Methods of preventing and / or treating side effects associated with anti-cancer agents using non-naturally occurring melanocortin analogs and anti-GDF-15 antibodies

Abstract

Provided herein are compositions comprising a non-naturally occurring melanocortin analogue in combination with a spiro compound and / or an antibody or antigen-binding fragment thereof. The composition may further include an anti-cancer agent (e.g., a chemotherapeutic agent). Also provided herein are pharmaceutical compositions incorporating the compositions; methods of using the compositions to modulate weight, including but not limited to increasing appetite, preventing inappetence, promoting weight gain, preventing weight loss, and / or treating, preventing, or otherwise reducing cachexia and / or anorexia in a subject in need thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 485,867, filed February 17, 2023; U.S. Provisional Application No. 63 / 453,664, filed March 21, 2023; and U.S. Provisional Patent Application No. 63 / 514,271, filed July 18, 2023. The contents of each of these provisional applications are incorporated herein by reference in their entirety.

[0003] By referencing the merged sequence list

[0004] This application contains a sequence list conforming to the ST.26 standard, which was filed concurrently with the Patent Centre in .xml format and is hereby incorporated by reference in its entirety. A copy of the .xml file created on February 16, 2024, is named 146316_8009_WO00_SL.xml and has a size of 1,382,825 bytes. Technical Field

[0005] This article describes compositions comprising a combination of a non-naturally occurring melanocortin analogue and a spirocyclic compound and / or an anti-GDF-15 antibody or an antigen-binding fragment thereof, and methods of using the compositions. Background Technology

[0006] Melanocortin analogues have been synthesized for the potential regulation and treatment of a variety of conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormone secretion and multiple exocrine gland insufficiency (e.g., Sjögren's syndrome), immune-related conditions, and sexual dysfunction.

[0007] If left untreated, loss of appetite (e.g., anorexia) can lead to fatigue, malnutrition, weight loss, decreased muscle or fat mass, and a decline in overall physical condition. Decreased appetite and / or weight loss are symptoms of cachexia (including cancer cachexia) and can negatively impact a patient's quality of life and survival.

[0008] Despite recent progress, more effective treatments are still needed to treat patients experiencing decreased appetite and / or weight loss. Furthermore, there is a need for more selective, less toxic appetite-stimulating therapies that can effectively promote appetite, increase food consumption, and increase weight (e.g., muscle mass, fat mass) in patients in need.

[0009] The use of anticancer agents (including chemotherapy agents) is often limited by associated side effects such as anorexia, vomiting, weight loss, fat and muscle wasting, and fatigue. These limitations may include restricted duration of cancer treatment and dosage of anticancer therapies. Therefore, these side effects limit treatment tolerance in cancer patients and reduce their quality of life. Despite advances in cancer treatment in recent years, there remains a need for new therapies with robust activity that reduces the adverse side effects of cancer treatments. Summary of the Invention

[0010] In some embodiments, the present invention includes a composition comprising:

[0011] A first compound comprising a non-naturally occurring melanocortin analogue, the non-naturally occurring melanocortin analogue comprising the sequence according to formula (I),

[0012] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8

[0013] (I)

[0014] in:

[0015] R 1The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0016] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0017] R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0018] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0019] R5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0020] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0021] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0022] R 8 It is absent or contains lysine or arginine;

[0023] R 9 It is absent or contains tryptophan;

[0024] R 10 It is absent or contains lysine;

[0025] R 11 To R 20 It does not exist;

[0026] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0027] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0028] X3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0029] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0030] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[0031] Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[0032] Y 4 It is absent or is either D-proline or D-valine;

[0033] Y 5 It is absent or is either D-proline or D-valine;

[0034] Y 6 It is absent or is either D-proline or D-valine;

[0035] Y 7 It is absent or is either D-proline or D-valine;

[0036] Y 8 It is absent or is either D-proline or D-valine;

[0037] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0038] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R2 With R 7 or X 1 Disulfide bonds between them;

[0039] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0040] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0041] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0042] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0043] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0044] The conditions are:

[0045] When R 2 When it is dAsp, then R 7 Not for dLys;

[0046] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7Not Arg-Trp-Lys; and

[0047] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0048] When R 7 When it is Aia, R 4 dNal(2');

[0049] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[0050] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO:661), then Y 1 To Y 2 Not dPro-dVal;

[0051] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[0052] When this non-natural melanocortin analogue is linear, R 2 It does not not exist.

[0053] and

[0054] Second compound and / or third compound,

[0055] The second compound comprises a structure according to formula (X).

[0056]

[0057] Or its pharmaceutically acceptable salt, wherein:

[0058] Rx 1 H, halogen, C 1-4 Alkyl, C1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a , of which C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0059] Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. ATogether with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0060] Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0061] Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0062] Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0063] Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form halogens, optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C, and C.1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl;

[0064] Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups

[0065] Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 Alkyl; and

[0066] Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N, and

[0067] The third compound comprises an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), and the antibody or antigen-binding fragment thereof comprises at least one of the following:

[0068] a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52;

[0069] b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184;

[0070] c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185;

[0071] d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186;

[0072] e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179;

[0073] f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180;

[0074] g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181;

[0075] h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:163.

[0076] i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039.

[0077] j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:163. L );

[0078] k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ;

[0079] l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162;

[0080] m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; and GDF-15

[0081] n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

[0082] In some embodiments, the present invention includes a composition comprising:

[0083] A first compound comprising a non-naturally occurring melanocortin analogue, the non-naturally occurring melanocortin analogue comprising the sequence according to formula (I),

[0084] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8

[0085] (I)

[0086] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0087] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0088] R 3The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0089] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0090] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0091] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0092] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0093] R 8 It is absent or contains lysine or arginine;

[0094] R 9 It is absent or contains tryptophan;

[0095] R 10 It is absent or contains lysine;

[0096] R 11 To R 20 It does not exist;

[0097] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0098] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0099] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0100] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0101] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[0102] Y3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[0103] Y 4 It is absent or is either D-proline or D-valine;

[0104] Y 5 It is absent or is either D-proline or D-valine;

[0105] Y 6 It is absent or is either D-proline or D-valine;

[0106] Y 7 It is absent or is either D-proline or D-valine;

[0107] Y 8 It is absent or is either D-proline or D-valine;

[0108] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0109] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0110] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0111] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0112] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0113] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0114] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0115] The conditions are:

[0116] When R 2 When it is dAsp, then R 7 Not for dLys;

[0117] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and

[0118] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0119] When R 7 When it is Aia, R 4 dNal(2');

[0120] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[0121] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y1 To Y 2 Not dPro-dVal;

[0122] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[0123] When this non-natural melanocortin analogue is linear, R 2 It does not not exist, and

[0124] A second compound comprising the structure according to formula (X)

[0125]

[0126] Or its pharmaceutically acceptable salt, wherein:

[0127] Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a , of which C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0128] Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx ASubstituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0129] Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0130] Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0131] Rx 2 and Rx 3Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0132] Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form halogens, optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl;

[0133] Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups

[0134] Xx 1 For C(Rx) X)2, where each Rx X Independently H or C 1-4 Alkyl; and

[0135] Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N.

[0136] In some embodiments, the present invention includes a composition comprising:

[0137] A first compound comprising a non-naturally occurring melanocortin analogue, the non-naturally occurring melanocortin analogue comprising the sequence according to formula (I),

[0138] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8

[0139] (I)

[0140] in:

[0141] R 1The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0142] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0143] R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0144] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0145] R5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0146] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0147] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0148] R 8 It is absent or contains lysine or arginine;

[0149] R 9 It is absent or contains tryptophan;

[0150] R 10 It is absent or contains lysine;

[0151] R 11 To R 20 It does not exist;

[0152] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0153] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0154] X3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0155] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0156] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[0157] Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[0158] Y 4 It is absent or is either D-proline or D-valine;

[0159] Y 5 It is absent or is either D-proline or D-valine;

[0160] Y 6 It is absent or is either D-proline or D-valine;

[0161] Y 7 It is absent or is either D-proline or D-valine;

[0162] Y 8 It is absent or is either D-proline or D-valine;

[0163] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0164] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R2 With R 7 or X 1 Disulfide bonds between them;

[0165] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0166] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0167] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0168] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0169] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0170] The conditions are:

[0171] When R 2 When it is dAsp, then R 7 Not for dLys;

[0172] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7Not Arg-Trp-Lys; and

[0173] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0174] When R 7 When it is Aia, R 4 dNal(2');

[0175] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[0176] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal;

[0177] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[0178] When this non-natural melanocortin analogue is linear, R 2 It does not not exist, and

[0179] A third compound comprising an antibody or an antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), wherein the antibody or antigen-binding fragment thereof comprises at least one of the following:

[0180] a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52;

[0181] b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184;

[0182] c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185;

[0183] d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186;

[0184] e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179;

[0185] f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180;

[0186] g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181;

[0187] h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:163.

[0188] i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039.

[0189] j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:163. L );

[0190] k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ;

[0191] l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162;

[0192] m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; and

[0193] n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

[0194] In some embodiments, the present invention includes a composition comprising:

[0195] A first compound comprising a non-naturally occurring melanocortin analogue, the non-naturally occurring melanocortin analogue comprising the sequence according to formula (I),

[0196] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8

[0197] (I)

[0198] in:

[0199] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0200] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0201] R 3The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0202] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0203] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0204] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0205] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0206] R 8 It is absent or contains lysine or arginine;

[0207] R 9 It is absent or contains tryptophan;

[0208] R 10 It is absent or contains lysine;

[0209] R 11 To R 20 It does not exist;

[0210] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0211] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0212] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0213] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0214] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[0215] Y3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[0216] Y 4 It is absent or is either D-proline or D-valine;

[0217] Y 5 It is absent or is either D-proline or D-valine;

[0218] Y 6 It is absent or is either D-proline or D-valine;

[0219] Y 7 It is absent or is either D-proline or D-valine;

[0220] Y 8 It is absent or is either D-proline or D-valine;

[0221] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0222] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0223] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0224] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0225] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0226] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0227] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0228] The conditions are:

[0229] When R 2 When it is dAsp, then R 7 Not for dLys;

[0230] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and

[0231] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0232] When R 7 When it is Aia, R 4 dNal(2');

[0233] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[0234] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y1 To Y 2 Not dPro-dVal;

[0235] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[0236] When this non-natural melanocortin analogue is linear, R 2 It does not not exist.

