at 37°C with 5% CO2 using standard laboratory practices. Cells were maintained in DMEM (Gibco) supplemented with 10% heat-inactivated FBS, 1x GlutaMax (Gibco), 100 U / mL Pen / Strep, and a selected antibiotic. Compounds were serially diluted in DMSO and transferred to assay plates using an ECHO acoustic liquid handler (Labcyte).

[0279] Functional determination was performed using Y2R and Y5R to determine the potency and efficacy of the compounds. The stable HEK293 cell line used for cAMP assays was generated by antibiotic selection of cells co-transfected with Promega Glosensor plasmid 22F and mammalian expression plasmids containing open reading frames of human Y2R, mouse Y2R, or human Y5R. ACS Chem. Biol. 2011, 6, 11, 1193–1197 (the contents of which are incorporated herein by reference). Cells were tested in suspension at 10,000 cells per well in 384-well low-volume plates in CO2-independent medium (Gibco 18-045-088) containing 2% Glosensor substrate (Promega E1291). 10 µM NECA (5'-(N-ethylcarboxamide)adenosine, Sigma E2387) was added to stimulate cAMP accumulation. Positive controls included human PYY. 3-36 (Tocris 6288), mouse PYY 3-36 (Tocris 1618) or human NPY 1-36(Tocris1153), targeting human Y2R, mouse Y2R, or human Y5R respectively. Efficacy was measured using an EnVision multimodal plate reader (PerkinElmer) 30 minutes after NECA addition. Data were normalized to mediator and positive control before nonlinear regression analysis of the dose-response curves. Compound potency (EC) was extracted from this regression analysis. 50 ) and efficacy (E) max When the maximum activity is less than 10%, the curve does not fit.

[0280] Determination of β-repressor protein recruitment Promega's NanoBiT technology was used to measure Y2R-mediated β-repressor protein recruitment. ACS Chem. Biol. 2016, 11, 2, 400–408 (the contents of which are incorporated herein by reference), in which the plasmid encoding the fusion protein of human Y2R-LgBit and SmBiT-β-inhibitory protein-2 was stably expressed in HEK293 cells (selected by antibiotics). 24 hours prior to assay, cells were floated and plated at a density of 10,000 cells per well in TC-treated 384-well low-volume plates. The next day, the culture medium was removed and replaced with 10 μL of Nano-Glo® live cell substrate (PromegaN2012) diluted 1:100 in Optimem (Gibco 31985062), and equilibrated to room temperature for 10 minutes. Background luminescence was measured using an ECHO acoustic liquid handling system before adding the compound. Luminescence was measured at 1.5-minute intervals for 30 minutes, and the maximum luminescence response during this interval was normalized to the background signal for each well. Before performing nonlinear regression analysis using the Collaborative Drug Discovery Vault platform, the data were further standardized to include drug candidates and positive controls. Compound potency (EC) was then extracted from this regression analysis. 50 ) and efficacy (E) max When the maximum activity is less than 10%, the curve does not fit.

[0281] Acute food intake / weight loss study in mice C57BL / 6J mice were randomly assigned to groups based on body weight. Treatment was administered via a single subcutaneous injection. Mice were returned to their cages with pre-weighed food in the feed hoppers. Body weight and food intake were measured at 24, 48, and up to 72 hours post-treatment. Standardized body weight was calculated as follows: the mouse's body weight on the day of treatment was divided by the body weight of the day before treatment, and then multiplied by 100%.

[0282] Chronic food intake / weight loss study in mice C57BL / 6J diet-induced obesity (DIO) mice were acclimatized to daily weighing and treatment for approximately one week until their weight stabilized. Based on their current weight, mice were administered a specified dose of peptide or mediator subcutaneously once daily. Injections were given approximately 6 hours before the start of the dark cycle. Food intake was measured daily by weighing the feed hopper; results are expressed as daily and cumulative food intake. The percentage of body weight to initial body weight was calculated daily as follows: daily body weight divided by the body weight before the first peptide administration, then multiplied by 100%.

[0283] Details of one or more embodiments are set forth in the accompanying drawings and the following description. Other features, objects, and advantages will become apparent from the specification, drawings, and claims. Although several embodiments of the invention have been described, it should be understood that various modifications can be made without departing from the spirit and scope of the invention. It should also be understood that the drawings are not necessarily drawn to scale, but rather present a slightly simplified representation of the various features and basic principles of the invention.