[0237] A second compound comprising the structure according to formula (X):

[0238]

[0239] Or its pharmaceutically acceptable salt, wherein:

[0240] Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a , of which C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0241] Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx ASubstituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0242] Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0243] Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0244] Rx 2 and Rx 3Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0245] Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form halogens, optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl;

[0246] Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups

[0247] Xx 1 For C(Rx) X)2, where each Rx X Independently H or C 1-4 alkyl;

[0248] Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N, and

[0249] A third compound comprising an antibody or an antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), wherein the antibody or antigen-binding fragment thereof comprises at least one of the following:

[0250] a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52;

[0251] b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184;

[0252] c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185;

[0253] d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186;

[0254] e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179;

[0255] f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180;

[0256] g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181;

[0257] h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:163.

[0258] i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039.

[0259] j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:163. L );

[0260] k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ;

[0261] l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162;

[0262] m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; GDF-15 and

[0263] n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

[0264] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

[0265] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an acyl group.

[0266] In some embodiments, the acyl group is an acetyl group.

[0267] In some embodiments, the acyl group is a formyl group.

[0268] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an imine group.

[0269] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an amide group.

[0270] In some embodiments, the amide group is a pyroglutamyl (pGlu) group.

[0271] In some embodiments, the amide group is derived from a fatty acid.

[0272] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analogue is not modified.

[0273] In some embodiments, if present, the C-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

[0274] In some embodiments, if present, the C-terminus of the non-naturally occurring melanocortin analog is modified with an amide group.

[0275] In some embodiments, the amide group is a -NH alkylamide group or a -NH arylamide group.

[0276] In some embodiments, the -NH arylamide group is a p-nitroaniline group or 7-amino-4-methylcoumarin.

[0277] In some embodiments, the C-terminus of the non-natural melanocortin analog is modified with an ester group.

[0278] In some embodiments, the C-terminus of the non-natural melanocortin analogue is not modified.

[0279] In some embodiments, R 1 It does not exist, and R 2It is D-aspartic acid.

[0280] In some embodiments, X 1 X 2 and X 3 It does not exist.

[0281] In some embodiments, R 4 It is not D-phenylalanine.

[0282] In some embodiments, R 4 It is dNal(2').

[0283] In some embodiments, Y 3 To Y 8 It does not exist.

[0284] In some embodiments, Y 1 It is D-valine and Y 2 It is D-proline; or

[0285] Y 1 It is D-proline and Y 2 It is D-valine.

[0286] In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist.

[0287] In some embodiments, Y 1 It is either D-valine or D-proline;

[0288] Y 2 It is D-valine or D-proline; and / or

[0289] Y 3 It is either D-valine or D-proline.

[0290] In some embodiments, Y 1 For D-valine, Y 2 It is D-valine and Y 3 It is D-proline;

[0291] Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-valine;

[0292] Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine; or

[0293] Y 1For D-proline, Y 2 It is D-valine and Y 3 It is D-proline.

[0294] In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist.

[0295] In some embodiments, Y 1 It is either D-valine or D-proline;

[0296] Y 2 It is either D-valine or D-proline;

[0297] Y 3 It is D-valine or D-proline; and / or

[0298] Y 4 It is either D-valine or D-proline.

[0299] In some embodiments, Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-proline; Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-valine;

[0300] Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-valine;

[0301] Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine; or

[0302] Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-proline.

[0303] In some embodiments, R 1 R 2 and R 7 Existence and R8 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 7 Cyclation via lactam bonds.

[0304] In some embodiments, R 1 It is acetylated leucine;

[0305] R 2 It is aspartic acid;

[0306] R 3 Choose the group consisting of the following: proline, hydroxyproline, and hydroxy-D-proline;

[0307] R 4 For D-Nal(2');

[0308] R 5 It is arginine;

[0309] R 6 It is either D-tryptophan or L-tryptophan;

[0310] R 7 It is lysine;

[0311] Y 1 For D-valine; and / or

[0312] Y 2 It is D-proline.

[0313] In some embodiments, the sequence of equation (I) is:

[0314] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 306; B07) or

[0315] Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:307; D3), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

[0316] In some embodiments, R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 8Cyclation via lactam bonds.

[0317] In some embodiments, R 1 It is acetylated leucine;

[0318] R 2 It is aspartic acid;

[0319] R 3 Choose the group consisting of the following: proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine;

[0320] R 4 For histidine or D-Nal(2');

[0321] R 5 It is D-Nal(2') or arginine;

[0322] R 6 Choose the group consisting of the following: arginine, D-tryptophan, and L-tryptophan;

[0323] R 7 It is tryptophan or proline;

[0324] R 8 It is lysine;

[0325] Y 1 Choose from the group consisting of: D-valine, D-leucine, and D-isoleucine; and / or

[0326] Y 2 It is D-proline.

[0327] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0328] Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 308; D1);

[0329] Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 309; D1γ);

[0330] Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 310; D1δ);

[0331] Ac-Nle- c (Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 311; D2); and

[0332] Ac-Nle- c (Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 312; D4),

[0333] Where c represents through R 2 and R 8 Cyclation via lactam bonds.

[0334] In some embodiments, R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 10 Cyclation via lactam bonds.

[0335] In some embodiments, the sequence of equation (I) is:

[0336] Ac-Nle- c (Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQID NO:313;D1α), where c represents through R 2 and R 10 Cyclation via lactam bonds.

[0337] In some embodiments, R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 4 and R 10 Cyclation via lactam bonds.

[0338] In some embodiments, the sequence of equation (I) is:

[0339] Ac-Nle-Phe-Phe-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQID NO:314; D1β), where c represents the result of passing through R4 and R 10 Cyclation via lactam bonds.

[0340] In some embodiments, the sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro(SEQ ID NO:305; B07a), where c represents the sequence via R. 2 and R 7 Cyclation via lactam bonds.

[0341] In some embodiments, the sequence of equation (I) is linear.

[0342] In some embodiments, the sequence of equation (I) is:

[0343] Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 315; A1).

[0344] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0345] Ac-dArg- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 316);

[0346] Ac-dMet- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 317);

[0347] Ac-dIle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 318);

[0348] Ac-dLeu- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 319);

[0349] Ac-dVal- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 320);

[0350] Ac-dAla-c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:321);

[0351] Ac-Ala- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:322);

[0352] Ac-Tle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:323);

[0353] Ac-dTle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:324);

[0354] Ac-dNle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:325);

[0355] Ac-Nva- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:326);

[0356] Ac-Gly- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:327);

[0357] Ac-dPro- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:328);

[0358] Ac-dCys- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:329);

[0359] Ac-dPhe- c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 330);

[0360] Ac-dTyr- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 331);

[0361] Ac-dGln- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 332); and

[0362] Ac-dAsn- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:333),

[0363] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0364] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0365] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 334);

[0366] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 335);

[0367] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 336);

[0368] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 337);

[0369] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 338);

[0370] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:339);

[0371] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:340);

[0372] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:341);

[0373] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:342);

[0374] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:343);

[0375] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:344);

[0376] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:345);

[0377] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:346);

[0378] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:347);

[0379] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:348);

[0380] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:349);

[0381] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:350);

[0382] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:351);

[0383] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:352);

[0384] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:353);

[0385] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:354);

[0386] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:355);

[0387] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:356);

[0388] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:357);

[0389] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:358);

[0390] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:359);

[0391] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 360);

[0392] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 361);

[0393] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 362); and

[0394] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO:363),

[0395] Where c represents through R 2 and R 6 or R 7 Cycling via lactam bonds or disulfide bonds.

[0396] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0397] Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 364);

[0398] Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 365);

[0399] Ac-Nle-c(Asp-dPro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366);

[0400] Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 367);

[0401] Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368);

[0402] Ac-Nle-c(Asp-Pro-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 369);

[0403] Ac-Nle-c(Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 370);

[0404] Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 371);

[0405] Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372);

[0406] Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 373); and

[0407] Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:374),

[0408] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0409] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0410] Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375);

[0411] Ac-Nle-c(Asp-Pro-dNal(2')-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376);

[0412] Ac-Nle-c(Asp-Pro-dNal(2')-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377);

[0413] Ac-Nle-c(Asp-Pro-dNal(2')-dArg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 378);

[0414] Ac-Nle-c(Asp-Pro-dNal(2')-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379);

[0415] Ac-Nle-c(Asp-Pro-dNal(2')-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 380);

[0416] Ac-Nle-c(Asp-Pro-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381);

[0417] Ac-Nle-c(Asp-Pro-dNal(2')-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382);

[0418] Ac-Nle-c(Asp-Pro-dNal(2')-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383);

[0419] Ac-Nle-c(Asp-Pro-dNal(2')-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); and

[0420] Ac-Nle-c(Asp-Pro-dNal(2')-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:385),

[0421] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0422] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0423] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH2 (SEQ ID NO: 386);

[0424] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Nal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387);

[0425] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 388);

[0426] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389);

[0427] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 390);

[0428] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and

[0429] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO:392),

[0430] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0431] In some embodiments, the sequence of formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:393), where c represents the sequence via R. 2 and R 7 Cyclation via lactam bonds.

[0432] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0433] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ ID NO: 394);

[0434] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH(SEQ ID NO:395);

[0435] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH(SEQ ID NO:396);

[0436] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:397);

[0437] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH2(SEQ ID NO:398);

[0438] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO:399);

[0439] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH2(SEQ ID NO:400);

[0440] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO:401);

[0441] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH2(SEQ ID NO:402);

[0442] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO:403);

[0443] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO:404);

[0444] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO:405);

[0445] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO:406);

[0446] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO:407);

[0447] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2(SEQ ID NO:408);

[0448] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH2(SEQ ID NO:409);

[0449] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO:410);

[0450] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO:411);

[0451] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH2(SEQ ID NO:412);

[0452] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO:413);

[0453] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO:414);

[0454] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO:415);

[0455] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO:416);

[0456] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO:417);

[0457] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO:418);

[0458] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO:419);

[0459] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH2(SEQ ID NO:420);

[0460] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH2(SEQ ID NO:421);

[0461] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ ID NO:422);

[0462] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO:423);

[0463] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO:424);

[0464] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO:425);

[0465] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH2(SEQ ID NO:426);

[0466] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO:427);

[0467] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO:428);

[0468] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO:429);

[0469] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO:430);

[0470] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO:431);

[0471] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO:432);

[0472] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO:433);

[0473] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO:434);

[0474] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO:435);

[0475] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Pro-Val-NH2(SEQ ID NO:436);

[0476] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-dVal-NH2(SEQ ID NO:437);

[0477] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO:438);

[0478] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO:439);

[0479] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO:440);

[0480] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO:441);

[0481] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO:442);

[0482] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dVal-dPro-NH2(SEQ ID NO:443);

[0483] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Pro-Val-NH2(SEQ ID NO:444);

[0484] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-dVal-NH2(SEQ ID NO:445);

[0485] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-dVal-NH2(SEQ ID NO:446);

[0486] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Val-Pro-NH2(SEQ ID NO:447);

[0487] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 448); and

[0488] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO:449),

[0489] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0490] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0491] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 450);

[0492] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 451);

[0493] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ IDNO: 452);

[0494] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 453); and

[0495] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 454),

[0496] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0497] In some embodiments, X 1 It exists and is acetylated leucine, and R 1 It exists and is leucine.

[0498] In some embodiments, X 2 It exists and is leucine.

[0499] In some embodiments, it is present and is leucine.

[0500] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0501] Ac-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 455);

[0502] Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 456); and

[0503] Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 457),

[0504] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[0505] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[0506] Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 458);

[0507] Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 459);

[0508] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 460);

[0509] c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ IDNO: 461);

[0510] Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 462);

[0511] Ac-Nle-c(Asp-β-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 463);

[0512] Ac-Nle-c(Asp-Mamb-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 464);

[0513] Ac-Nle-c(Asp-Acpc-dNal(2')Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 465);

[0514] Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO:466); and

[0515] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO:467),

[0516] Where c represents through R 2 and R 7 or R 8 via lactam cyclization or through R 2 and R 5 Cycling via disulfide bonds.

[0517] In some embodiments, the sequence of equation (I) is:

[0518] Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:468); or

[0519] Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:469),

[0520] Where c represents through R 2 and R 7 or R 8 Cyclation via lactam bonds.

[0521] In some embodiments, the non-naturally occurring melanocortin analogue comprises any one of the sequences of SEQ ID NO: 306, 428, 481 to 483, 493 to 495, 528 to 531, and 552 to 555.

[0522] In some embodiments, the non-naturally occurring melanocortin analogue comprises the sequence of SEQ ID NO:306.

[0523] In some embodiments, the second compound is a compound of formula (Xi):

[0524]

[0525] Or its pharmaceutically acceptable salt.

[0526] In some embodiments, the second compound is a compound of formula (Xii):

[0527]

[0528] Or its pharmaceutically acceptable salt.

[0529] In some embodiments,

[0530] Rx 1 For Rx 1a And Rx 1a Rx can be optionally selected independently by 1, 2, 3 or 4 A Substituted 6-membered heteroaryl group, where each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 14 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C3-C4 cycloalkyl or (C 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 alkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two ring atoms of the 6-membered heteroaryl group to which they are attached, they form a fused benzene ring or a fused 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogens, -OH, -CN, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 14 Substituents of haloalkoxy groups.

[0531] In some embodiments, Rx 1a Rx can be optionally selected independently by 1, 2 or 3 A Substituted pyrimidine groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-4 Cycloalkyl.

[0532] In some embodiments, Rx 1a It is pyrimidin-2-yl.

[0533] In some embodiments, Xx 1 It is CH2.

[0534] In some embodiments, Rx 2 and Rx 3 Each of them is independently H, F, or C. 1-4 alkyl.

[0535] In some embodiments, Rx 2 It is methyl and Rx 3 For H.

[0536] In some embodiments, Yx 3 Let N be the number of elements, and Yx be the number of elements. 1 Yx 2 Yx 4 and Yx 5 Each of them is independently CRx 4 .

[0537] In some embodiments, Rx 4 Independent of H, halogen or C 1-2 Alkyl group.

[0538] In some embodiments, the second compound is selected from:

[0539] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1;

[0540] 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1;

[0541] 2-(6-(difluoromethoxy)pyridin-3-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-2;

[0542] 1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)-2-(4-(trifluoromethyl)phenyl)prop-1-one, DIAST-1;

[0543] 1-(4,7-Dimethyl-3,4-dihydro-1H-spiro(1,8-naphthid-2,3'-pyrrolidine)-1'-yl)-2-(4-fluorophenyl)ethyl-1-one, DIAST-1;

[0544] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one;

[0545] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one;

[0546] (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one;

[0547] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1; and

[0548] (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-((4,6- 2H2)pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl}prop-1-one,

[0549] Or its pharmaceutically acceptable salt.

[0550] In some embodiments, the second compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidine-2,3'-pyrrolidine)-1'-yl)prop-1-one, or a pharmaceutically acceptable salt thereof.

[0551] In some embodiments, the second compound is the crystalline form of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidine-2,3'-pyrrolidine)-1'-yl)prop-1-one.

[0552] In some embodiments, the antibody or its antigen-binding fragment comprises a human Fc domain selected from the group consisting of IgA1, IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, or IgG4.

[0553] In some embodiments, the antibody or its antigen-binding fragment has a K value that is about or less than the value selected from the group consisting of the following. D Combined with human or cynomolgus monkey GDF-15: approximately 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, and 10 pM.

[0554] In some embodiments, the antibody or its antigen-binding fragment comprises an anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group consisting of amino acid sequences of the following: SEQ ID NO: 32, 165, 52, 25, 166, 22, 23, 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

[0555] In some embodiments, the composition further comprises an anticancer agent.

[0556] In some embodiments, the anticancer agent is at least one chemotherapeutic agent.

[0557] In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of platinum coordination complexes, antimetabolites, microtubule binders, alkylated antitumor agents, and cytotoxic antibiotics.

[0558] In some embodiments, the platinum coordination complex is cisplatin.

[0559] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU).

[0560] In some embodiments, the tubulin binder is vincristine.

[0561] In some embodiments, the alkylated antitumor agent is cyclophosphamide.

[0562] In some embodiments, the cytotoxic antibiotic is doxorubicin.

[0563] In some embodiments, the first compound and the second compound are present in a single pharmaceutical composition.

[0564] In some embodiments, the first compound and the third compound are present in a single pharmaceutical composition.

[0565] In some embodiments, the first compound, the second compound, and the third compound, if present, are present in a single pharmaceutical composition.

[0566] In some embodiments, the single pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intraventricular, or oral administration.

[0567] In some embodiments, the single pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0568] In some embodiments, the first compound is present in the single pharmaceutical composition at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the single pharmaceutical composition.

[0569] In some embodiments, the first compound is present in a first pharmaceutical composition; and the second compound is present in a second pharmaceutical composition.

[0570] In some embodiments, the first compound is present in a first pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

[0571] In some embodiments, the first compound is present in a first pharmaceutical composition; the second compound is present in a second pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

[0572] In some embodiments, the first pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intraventricular, or oral administration.

[0573] In some embodiments, the first pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0574] In some embodiments, the first compound is present in the first pharmaceutical composition at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the first pharmaceutical composition.

[0575] In some embodiments, the present invention includes a composition comprising:

[0576] The first compound with primary therapeutic effects; and

[0577] Second and / or third compounds, each possessing secondary therapeutic effects,

[0578] The first compound is a non-natural melanocortin analogue, the second compound is a spirocyclic compound, and the third compound is an antibody or its antigen-binding fragment.

[0579] In some embodiments, the non-natural melanocortin analogue is a melanocortin 3 receptor (MC3R) agonist and a melanocortin 4 receptor (MC4R) agonist.

[0580] In some embodiments, the primary therapeutic effect occurs after activation of the MC3R and / or the MC4R.

[0581] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to formula (I),

[0582] X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8

[0583] (I)

[0584] in:

[0585] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0586] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0587] R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0588] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0589] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0590] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0591] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0592] R 8 It is absent or contains lysine or arginine;

[0593] R 9 It is absent or contains tryptophan;

[0594] R 10 It is absent or contains lysine;

[0595] R 11 To R 20 It does not exist;

[0596] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0597] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0598] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0599] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0600] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[0601] Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[0602] Y 4 It is absent or is either D-proline or D-valine;

[0603] Y 5 It is absent or is either D-proline or D-valine;

[0604] Y 6 It is absent or is either D-proline or D-valine;

[0605] Y 7 It is absent or is either D-proline or D-valine;

[0606] Y 8It is absent or is either D-proline or D-valine;

[0607] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0608] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0609] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0610] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0611] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0612] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0613] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0614] The conditions are:

[0615] When R 2 When it is dAsp, then R 7 Not for dLys;

[0616] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and

[0617] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[0618] When R 7 When it is Aia, R 4 dNal(2');

[0619] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[0620] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal;

[0621] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[0622] When this non-natural melanocortin analogue is linear, R 2 It does not not exist.

[0623] In some embodiments, the non-naturally occurring melanocortin analogue comprises the sequence of SEQ ID NO:306.

[0624] In some embodiments, the spirocyclic compound is an MC4R antagonist.

[0625] In some embodiments, the secondary therapeutic effect occurs after the MC4R.

[0626] In some embodiments, the spirocyclic compound comprises a structure according to formula (X).

[0627]

[0628] Or its pharmaceutically acceptable salt, wherein:

[0629] Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a , of which C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0630] Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0631] Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0632] Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0633] Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[0634] Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form halogens, optionally composed of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl;

[0635] Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups

[0636] Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 alkyl;

[0637] Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N.

[0638] In some embodiments, the spirocyclic compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidine-2,3'-pyrrolidine)-1'-yl)prop-1-one, or a pharmaceutically acceptable salt thereof.

[0639] In some embodiments, the antibody or its antigen-binding fragment specifically binds to a portion of human growth differentiation factor 15 (GDF-15).

[0640] In some embodiments, the antibody or its antigen-binding fragment binds to GDF-15, thereby preventing GDF-15 from binding to the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) receptor.

[0641] In some embodiments, the antibody or its antigen-binding fragment comprises at least one of the following:

[0642] a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52;

[0643] b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184;

[0644] c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185;

[0645] d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186;

[0646] e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179;

[0647] f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180;

[0648] g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181;

[0649] h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:163.

[0650] i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039.

[0651] j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:163. L );

[0652] k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ;l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162;

[0653] m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; GDF-15; and

[0654] n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

[0655] In some embodiments, the antibody or its antigen-binding fragment comprises an anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group consisting of amino acid sequences of the following: SEQ ID NO: 32, 165, 52, 25, 166, 22, 23, 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

[0656] In some embodiments, the secondary therapeutic effect is a supportive therapeutic effect compared to the primary therapeutic effect.

[0657] In some embodiments, the composition contains a lower dose unit of the second compound and / or the third compound compared to a dose unit of the second compound and / or the third compound in which the first compound is absent.

[0658] In some embodiments, the composition contains a lower dose of the second compound and / or the third compound compared to a dose of the second compound and / or the third compound in the absence of the first compound.