Claims

1. A peptide comprising the following amino acid sequence: X3X4PEX7PX9X 10 X 11 AX 13 PEEX 17 X 18 RYYX 22 X 23 LRHYX 28 NX 30 X 31 TRQX 35 X 36 (SEQ ID: 39) in: X3 is V, I, or P; X4 is R, K, or P; X7 is ,in It has the following structure: in Each Z 1 Independently, it consists of amino acid residues, sugar residues, and -C(O)-Z residues. 2 -O- or -C(O)-Z 2 -NH-; Each Z 2 Independently, it is a 2 to 8-carbon alkylene linker, wherein one or two carbon atoms are optionally independently substituted by -NH2, -OH, or -COOH, and wherein the alkylene linker is straight-chain or branched and optionally includes C. 3-8 cycloalkyl moiety; or each Z 2 Independently -((CH2) a -O-(CH2) b ) c - where 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; R 1 -L 3 -R 2 or -C(O)-Z 3 -R 2 ; Z 3 It is a straight-chain or branched, saturated or unsaturated 16 to 22 carbonyl or alkenyl group; and R 2 It is -P(O)(OH)2; X9 is either G or E; X 10 For E or K; X 11 For D or ,in It is either β-aspartic acid or d-aspartic acid; X 13 For A, C, K, M, N, P, R, S, T, W, Y, V, I, or P; X 17 For W or L; X 18 For N or Q; X 22 The values ​​are A, D, E, F, I, L, M, or V; X 23 It can be D, S, or E; X 28 For I, L, or Aib; X 30 For E, L, W or ,in Tryptophan substituted with halogen, cyano, methyl, trifluoromethyl, carboxylic acid, carboxamide or heteroaryl, or tryptophan in which the cyclic CH is substituted with N; X 31 For V or L; X 35 For C, G, H, K, L, M, P, R, Q, T, or W, where It is N(α)-methylarginine or β-homogeneous acid; X 36 For Y or Z Z Having formulas Ia, Ib, or Ic: in R a For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R b For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or R a and R b They form together with the carbon atoms they are attached to: (i) optionally selected by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; (ii) A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; (iii) A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; or (iv) A 6-membered aryl group, wherein the 6-membered aryl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R c It is phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It does not exist; R d It is H or methyl; R e It is a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and optionally surrounded by 1 to 5 independently selected halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or R e -COC(R) a (R) b )R c ; Ar is a 5- to 6-membered heteroaryl group or a 6-membered aryl group having 1 to 3 ring atoms selected from O, N, and S, wherein Ar is optionally surrounded by 1 to 5 ring atoms independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; The C-terminal amino acid of the peptide is optionally amidated; Or its pharmaceutically acceptable salt.

2. The peptide according to claim 1, comprising the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 40), in: X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 The values ​​are A, D, E, F, I, L, M, or V; X 30 For W W Tryptophan that has been substituted with halogen or cyano groups; X 35 For C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib or Ic.

3. The peptide according to any one of claims 1 to 2, wherein: Each Z 1 Selected independently from: , , , , , , and ; R 1 -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k is 16, 17, 18, 19, 20, 21 or 22.

4. The peptide according to any one of claims 1 to 3, comprising the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 41), in: X7 can be K ; X 13 It can be A, C, K, M, N, P, R, S, T, W, or Y; X 22 The values ​​are A, D, E, F, I, L, M, or V; X 30 For W or W W Tryptophan that has been substituted with halogen or cyano groups; X 35 For C, G, H, K, L, M, P, R, R , Q, T or W, where R It is N(α)-methylarginine or β-homogeneous; and X 36 It can be Y or Z Z It has the formula Ia, Ib, or Ic; Each Z 1 Selected independently from: , , , , , , and ; R 1 -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k is 16, 17, 18, 19, 20, 21 or 22.

5. The peptide according to any one of claims 1 to 4, wherein: X 13 For S or T; X 22 For I or V; X 30 For W or W W Tryptophan that has been substituted with a halogen or cyano group; and X 35 It is R or β-high arginine.