[0659] In some embodiments, the composition comprises a shorter dosing regimen of the second compound and / or the third compound compared to a dosing regimen of the second compound and / or the third compound in which the first compound is absent.

[0660] In some embodiments, the composition contains a smaller dose of the second compound and / or the third compound compared to a dose of the second compound and / or the third compound in which the first compound is absent.

[0661] In some embodiments, the composition has an improved net effect on MC4R compared to the effect of the second compound on MC4R in the absence of the first compound and / or the effect of the third compound on MC4R.

[0662] In some embodiments, the present invention includes a method for increasing the appetite of a subject in need relative to a control, the method comprising:

[0663] Compositions for which the technology of the present invention is applied.

[0664] In some embodiments, the subject experienced an increased appetite compared to the control, as measured by an increase in food intake of approximately 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, or 3000.

[0665] In some embodiments, the subject does not follow a high-carbohydrate, high-calorie (HCHC) diet.

[0666] In some embodiments, the HCHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of that energy comes from carbohydrates.

[0667] In some embodiments, the subject did not follow a high-fat, high-calorie (HFHC) diet.

[0668] In some embodiments, the HFHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of that energy comes from fat.

[0669] In some embodiments, the first compound, the second compound, and the third compound are applied simultaneously as a single composition.

[0670] In some embodiments, the first compound is present in the first pharmaceutical composition;

[0671] If present, the second compound is present in the second pharmaceutical composition; and

[0672] If present, the third compound is present in the third pharmaceutical composition.

[0673] In some embodiments, the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and are administered simultaneously but separately.

[0674] In some embodiments, the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and are administered sequentially.

[0675] In some embodiments, the first pharmaceutical composition is administered prior to the initial administration of the second pharmaceutical composition.

[0676] In some embodiments, the first pharmaceutical composition is administered prior to the initial administration of the third pharmaceutical composition.

[0677] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially over approximately 24 hours.

[0678] In some embodiments, the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered at night.

[0679] In some embodiments, the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially over approximately 24 hours.

[0680] In some embodiments, the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered at night.

[0681] In some embodiments, the first compound comprises the sequence of SEQ ID NO:306.

[0682] In some embodiments, the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the subject's weight.

[0683] In some embodiments, the first compound is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the subject's weight.

[0684] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10% to 75% lower than the therapeutically effective amount of the second compound when administered alone.

[0685] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25% to 50% lower than the therapeutically effective amount of the second compound when administered alone.

[0686] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10% to 75% lower than the therapeutically effective amount of the third compound when administered alone.

[0687] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25% to 50% lower than the therapeutically effective amount of the third compound when administered alone.

[0688] In some embodiments, the composition is applied to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0689] In some embodiments, the composition is applied to the subject for 1, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

[0690] In some embodiments, the subject experienced loss of appetite, reduced food consumption, and / or weight loss prior to administration.

[0691] In some embodiments, the loss of appetite, reduced food consumption, and / or weight loss are caused by cachexia.

[0692] In some embodiments, the weight loss is a loss of muscle mass, a loss of fat mass, or both.

[0693] In some embodiments, the method (i) stimulates the subject's appetite; (ii) increases the subject's food consumption; (iii) prevents or alleviates the subject's nausea, vomiting, and / or anorexia; (iv) increases or maintains the subject's weight; (v) prevents or reduces the subject's weight loss; (vi) increases or maintains the subject's muscle mass; (vii) prevents or reduces the subject's muscle mass loss; (viii) increases or maintains the subject's fat mass; and / or (ix) prevents or reduces the subject's fat mass loss.

[0694] In some embodiments, the present invention includes a method of treating cancer in a subject in need, the method comprising administering to the subject a composition according to any one of Examples 77 to 96.

[0695] In some embodiments, compared to the control, the subject experienced a tumor size reduction of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0696] In some embodiments, the subject experienced a reduction in cancer metastasis compared to a control, as measured by a reduction in cancer cell proliferation of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

[0697] In some embodiments, the present invention includes a method of treating a subject suffering from cancer, the method comprising: administering to the subject a composition according to any one of Examples 77 to 96,

[0698] in:

[0699] This method reduces or prevents side effects associated with the anticancer agent in combination therapy, wherein the side effects are at least one of the following groups: cachexia, anorexia, weight loss, loss of fat mass, and loss of muscle mass.

[0700] In some embodiments, the present invention includes a method for improving the survival of subjects suffering from cancer, the method comprising:

[0701] The subject was given the composition according to any one of Examples 77 to 96.

[0702] in:

[0703] This method reduces or prevents side effects associated with the anticancer agent in combination therapy, thereby improving the survival of the subject, wherein the side effects are selected from at least one of the following groups: cachexia, anorexia, weight loss, loss of fat mass and loss of muscle mass.

[0704] In some embodiments, the present invention includes a method for increasing the weight of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0705] In some embodiments, compared to the control, the subject experienced a weight gain of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500%.

[0706] In some embodiments, the present invention includes a method for increasing muscle mass in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0707] In some embodiments, compared to the control, the subject experienced an increase in muscle mass of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0708] In some embodiments, the present invention includes a method for increasing the fat mass of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0709] In some embodiments, compared with the control, the subject experienced an increase in fat mass of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0710] In some embodiments, the present invention includes a method for increasing the heart mass of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0711] In some embodiments, compared to the control, the subject experienced an increase in heart mass of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0712] In some embodiments, the present invention includes a method for increasing bone mineral density in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0713] In some embodiments, the subject experienced an increase in bone mineral density of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0714] In some embodiments, the present invention includes a method for reducing fatigue in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0715] In some embodiments, the present invention includes a method for reducing vomiting in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0716] In some embodiments, the present invention includes a method for reducing diarrhea in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0717] In some embodiments, the present invention includes a method for increasing the cumulative mass of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0718] In some embodiments, the subject experienced a cumulative mass increase of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0719] In some embodiments, the present invention includes a method for increasing the net weight gain of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0720] In some embodiments, the subject experienced an increase in net weight gain of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0721] In some embodiments, the present invention includes a method for reducing the rate of cumulative mass loss in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0722] In some embodiments, compared with the control, the subject experienced a reduction in the rate of cumulative mass loss of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0723] In some embodiments, the present invention includes a method for increasing the cumulative food intake of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0724] In some embodiments, compared with the control, the subject experienced a cumulative increase in food intake of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0725] In some embodiments, the present invention includes a method for increasing a subject's body mass index (BMI) compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0726] In some embodiments, the subject experienced a BMI increase of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points compared to the control.

[0727] In some embodiments, the present invention includes a method for reducing the level of pro-inflammatory transcripts or proteins in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0728] In some embodiments, compared with the control, the subject experienced a reduction of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% in inflammatory transcript or protein levels.

[0729] In some embodiments, the pro-inflammatory transcript is selected from the group consisting of: IL1b transcript, IL1R1 transcript, IL6 transcript, CCL2 transcript, and GDF-15 transcript.

[0730] In some embodiments, the pro-inflammatory protein is selected from the group consisting of: IL1b protein, IL1R1 protein, IL6 protein, CCL2 protein, and GDF-15 protein.

[0731] In some embodiments, the present invention includes a method for increasing the treatment function assessment of anorexia / cachexia (FAACT) score of a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0732] In some embodiments, the subject experienced an increase of at least 1, 2, 3, 4, or 5 points in FAACT score compared to the control.

[0733] In some embodiments, the present invention includes a method for increasing the persistence of BMI in a subject compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0734] In some embodiments, the subject experienced a sustained increase in BMI of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

[0735] In some embodiments, the subject has cancer.

[0736] In some embodiments, the present invention includes a method for reducing or maintaining the Eastern Cooperative Oncology Group (ECOG) performance status score of a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0737] In some embodiments, the subject experienced a decrease in ECOG score of approximately 1, 2, or 3 compared to the control.

[0738] In some embodiments, the present invention includes a method for increasing or maintaining the Karnofsky Performance Status (KPS) score of a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0739] In some embodiments, the subject experienced an increase in KPS score of approximately 100, 90, 80, 70, 60, 50, 40, or 30 compared to the control.

[0740] In some embodiments, the present invention includes a method for increasing the overall survival (OS) of a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0741] In some embodiments, the subject experienced an increase in OS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

[0742] In some embodiments, the present invention includes a method for increasing progression-free survival (PFS) in a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0743] In some embodiments, the subject experienced an increase in PFS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

[0744] In some embodiments, the present invention includes a method for increasing the time to cancer treatment failure in a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of Examples 1 to 115.

[0745] In some embodiments, the subject experienced a reduction in cancer treatment failure time of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

[0746] In some embodiments, the control group includes a subject at baseline or a second subject who has not received the composition according to any one of Examples 1 to 115.

[0747] In some embodiments, the subject does not follow a high-carbohydrate, high-calorie (HCHC) diet.

[0748] In some embodiments, the HCHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of that energy comes from carbohydrates.

[0749] In some embodiments, the subject did not follow a high-fat, high-calorie (HFHC) diet.

[0750] In some embodiments, the HFHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of that energy comes from fat.

[0751] In some embodiments, the first compound, the second compound, the third compound, and the anticancer agent are administered simultaneously as a single composition.

[0752] In some embodiments, the first compound is present in the first pharmaceutical composition;

[0753] If present, the second compound is present in the second pharmaceutical composition;

[0754] If present, the third compound is present in the third pharmaceutical composition; and

[0755] The anticancer agent is present in the fourth pharmaceutical composition.

[0756] In some embodiments, the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition are different and are administered simultaneously but separately.

[0757] In some embodiments, the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition are different and are administered sequentially.

[0758] In some embodiments, the first pharmaceutical composition is administered prior to the initial administration of the second pharmaceutical composition.

[0759] In some embodiments, the first pharmaceutical composition is administered prior to the initial administration of the third pharmaceutical composition.

[0760] In some embodiments, the first pharmaceutical composition is administered prior to the initial administration of the fourth pharmaceutical composition.

[0761] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially over approximately 24 hours.

[0762] In some embodiments, the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered at night.

[0763] In some embodiments, the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially over approximately 24 hours.

[0764] In some embodiments, the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered at night.

[0765] In some embodiments, the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the subject's weight.

[0766] In some embodiments, the first compound is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the subject's weight.

[0767] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10% to 75% lower than the therapeutically effective amount of the second compound when administered alone.

[0768] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25% to 50% lower than the therapeutically effective amount of the second compound when administered alone.

[0769] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10% to 75% lower than the therapeutically effective amount of the third compound when administered alone.