6. The peptide according to any one of claims 1 to 5, comprising the following amino acid sequence: PKPEX7PEEDAX 13 PEEWQRYYX 22 ELRHYLNX 30 LTRQX 35 X 36 (SEQ ID NO: 42), in: X7 can be K ; X 13 For S or T; X 22 For I or V; X 30 For W or W W Tryptophan that has been substituted with halogen or cyano groups; X 35 It is R or β-high arginine; X 36 It can be Y or Z Z It has the formula Ia, Ib, or Ic; Each Z 1 Selected independently from: , , , , , , and ; R 1 -(CH2) k -R 2 Or -C(O)-(CH2) k -R 2 ;and k is 16, 17, 18, 19, 20, 21 or 22.

7. The peptide according to any one of claims 1 to 6, wherein the amino acid sequence is selected from the group consisting of: PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRY (SEQ ID NO: 43); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRY (SEQ ID NO: 44); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRY (SEQ ID NO: 45); PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRY (SEQ ID NO: 46); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 47) PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 48) PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQRZ (SEQ ID NO: 49) PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQRZ (SEQ ID NO: 50); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Y (SEQ ID NO: 51); PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Y (SEQ ID NO: 52); PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Y (SEQ ID NO: 53);PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Y (SEQ ID NO: 54); PKPEK PEEDASPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 55) PKPEK PEEDASPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 56) PKPEK PEEDATPEEWQRYYIELRHYLNWLTRQR Z (SEQ ID NO: 57) PKPEK PEEDATPEEWQRYYVELRHYLNWLTRQR Z (SEQ ID NO: 58) PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRY (SEQ ID NO: 59); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRY (SEQ ID NO: 60); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRY (SEQ ID NO: 61); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRY (SEQ ID NO: 62); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 63) PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 64) PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQRZ (SEQ ID NO: 65); PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQRZ (SEQ ID NO: 66); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Y (SEQ ID NO: 67); PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Y (SEQ ID NO: 68); PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Y (SEQ ID NO: 69);PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQR Y (SEQ ID NO: 70); PKPEK PEEDASPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 71) PKPEK PEEDASPEEWQRYYVELRHYLNW LTRQR Z (SEQ ID NO: 72) PKPEK PEEDATPEEWQRYYIELRHYLNW LTRQR Z (SEQ ID NO: 73); and PKPEK PEEDATPEEWQRYYVELRHYLNW LTRQR Z (SEQ ID NO: 74)。 8. The peptide according to any one of claims 1 to 7, wherein: Each Z 1 Selected independently from: , and ; n is 2 or 3; R 1 -C(O)-Z 3 -R 2 ;and Z 3 It consists of straight-chain or branched saturated 16 to 20 carboalkylene links.

9. The peptide according to any one of claims 1 to 8, wherein: R 1 It is -C(O)-(CH2) k -P(O)(OH)2; and k is 16, 17, 18, 19, 20, 21 or 22.

10. The peptide according to any one of claims 1 to 9, wherein: It has the following structure: Where Z is: or ;and R 1 It is -C(O)-(CH2) k -R 2 .

11. The peptide of claim 10, wherein R 1 It is -C(O)-(CH2) k -R 2 .

12. The peptide according to any one of claims 1 to 11, wherein: Z Having formula Ia: in R a For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R b For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or R a and R b They form together with the carbon atoms they are attached to: (i) optionally selected by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; (ii) A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; (iii) A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; or (iv) A 6-membered aryl group, wherein the 6-membered aryl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R c It is phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It does not exist.

13. The peptide according to claim 12, wherein: Z Having formula Ia: Ia in R a and R b Together with the carbon they are attached to, they form C 3-6 Cycloalkyl groups, optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; and R c It is phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents.

14. The peptide according to claim 13, wherein: Z It has the following structure in: Each R 3 Independently selected from halogen, cyano, amino, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl or -OC 1-3 Halogenated alkyl groups; i is 1, 2, 3, or 4; and j can be 0, 1, 2 or 3.