[0770] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25% to 50% lower than the therapeutically effective amount of the third compound when administered alone.

[0771] In some embodiments, the composition is applied to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0772] In some embodiments, the composition is applied to the subject for 1, 7, 14, 21, 28, 35, 40, 45, 50, 60, 75, 90, 100, 110, or 120 days.

[0773] In some embodiments, the subject is a human being.

[0774] In some embodiments, the subject is an animal.

[0775] In some embodiments, the present invention does not reduce the efficacy of the anticancer agent.

[0776] In some embodiments, the cancer is at least one selected from the group consisting of: bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary gland cancer, liver cancer, gastric cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

[0777] In some embodiments, the cancer is at least one selected from the group consisting of: bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

[0778] In some embodiments, the subject with cancer has previously undergone treatment with the anticancer agent.

[0779] In some embodiments, the subject has previously experienced one or more adverse side effects while being treated with the anticancer agent, wherein the adverse side effects are selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass and loss of muscle mass.

[0780] In some embodiments, when the one or more anticancer agents are present in a composition containing the first compound and the third compound, the one or more anticancer agents are administered at a higher amount compared to a composition containing the one or more anticancer agents and the first compound or the one or more anticancer agents and the third compound.

[0781] In some embodiments, administering the one or more anticancer agents at higher doses includes increasing the dose amount, administering the dose more frequently, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

[0782] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, 7 mg / mL or 8 mg / mL, compared to about 2 mg / mL or about 3 mg / mL of the first compound or the third compound.

[0783] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

[0784] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

[0785] 229. The method according to Example 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

[0786] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

[0787] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

[0788] In some embodiments, the combination of one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

[0789] In some embodiments, the one or more anticancer agents include cisplatin.

[0790] In some embodiments, the method reduces or prevents one or more side effects in the subject, and further includes administering the one or more anticancer agents at higher doses, thereby enhancing the efficacy of the one or more anticancer agents in the subject.

[0791] In some embodiments, the method increases the efficacy of the anticancer agent. Attached Figure Description

[0792] Figures 1A to 1WWThe following illustrations show the percentage activation of the melanocortin 3 receptor (MC3R) after stimulation with a non-naturally occurring melanocortin analogue, as measured by cAMP levels, according to embodiments of the invention. Graphs showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Tables 3 and 4 are provided.

[0793] Figures 2A to 2Y The following illustration shows the percentage of MC3R activation, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue, according to an embodiment of the invention. A graph showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Tables 5 to 7 is provided.

[0794] Figures 3A to 3ZZ The following illustration shows the percentage inhibition of MC3R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue, according to an embodiment of the invention. A graph showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Table 8 is provided.

[0795] Figures 4A to 4H The following illustration shows the percentage inhibition of MC3R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue, according to an embodiment of the invention. A graph showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Table 9 is provided.

[0796] Figures 5A to 5AAA The following illustrations show the percentage activation of the melanocortin 4 receptor (MC4R) after stimulation with a non-naturally occurring melanocortin analogue, as measured by cAMP levels, according to embodiments of the invention. Graphs showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Tables 3 and 4 are provided.

[0797] Figures 6A to 6HH The following illustrations show the percentage of MC4R activation, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue, according to embodiments of the invention. Graphs showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Tables 5 through 7 are provided.

[0798] Figures 7A to 7JJJ An embodiment of the invention is illustrated, showing the percentage inhibition of MC4R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. A graph showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Table 8 is provided.

[0799] Figures 8A to 8NAn embodiment of the invention is illustrated, showing the percentage inhibition of MC4R, as measured by cAMP levels, after stimulation with a non-naturally occurring melanocortin analogue. A graph is provided showing cAMP data from selected exemplary non-naturally occurring melanocortin analogues from Table 9.

[0800] Figure 9 The following figures are shown: (i) the binding curves of compound A1 (SEQ ID NO: 315) and TCMCB07 (“B07”) with human melanocortin 1 receptor (hMC1R; genotype: 4157), human melanocortin 3 receptor (hMC3R; genotype: 4159), and human melanocortin 4 receptor (hMC4R; genotype: 4160), respectively; and (ii) the IC50 values ​​of SM-001 binding with ligands of hMC1R, hMC3R, and hMC4R, respectively. 50 Summary of values; and (iii) IC binding of B07 to ligands of hMC1R, hMC3R and hMC4R respectively. 50 Summary of values.

[0801] Figure 10 A table summarizing the SEQ ID NOs of some GDF-15 antibodies corresponding to the technology of this invention is provided.

[0802] Figures 11A to 11D The diagram depicts the daily food intake of Sprague Dawley rats. Figure 11A ), weekly food intake ( Figure 11B Daily cumulative food intake ( Figure 11C ) and total food intake after 21 days ( Figure 11D The figure compares the dietary intake of three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and an anti-GDF-15 monoclonal antibody (mAb) containing the human persegumab Fab region and mouse Fc region of SEQ ID NO:288 and 289; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO:306), and an anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14.

[0803] Figures 12A to 12D The daily body weight of Sprague Dawley rats is shown. Figure 12A ), weekly cumulative weight ( Figure 12B Daily weight gain Figure 12C ) and the overall weight increase after 21 days ( Figure 12DThe figure compares the body weight and weight gain of the three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 mouse mAb (containing SEQ ID NO: 288 and 289); and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14.

[0804] Figures 13A to 13E This shows the presence of the cytokine IL1β in the hypothalamus of Sprague Dawley rats. Figure 13A ), IL1R1 Figure 13B ), IL6 Figure 13C CCL2 Figure 13D ) and GDF-15 ( Figure 13E The graph shows the relative quantification (RQ) of mRNA expression, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five groups of rats. Group 1 rats were administered cisplatin and IgG light chain (IgG-L); Group 2 rats were administered cisplatin and IgG heavy chain (IgG-H); Group 3 rats were administered cisplatin and persegumab light chain (GDF-15Ab-L, SEQ ID NO:289); Group 4 rats were administered cisplatin and persegumab heavy chain (GDF-15Ab-H, SEQ ID NO:288); and Group 5 rats were administered saline (saline / saline). Detailed Implementation

[0805] This document describes compositions comprising a first compound containing a non-naturally occurring melanocortin analog; a second compound containing a spirostructure; and / or a third compound containing an antibody or an antigen-binding fragment thereof. The compositions may further comprise one or more anticancer agents. This document also describes methods of using the compositions to modulate body weight (including, but not limited to, increasing appetite, preventing anorexia, promoting weight gain, preventing weight loss, treating, preventing, or otherwise alleviating cachexia and / or anorexia) and / or enhancing the efficacy of the anticancer agents by administering the compositions to the subjects in need. Methods of treating subjects with cancer without causing one or more side effects are also described.

[0806] The following description is merely exemplary in nature and is not intended to limit the technology of the invention, its application, or its uses. It should be understood that in all the drawings, corresponding reference numerals indicate the same or corresponding parts and features. The description of specific examples shown in various embodiments of the technology of the invention is for illustrative purposes only and is not intended to limit the scope of the technology of the invention. Furthermore, listing multiple embodiments having the described features does not imply the exclusion of other embodiments having additional features or other embodiments incorporating different combinations of the described features.

[0807] Furthermore, the detailed description of various embodiments herein is referenced to the accompanying drawings, which illustrate various embodiments by way of illustration. While the embodiments have been described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments can be implemented and logical and mechanical changes can be made without departing from the spirit and scope of the invention. Therefore, the specific embodiments described herein are presented for illustrative purposes only and not for limiting purposes. For example, the steps or functions, any methods, systems, or processes described in the specification can be performed in any order and are not limited to the order shown. Furthermore, any step or function may be outsourced to or performed by one or more third parties.

[0808] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For the purposes of this invention, the following terms are defined.

[0809] The articles “a” and “an” refer herein to one or more (i.e., at least one) grammatical object of the article. For example, “element” means one or more elements. Similarly, any reference to the singular includes plural embodiments, and any reference to more than one element can include singular embodiments.

[0810] The term “about” means a quantity, level, value, number, frequency, percentage, size, volume, weight, or length that varies within a level acceptable in the art. In some embodiments, such variation can be up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a reference quantity, level, value, number, frequency, percentage, size, volume, weight, or length. When the term “about” is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the listed numerical values.

[0811] The term "administering" or "administer" includes the delivery of the techniques of the present invention to a subject by local or systemic administration (e.g., combination therapies, non-natural melanocorticoid analogs (also referred to herein as peptides), anticancer agents). Administration can be local (including ocular and mucous membranes, including vaginal and rectal delivery), pulmonary (e.g., by inhalation or blowing of powders or aerosols, including via nebulizers), intratracheal, intranasal, epidermal and percutaneous, oral, or parenteral administration. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration.

[0812] As used herein, a “pharmaceutically acceptable carrier” for a first, second, or third pharmaceutical composition means a carrier or diluent that does not cause significant irritation to a living organism, does not eliminate the bioactivity and properties of the applied active ingredient, and / or does not interact adversely with other components of the composition it contains. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, stabilizer, lipid, or other material well known in the art for use in pharmaceutical formulations. The choice of carrier for use in a composition will depend on the intended mode of administration of the composition. Preparation of pharmaceutically acceptable carriers and formulations containing these materials is described, for example, in Remington's Pharmaceutical Sciences, 21st edition, edited by University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety. Some examples of physiologically acceptable carriers include antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) peptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as... (ICI, Inc.; Bridgewater, NJ), polyethylene glycol (PEG) and PLURONICS TM (BASF; Florlem Park, NJ). An “excipient” in a first or second pharmaceutical composition means an inert substance added to the composition to further facilitate the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and types of polyethylene glycol.

[0813] As used herein, “anticancer agent-related side effects” or “anticancer agent-related adverse side effects” refers to any unwanted, adverse, or harmful biological activity that occurs during or after the use of an anticancer agent alone.

[0814] As used herein, the terms “treat,” “treatment,” and “treating” refer to the reduction or inhibition of the progression and / or duration of a disease (e.g., cancer), the alleviation or improvement of the severity of the disease, and / or the improvement of one or more of its symptoms by the application of one or more therapies. Specifically, these terms may refer to: (1) stabilizing, reducing (e.g., reducing more than 10%, 20%, 30%, 40%, 50%, or more than 60% of a population of cancer cells and / or tumor size prior to application) or eliminating cancer cells; (2) inhibiting cancer cell division and / or cancer cell proliferation; (3) alleviating (or eliminating) to some extent one or more symptoms associated with a pathology related to or partially caused by uncontrolled or abnormal cell division; (4) increasing disease-free, relapse-free, progression-free, and / or overall survival, duration, or rate; (5) reducing hospitalization rates; (6) shortening hospital stays; and (7) eradicating cancer. (8) Remove or control primary, regional, and / or metastatic cancer; (9) Stabilize or reduce (e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% relative to the initial growth rate); (10) Inhibit tumor formation; (11) Reduce mortality; (12) Increase remission rate, duration of remission, or number of patients responding to or in remission; (13) Maintain tumor size and not increase it or increase it by less than 10%, less than 5%, less than 4%, or less than 2%; (14) Reduce the need for surgery (e.g., colectomy, mastectomy); and (15) Prevent or reduce cancer cell metastasis. The terms “treat,” “treatment,” and “treating” include both preventative and / or therapeutic treatment. If treatment is administered before the clinical manifestation of the disease, it is considered preventative. Therapeutic treatment includes, for example, improving or reducing the severity of the disease, or shortening the duration or frequency of the disease.

[0815] As used herein, the term "effective dose" or "therapeutic effective dose" refers to the amount of active ingredient administered that will, to a certain extent, alleviate one or more symptoms of the disease being treated. This result can be a reduction and / or relief of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. An appropriate "effective dose" can vary from person to person. In any individual case, an appropriate "effective dose" can be determined using techniques such as dose-escalation studies.

[0816] The term "post-administration" refers to any duration following administration of a combination therapy, a non-natural melanocorticoid analogue, or a pharmaceutical composition thereof, and / or an anticancer agent to a subject. Unless otherwise stated, the duration covered by "post-administration" may include seconds, minutes, hours, days, weeks, months, and years.

[0817] "Cachexia" refers to a state of poor general health and malnutrition, characterized by weight loss, including weight loss, loss of muscle mass (skeletal muscle, smooth muscle, and / or cardiac muscle), loss of fat mass, or a combination thereof, and emaciation. It is often associated with and induced by certain diseases or conditions, such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term "cancer cachexia" refers to cachexia induced by cancer. Diagnostic criteria for cachexia may include: (i) a weight loss of more than 5% in the past 6 months; and (ii) a body mass index (BMI) below 20 kg / m². 2 (iii) Patients with sarcopenia (or limb skeletal muscle index consistent with sarcopenia) have a weight loss greater than 2%. See Fearon K et al., Lancet Oncol. 12(5):489-95 (2011). Cachexia may be used interchangeably with the term “protein energy consumption” (i.e., PEW).

[0818] "Anorexia" simply refers to loss of appetite, whether caused by medical, physiological, or psychological factors. Anorexia is often closely associated with cachexia observed in patients with advanced cancer and other diseases, and is often a trigger for cachexia.

[0819] The terms “melanocortin analogue,” “non-naturally occurring melanocortin analogue,” “melanocortin peptide,” “melanocortin receptor peptide,” or “melanocortin” are used interchangeably and refer to melanocortin receptor ligands, which are large molecules containing at least one melanocortin pharmacophore. Melanocortin analogues are typically peptides that bind to melanocortin receptors under physiological conditions. Melanocortin analogues include naturally occurring and non-naturally occurring melanocortin analogues (i.e., “synthetic peptides” or “synthetic analogues”) as well as truncated and / or modified forms of full-length melanocortin proteins or peptides. For example, full-length POMC consists of 241 amino acids before proteolytic cleavage into “subpeptides.” Tissue-specific proteolytic cleavage of POMC produces peptides ranging in size from 13 to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, Vol. 3, pp. 257–265, Academic Press (2000). As discussed herein, synthetic, non-natural melanocortin analogs with increased melanocortin receptor activity are approximately 7 to 12 amino acids in size. Melanocortin analogs exhibit binding functionality to the melanocortin receptor. Binding to the melanocortin receptor is inhibitory (antagonistic). In addition to peptides, non-natural melanocortin analogs also include small molecule analogs of melanocortin or its components, consisting of organic compounds, inorganic compounds, or combinations of peptides and small molecules (i.e., peptide mimics), or various combinations thereof. “Non-natural melanocortin analogs” are structurally similar to and / or may be functionally similar to the biological melanocortin protein in their ability to bind to the melanocortin receptor. Furthermore, non-natural melanocortin analogs typically contain a pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 304) or its modified form, or a structural or functional peptide mimic.

[0820] A peptide or amino acid "analyte" is a non-amino acid molecule that mimics a peptide (amino acid chain) or a single amino acid residue.

[0821] "Significant degradation" refers to the manner or extent by which non-naturally occurring melanocortin analogs, through physiological enzymatic activity or other factors, result in side effects due to N-terminal extension, C-terminal extension, degradation of both the N-terminus and C-terminus, or degradation of other regions. According to one aspect, non-naturally occurring melanocortin analogs with C-terminal extension and low susceptibility to significant degradation are defined as those in which no more than 50% of the applied peptide causes side effects and / or exhibits a short half-life. In some aspects, no more than 25% of the applied peptide causes side effects and / or exhibits a short half-life. Furthermore, in some aspects, compared to non-naturally occurring melanocortin analogs lacking C-terminal extension, less than 10% of the applied peptide causes side effects and / or exhibits a short half-life.

[0822] The “peptide” as described herein may be (a) naturally occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of a larger molecule, (e) produced by a combination of the methods listed above (a) to (d), or (f) produced by any other method for producing peptides.

[0823] As used herein, the term "peptide" includes any structure consisting of two or more amino acids, including chemical modifications and derivatives of amino acids. All or part of the amino acids forming a peptide can be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, etc. Therefore, the term "peptide" includes pseudopeptides and peptide mimics, including structures with a non-peptide backbone. The term "peptide" also includes dimers or polymers of peptides. "Manufactured" peptides include peptides produced by chemical synthesis, recombinant DNA technology, biochemical or enzymatic fragmentation of larger molecules, combinations of the foregoing methods, or generally by any other method. The term "peptide" includes peptides containing a variable number of amino acid residues, optionally having non-amino acid residue groups at the N-terminus and C-terminus, such groups particularly including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups.

[0824] An "amino acid" is a molecule containing an amine group, a carboxylic acid group, and a side chain characteristic of each amino acid. The main elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen, and it has the general formula H₂N—CHR—COOH, where R represents a side chain group. Various α-amino acids differ in the side chain portion attached to the α-carbon. The "amino acid" in this invention includes known naturally occurring protein amino acids, referred to by their common three-letter and single-letter abbreviations. See, in general, Non-naturally occurring melanocortin analogs: A User's Guide, GAGrant, editor, WH Freeman & Co., New York (1992), whose teachings are incorporated herein by reference, including the text and tables shown on pages 11–24. As noted above, the term "amino acid" also includes naturally occurring protein amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically synthesized amino acids, derived amino acids, stereoisomers and modifications designed to mimic the structure of amino acids, etc. Modified and uncommon amino acids are generally described in Non-naturally occurring melanocortin analogs: A User's Guide, ibid.; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all these references are incorporated herein by reference.

[0825] As used herein, the phrase "amino acid side chain moiety" (including as used in the specification and claims) includes any side chain of any amino acid, as the term "amino acid" is defined herein. Therefore, this includes side chain moiety present in naturally occurring amino acids. It further includes side chain moiety of modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moiety in the form of naturally occurring protein amino acids, non-protein amino acids, post-translational modified amino acids, enzymatically synthesized amino acids, derived amino acids, stereoisomers designed to mimic the structure of amino acids, etc., and modified side chain moiety. For example, side chain moiety of any amino acid of the present invention is included within the definition. "Derivatives" of amino acid side chain moiety are included within the definition of amino acid side chain moiety.

[0826] The term "derivative" of an amino acid side chain moiety includes any modification or variation of any amino acid side chain moiety, including modifications of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight-chain or branched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, or aralkyl moieties.

[0827] In the peptides described herein, the conventional amino acid residues have the conventional meanings given in section 2400 of the Manual of Patent Examining Procedure, 8th edition. Therefore, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tyrosine; and “Val” is valine. Unless otherwise indicated, all amino acid abbreviations represent isomers, i.e., L-isomers, D-isomers, or combinations thereof may be used. Therefore, for example, "L-Phe" is L-phenylalanine; "D-Phe" is D-phenylalanine; "D- / L-Phe" is D-phenylalanine, L-phenylalanine, or a combination thereof; "Phe" also refers to D-phenylalanine, L-phenylalanine, or a combination thereof, etc. Non-standard amino acids "Nle" is leucine; "Nal" is naphthylalanine; "D-Nal" is D-naphthylalanine; D-Nal(2') is D-2'-naphthylalanine; L-Nal(2') is L-2'-naphthylalanine; L-Nal(1') is L-1'-naphthylalanine; D-Nal(1') is D-1'-naphthylalanine; Tle is tertiary leucine; Nva is valine; Orn is ornithine; Bip is biphenyl amino acid; etc.

[0828] α-amino acids have the general formula H2N—C α HR—COOH, where R is the side chain portion, and the amino group is attached to the carbon atom (i.e., the α-carbon) immediately adjacent to the carboxylic acid group. Other types of amino acids exist when the amino group is attached to different carbon atoms. For example, β-amino acids, where the carbon atom to which the amino group is attached is connected to the carboxylic acid group by a single carbon atom (C). β Separated. For example, α-alanine has the formula H2N—C α H(CH3)—COOH. In contrast, β-alanine has the general formula H2N—C. β H2—C α H2—COOH (i.e., 3-aminopropionic acid).

[0829] When β-amino acids are incorporated into peptides, there are two main types of β-peptides: those with a side chain residue R located on the carbon atom immediately adjacent to the amine are called β-peptides. 3Peptides, and those with side chain residues on the carbon atom immediately adjacent to the carbonyl group, are called β-peptides. 2 Amino acids. As a non-limiting example, "β-valine" can refer to:

[0830] —NH—C β H2—C α H(CH3)2—CO—, i.e., β 2 -Valine (R on the carboxyl side);

[0831] —NH—C β H(CH3)2—C α H2—CO—, that is, β 3 -valine (R on the amino side); or

[0832] —NH—C β H(CH3)2—C α H(CH3)2—CO—, i.e., β 2,3 -Valine (R at two positions).

[0833] Furthermore, β-amino acids can be represented by L- or D-stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent isomers, namely L-isomers, D-isomers, or combinations thereof.