15. The peptide according to claim 14, wherein: Z It has the following structure 。 16. The peptide according to any one of claims 1 to 11, wherein: Z Having formula Ib: Ib in R d It is H or methyl; R e It is a 9- or 10-membered heterocyclic group having 1 to 5 ring atoms selected from O, N, and S, and optionally surrounded by 1 to 5 independently selected halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or R e -COC(R) a (R) b )R c ; R a For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R b For H, C 1-3 Alkyl or C 1-3 Alkenyl, wherein the alkyl or alkenyl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or R a and R b They form together with the carbon atoms they are attached to: (i) optionally selected by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents substituted C 3-6 Cycloalkyl groups; (ii) A 5- to 6-membered heterocyclic group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heterocyclic group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; (iii) A 5- to 6-membered heteroaryl group having 1 to 3 ring atoms selected from O, N, and S, wherein the 5- to 6-membered heteroaryl group is optionally surrounded by 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; or (iv) A 6-membered aryl group, wherein the 6-membered aryl group is optionally composed of 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; R c It is phenyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, C 1-3 Alkyl or -OC 1-3 Alkyl, wherein R c Optionally, it is selected from 1 to 5 independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents; Or when R a and R b When R forms a 5- to 6-membered heteroaryl group or a 6-membered aryl group together with the carbons they are attached to, c It does not exist.

17. The peptide according to any one of claims 1 to 11, wherein: Z Having the formula Ic: Ic in R d It is H or methyl; and Ar is a 5- to 6-membered heteroaryl group or a 6-membered aryl group having 1 to 3 ring atoms selected from O, N, and S, wherein Ar is optionally surrounded by 1 to 5 ring atoms independently selected from halogen, cyano, nitro, oxo, CF3, C 1-3 Alkyl group, -C(O)NH-C 1-3 Alkyl group, -NHC(O)-C 1-3 Alkyl, -OH and -OC 1-3 Alkyl substituents.

18. The peptide according to any one of claims 1 to 17, wherein W It can be 4-fluorotryptophan, 5-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, 4-cyanotryptophan, 5-cyanotryptophan, 6-cyanotryptophan, or 7-cyanotryptophan.

19. The peptide of claim 18, wherein W It is 7-cyanotryptophan.

20. A peptide having the following structure: (SEQ ID NO: 24); Or its pharmaceutically acceptable salt.

21. A peptide having the following structure: (SEQ ID NO: 34); Or its pharmaceutically acceptable salt.

22. A peptide having the following structure: (SEQ ID NO: 11); Or its pharmaceutically acceptable salt.

23. A peptide having the following structure: (SEQ ID NO: 20); Or its pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising: a peptide according to any one of claims 1 to 23, and a pharmaceutically acceptable carrier, diluent, or excipient.

25. A method for treating diabetes and related diseases, eating disorders, diabetic complications, cardiovascular disease, or sleep apnea, said method comprising administering to a patient in need a therapeutically effective amount of the peptide according to any one of claims 1 to 23.

26. A method for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes, the method comprising administering to a patient in need a therapeutically effective amount of the peptide according to any one of claims 1 to 23, thereby reducing the patient's food intake, reducing weight, suppressing appetite, and / or inducing satiety.

27. A method for treating or preventing bulimia, bulimia nervosa, or obesity caused by the administration of antipsychotic drugs or steroids, the method comprising administering to a patient in need a therapeutically effective amount of the peptide according to any one of claims 1 to 23.

28. A method for reducing gastric motility, delaying gastric emptying, or improving physical activity, said method comprising administering to a patient in need a therapeutically effective amount of the peptide according to any one of claims 1 to 23.

29. A method for treating or preventing comorbidities of obesity, osteoarthritis, or urinary incontinence, the method comprising administering to a patient in need a therapeutically effective amount of the peptide according to any one of claims 1 to 23.

30. Use of the peptide according to any one of claims 1 to 23 in the treatment of diabetes and related diseases, eating disorders, diabetic complications, cardiovascular diseases or sleep apnea.

31. Use of the peptide according to any one of claims 1 to 23 for improving lipid parameters, improving β-cell function, or delaying or preventing the progression of diabetes.

32. Use of the peptide according to any one of claims 1 to 23 in the treatment or prevention of bulimia disorder, bulimia nervosa, or obesity caused by administration of antipsychotic drugs or steroids.

33. Use of the peptide according to any one of claims 1 to 23 for reducing gastric motility, delaying gastric emptying, or improving physical activity.

34. Use of the peptide according to any one of claims 1 to 23 in the treatment or prevention of complications of obesity, osteoarthritis, or urinary incontinence.

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