[0834] γ-amino acids are amino acids in which the carbon atom to which the amino group is attached is separated from the carboxylic acid moiety by two carbon atoms. For example, γ-aminobutyric acid has the formula H₂N—C. γ H2—C β H2—C α H2—COOH.

[0835] For information on other modified and less common amino acids, see §2422 of the MPEP, particularly Table 4 on pages 2400-24. Furthermore, “Ac” indicates an N-acetyl group, and “cyclic” indicates a cyclic structure, also referred to as “c” or “lactam” in the literature. “NH2” indicates an amine group, usually added to the C-terminus of the peptide. Therefore, as used herein, the –NH2 portion at the C-terminus of the peptide indicates an amide, i.e., –CO—NH2. Additionally, the following abbreviations are used herein: Harg for high arginine; Hlys for high lysine.

[0836] The following abbreviations are used: tBu for tert-butyl; Hyp(Bzl) for benzyl-L-hydroxy-proline; glutaric acid linker: CO—(CH2)3—CO; Pen for L-penicillamine; Aib for 2-aminoisobutyric acid; Aba for 4-amino-1,2,4,5-tetrahydro-2-benzozazepine-3-one; Pip for piperidine-2-carboxylic acid; Nip for piperidine-3-carboxylic acid; Tic for tetrahydroquinoline-3-carboxylic acid; Bip for biphenylalanine; Phg for α-phenyl-glycine; Sar for sarcosine; Azt for 3'-azido-3'-deoxythymidine; Oic for octahydroindole-2-carboxylic acid; Ata for 7-amino-7,8-dihydro4H-(1,2,3)triazolo(1,5-a)(1, 4) Diazazo-6(5H)-one; Aia is 4-amino-1,4,5,6-tetrahydrozazo-(4,3-b)indol-3(2H)-one; Aba is 4-amino-1,2,4,5-tetrahydro-2-benzozazo-3-one; Mamb is 3-aminomethylbenzoic acid; Atc is 2-aminotetrahydronaphthyl-2-carboxylic acid; APC is 1-amino-4-phenylcyclohexane-carboxylic acid; APPC is 4-aminophenylpiperidine-4-carboxylic acid; Accc is 1-aminocyclo-propane-1-carboxylic acid; Aic is 2-aminoindanone-2-carboxylic acid; p(Cl)Phe is p-chloro-phenylalanine (I-iodine, Br-bromine); and p(Cl)dPhe is p-chloro-D-phenylalanine (I-iodine, Br-bromine).

[0837] The term "olefin" includes unsaturated hydrocarbons containing one or more carbon-carbon double bonds. Examples of such olefin groups include ethylene, propylene, etc.

[0838] The term "alkenyl" includes straight-chain monovalent hydrocarbon groups with two to six carbon atoms containing at least one double bond, or branched monovalent hydrocarbon groups with three to six carbon atoms; examples include vinyl, 2-propenyl, etc.

[0839] The term "alkynyl" includes straight-chain monovalent hydrocarbon groups with two to six carbon atoms containing at least one triple bond, or branched monovalent hydrocarbon groups with three to six carbon atoms; examples include ethynyl, propynyl, butynyl, etc.

[0840] The term "aryl" includes a monovalent or bicyclic aromatic hydrocarbon group having 6 to 12 ring atoms, optionally substituted by one or more substituents selected from: alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxyl, or alkoxy-carbonyl. Examples of aryl groups include phenyl, biphenyl, naphthyl, 1-naphthyl and 2-naphthyl, and their derivatives.

[0841] The term "aliphatic" includes compounds with hydrocarbon chains, such as alkanes, alkenes, alkynes, and their derivatives.

[0842] The term "acyl" includes the group RCO—, where R is an organic group. An example is the acetyl group CH3CO—. This is referred to as "Ac" in this document.

[0843] The term "fatty acid" describes a carboxylic acid having an aliphatic chain, which may be fully saturated or partially unsaturated, and optionally attached to a functional group such as a hydroxyl group or a carboxyl group. The aliphatic chain may contain, for example, 6 to 26 carbon atoms and hydrogen atoms.

[0844] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded to one or more carbonyl {—(C═O)—} groups. Peptides are most commonly acylated at the N-terminus.

[0845] "ω-amino derivatives" include aliphatic moieties having terminal amino groups. Examples of ω-amino derivatives include aminoheptanoyl groups and amino acid side chain moieties of ornithine and lysine.

[0846] The term "heteroaryl" includes monocyclic and bicyclic aromatic rings containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or six-membered heteroaryl groups are monocyclic heteroaromatic rings; examples include thiazoles, oxazoles, thiophenes, furans, pyrroles, imidazoles, isoxazoles, pyrazoles, triazoles, thiadiazoles, tetraazoles, oxadiazoles, pyridines, pyridazines, pyrimidines, and pyrazines. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazoles, indole, benzothiophenes, benzofurans, benzimidazoles, benzoisoxazoles, benzothiazides, quinolines, benzotriazoles, benzoxazoles, isoquinolines, purines, furanopyridines, and thienopyridines.

[0847] "Amine" includes compounds containing an amine group (-NH2).

[0848] "Amide" includes compounds in which a trivalent nitrogen atom is attached to a carbonyl group (i.e., —CO—NH2), such as formamide, acetamide, and propionamide. Peptides are typically amidated at the C-terminus by adding an amine (—NH2) moiety to the C-terminal carboxyl group.

[0849] "Imine" includes compounds with carbon-nitrogen double bonds and nitrogen atoms also attached to hydrogen (NH═CH—R).

[0850] "Imine" includes compounds containing an imide group (-OC-NH-CO-).

[0851] "Nitriles" include compounds that are carboxylic acid derivatives and contain (-CN) groups that are bound to organic groups.

[0852] The term "halogen" is intended to include halogen atoms such as fluorine, chlorine, bromine, and iodine, as well as groups containing one or more halogen atoms, such as -CF3, etc.

[0853] Amino acids (including naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translational modified amino acids, enzyme-synthesized amino acids, derived amino acids, stereoisomers and modifications of constructs or structures designed to mimic amino acids (peptide mimics), etc., all of the above) are sometimes referred to herein as “residues”.

[0854] Melanocortin receptor "agonists" are naturally occurring substances or manufactured drugs or compositions that interact with melanocortin receptors and elicit the characteristic pharmacological response of the melanocortin receptor. Melanocortin receptor "antagonists" are naturally occurring substances or manufactured drugs or compositions that counteract the melanocortin receptor-related responses typically induced by melanocortin receptor agonists. Melanocortin receptor "inverse agonists" are drugs or compounds that stabilize the inactive conformation of the melanocortin receptor and inhibit its basal activity.

[0855] When used herein, “compound” includes any pharmaceutically acceptable derivative or variant, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures, diastereomers, and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term “prodrug” refers to a compound that serves as a drug precursor, which, upon administration, releases the drug in vivo via some chemical or physiological process (e.g., the prodrug is converted to the desired drug form upon reaching physiological pH or through enzymatic action).

[0856] The term "alkyl" refers to a non-cyclic saturated aliphatic hydrocarbon group, which can be straight / linear or branched. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by prefixes representing the upper and lower limits of the number of carbon atoms in that moieties, i.e., the prefix Ci-j indicates a moieties with an integer number of carbon atoms from "i" to "j" (inclusive of the end value). Thus, for example, C1-4 alkyl refers to an alkyl group with one to four carbon atoms (inclusive of the end value). Representative examples of C1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. For other examples, C1-4 alkyl refers to an alkyl group with one to two carbon atoms (inclusive of the end value) (i.e., methyl or ethyl). Alkyl groups may optionally be substituted by one or more (e.g., one to five) suitable substituents (if specified). The term "alkyl" as used herein includes alkyl groups with a straight-chain or branched configuration of a specified length. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, etc.

[0857] Throughout this specification, in various places relating to the second compound, the substituents of the compound are disclosed by groups or ranges. The techniques of this invention are particularly intended to include each individual subcombination of members of such groups and ranges. For example, the term "C1-4 alkyl" is particularly intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. For another example, the term "4- to 7-membered heterocyclic alkyl" is particularly intended to include any 4, 5, 6, or 7-membered heterocyclic alkyl group.

[0858] As used herein, the term "n-membered" (where n is an integer) typically describes the number of cyclic atoms in a portion having n cyclic atoms. For example, pyridyl is an example of a 6-membered heteroaryl ring, and pyrazolyl is an example of a 5-membered heteroaryl group.

[0859] As used herein, the term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, the term "C1-4 alkoxy" or "C1-4 alkyloxy" refers to an -O-(C1-4 alkyl) group; for another example, the term "C1-2 alkoxy" or "C1-2 alkyloxy" refers to an -O-(C1-2 alkyl) group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. An alkoxy or alkyloxy group may optionally be substituted with one or more (e.g., one to five) suitable substituents (if specified).

[0860] As used in this article, the term "halogenated" or "halogen" refers to -F, -Cl, -Br, or -I.

[0861] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C1-4 haloalkyl" refers to a C1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom); and the term "C1-2 haloalkyl" refers to a C1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -C2F5, -CH2Cl, etc.

[0862] “Fluoroalkyl” means an alkyl group as defined herein that is substituted with one or more fluorine (-F) substituents (up to perfluoroalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a fluorine atom). The term “C1-2 fluoroalkyl” means a C1-2 alkyl group having one or more fluorine substituents (i.e., methyl or ethyl) (up to perfluoroalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a fluorine atom); and the term “C1 fluoroalkyl” means a methyl group having one, two, or three fluorine substituents. Examples of C1 fluoroalkyl groups include fluoromethyl, difluoromethyl, and trifluoromethyl; some examples of C2 fluoroalkyl groups include 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, etc.

[0863] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group. For example, the term "C1-4 haloalkoxy" refers to an -O-(C1-4 haloalkyl) group; and the term "C1-2 haloalkoxy" refers to an -O-(C1-2 haloalkyl) group. For yet another example, the term "C1 haloalkoxy" refers to a methoxy group having one, two, or three halogen substituents. Examples of haloalkoxy groups are -OCF3 or –OCHF2.

[0864] As used herein, the term "fluoroalkoxy" refers to an -O-fluoroalkyl group. For example, the term "C1-2 fluoroalkoxy" refers to an -O-(C1-2 fluoroalkyl) group; and the term "C1 fluoroalkoxy" refers to an -O-(C1 fluoroalkyl) group. Examples of C1 fluoroalkoxy groups include -O-CH2F, -O-CHF2, and -O-CF3. Some examples of C2 fluoroalkoxy groups include -O-CH2CHF2, -O-CH2–-CHF2, -O-CH2 CF3, -O-CF2CH3, and -O-CF2CF3.

[0865] As used herein, the term "hydroxyalkyl" or "hydroxyalkyl group" refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term "C1-4 hydroxyalkyl" or "C1-4 hydroxyalkyl group" refers to a C1-4 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; and the term "C1-2 hydroxyalkyl" or "C1-2 hydroxyalkyl group" refers to a C1-2 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. Examples of hydroxyalkyl groups are -CH2OH or -CH2CH2OH.

[0866] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring, such as monocyclic, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl; or bicyclic, including spirosystems, fused systems, or bridging systems (e.g., bicyclic (1.1.1)pentyl, bicyclic (2.2.1)heptyl, bicyclic (3.2.1)octyl, or bicyclic (5.2.0)nonyl, decahydronaphthyl, etc.). The cycloalkyl group has 3 to 15 (e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6) carbon atoms. In some embodiments, the cycloalkyl group may optionally contain one, two, or more non-cumulative non-aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, the bicyclic alkyl group has 6 to 14 carbon atoms. As used herein, the term "C3-4 cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3 to 4 carbons. Examples of C3-4 cycloalkyl groups include cyclopropyl and cyclobutyl. The definition of cycloalkyl also includes a moiety having one or more aromatic rings (including aryl and heteroaryl) fused to a cycloalkyl ring, such as benzo or pyridyl derivatives of cyclopentane (5-membered cycloalkyl), cyclopentene, cyclohexane (6-membered cycloalkyl), etc., such as 6,7-dihydro-5H-cyclopentane(b)pyridyl, 5,6,7,8-tetrahydroquinolinyl, or 15,6,7,8-tetrahydroisoquinolinyl, each of which contains a 5- or 6-membered cycloalkyl moiety fused to a heteroaryl ring (i.e., a pyridyl ring). The cycloalkyl or C3-4 cycloalkyl group may optionally be substituted with one or more (e.g., 1 to 5) suitable substituents (if specified).

[0867] As used herein, the term “C3-4 cycloalkyl-C1-4 alkyl” means a C3-4 cycloalkyl group attached to a parent molecule moiety by means of a C3-4 alkyl group as defined herein. Some examples of C3-4 cycloalkyl-C1-4 alkyl- include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0868] As used herein, the term "heterocyclic alkyl" refers to a monocyclic or polycyclic (including two or more rings fused together, including spirosystems, fused systems, or bridging systems, such as bicyclic systems), saturated or unsaturated non-aromatic 4- to 15-membered ring systems (such as 4- to 14-membered, 4- to 12-membered, 5- to 10-membered, 4- to 7-membered, 4- to 6-membered, or 5- to 6-membered ring systems) comprising 1 to 14 cyclic carbon atoms and 1 to 10 cyclic heteroatoms, each independently selected from O, S, and N (and optionally P or B when present). The heterocyclic alkyl group may also optionally contain one or more oxo (i.e., =O) or thio (i.e., =S) groups. For example, the term "4- to 7-membered heterocyclic alkyl" refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 7-membered ring system comprising one or more cyclic heteroatoms, each independently selected from O, S, and N. For another example, the term "5- or 6-membered heterocyclic alkyl" refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- or 6-membered ring system containing one or more cyclic heteroatoms, each independently selected from O, S, and N. The heterocyclic alkyl group may optionally be substituted by one or more (e.g., 1 to 5) suitable substituents (if specified).

[0869] Some examples of 4- to 7-membered heterocyclic alkyl groups include aziridine, oxaziridine, tetrahydrofuranyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazine, oxazolyl, thiazolyl, pyrazolyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl, and tetrahydropyranyl (also known as oxazirpentyl). Some other examples of 4- to 7-heterocyclic alkyl groups include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), imidazolidine-1-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazine-1-yl, piperazine-2-yl, 1,3-oxazolidine- 3-yl, 1,4-oxazacycloheptane-2-yl, isothiazolyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolyl-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazin-3-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinone, 2-oxo-piperidinyl (e.g., 2-oxo-piperidin-1-yl), 2-oxoazacyclohexan-3-yl, etc.

[0870] As used herein, the term "heteroaryl" refers to a monocyclic or fused-ring polycyclic aromatic heterocyclic group having one or more heteroatom ring members (cyclic atoms) each independently selected from O, S, and N in at least one ring. A heteroaryl group has 5 to 14 cyclic atoms, including 1 to 13 carbon atoms and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, a heteroaryl group has 5 to 10 cyclic atoms, including one to four heteroatoms. A heteroaryl group may also contain one to three oxo or thio (i.e., =S) groups. In some embodiments, a heteroaryl group has 5 to 8 cyclic atoms, including one, two, or three heteroatoms. For example, the term "5-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above, having 5 cyclic atoms in the monocyclic heteroaryl ring; the term "6-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above, having 6 cyclic atoms in the monocyclic heteroaryl ring; and the term "5- or 6-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above, having 5 or 6 cyclic atoms in the monocyclic heteroaryl ring. The heteroaryl group may optionally be substituted by one or more (e.g., 1 to 5) suitable substituents (if specified). Examples of monocyclic heteroaryl groups include monocyclic heteroaryl groups having 5 cyclic atoms (including one to three heteroatoms) or monocyclic heteroaryl groups having 6 cyclic atoms (including one, two, or three nitrogen heteroatoms). Examples of fused bicyclic heteroaryl groups include two fused 5- and / or 6-membered monocyclic rings containing one to four heteroatoms.

[0871] Some examples of heteroaryl groups include pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl), thiopheneyl, furanyl, imidazolyl (e.g., 1H-imidazolyl-4-yl), pyrroleyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), and pyrazolyl (e.g., pyrazol-1-yl). Pyrazol-3-yl, pyrazol-4-yl), tetrazolyl (e.g., 2H-tetrazole-5-yl), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl), quinolinyl, isoquinolinyl, benzothiophene, benzofuranyl, indole, benzothiazolyl, 1,2-benzooxazolyl, 1H-imidazo(4,5-) c) Pyridyl, imidazo(1,2-a)pyridyl, 1H-pyrrolo(3,2-c)pyridyl, imidazo(1,2-a)pyrazinyl, imidazo(2,1-c)(1,2,4)triazinyl, imidazo(1,5-a)pyrazinyl, imidazo(1,2-a)pyrimidinyl, 1H-indazoleyl, 9H-purinyl, imidazo(1,2-a)pyrimidinyl, (1,2,4)triazol(1,5-a)pyridyl, (1,2,4)triazol(1,5-a)pyrimidinyl, (1,2,4)triazol(1,5-a)pyrimidinyl, (1,2,4)triazol(4,3-b) Pyridazinyl, isoxazolo(5,4-c)pyridazinyl, isoxazolo(3,4-c)pyridazinyl, pyrazolo(1,5-a)pyrimidinyl, 6,7-dihydro-5H-pyrrolo(1,2-b)(1,2,4)triazolyl, pyridine, pyrimidinone, pyrazinone, 1H-imidazol-2(3H)-one, 1H-pyrrolo-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,3H)dioxo-pyrimidinyl, 1H-2-oxo-pyrazinyl, etc.

[0872] An "antibody" or "Ab" is an immunoglobulin molecule capable of recognizing and specifically binding to a specific target or antigen (Ag) located at at least one antigen recognition site in the variable region of an immunoglobulin molecule. This target or antigen can be a carbohydrate, polynucleotide, lipid, polypeptide, etc. As used herein, the term "antibody" can encompass any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, and antigen-binding fragments (or portions) of intact antibodies that retain the ability to specifically bind to a given antigen (e.g., GDF-15).

[0873] The term "antigen" refers to a molecular entity used to immunize an immune vertebrate to generate antibodies that recognize Ag or to screen expression libraries (e.g., bacteriophage, yeast, or ribosome display libraries). In this document, the definition of Ag is broader and generally intended to include target molecules specifically recognized by Abs, thus including molecular fragments or mimics used in the immunization process to generate Abs or to screen libraries for Abs. Therefore, for antibodies binding to GDF-15 in the techniques of this invention, full-length GDF-15 from mammalian species (e.g., human, monkey, mouse, and rat GDF-15), including its monomers and multimers (e.g., dimers, trimers, etc.), as well as truncated variants and other variants of GDF-15, are all referred to as antigens.

[0874] An antibody's "antigen-binding fragment" refers to a segment of the full-length antibody that retains the ability to specifically bind antigens (having substantially the same binding affinity). Examples of antigen-binding fragments include (i) the Fab fragment, which consists of V... L V H (ii) a monovalent fragment composed of CL and CH1 domains; (iii) a F(ab')2 fragment, a divalent fragment containing two Fab fragments connected by a disulfide bridge at the hinge region; and (iv) an Fd fragment composed of V... H (iv) The Fv fragment, consisting of the V and CH1 domains of the antibody single arm. L Domain and V H Domain composition; (v)dAb fragment (Ward et al., 1989 Nature 341:544-546), which is composed of V H The domains consist of (vi) a separated complementarity-determining region (CDR), a disulfide-linked Fv (dsFv), and anti-idiotype (anti-Id) antibodies and intracellular antibodies. Furthermore, although the two domains V of the Fv fragment... L and V H Encoded by separate genes, these two domains can be linked using recombination methods by enabling them to act as synthetic linkers for a single protein chain in which V... L District and V H The regions pair to form a monovalent molecule (called a single-chain Fv (scFv)); see, for example, Bird et al., Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883. Other forms of single-chain antibodies are also covered, such as biantibodies. Biantibodies are bivalent and bispecific antibodies, where V... H and V LThe domains are expressed on a single polypeptide chain, but the linkers used are too short to allow two domains on the same chain to pair, thus forcing the domains to pair with complementary domains on another chain and creating two antigen-binding sites (see, for example, Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121-1123).

[0875] Antibody "variable domain" refers to the variable region (V) of the antibody light chain. L ) or the variable region (V) of the antibody heavy chain H One or a combination of the following. It is known in the art that the variable regions of the heavy and light chains each consist of four frame regions (FRs) connected by three complementarity-determining regions (CDRs) and contribute to the formation of the antigen-binding site of the antibody.

[0876] The “complementarity-determining region” (CDR) can be identified according to the definitions of Kabat, Chothia, and both Kabat and Chothia, including their cumulative, AbM, contact, North, and / or conformational definitions, or any CDR identification method well known in the art. See, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th edition (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The identity of the amino acid residues constituting the CDR in a particular antibody can be determined using methods well known in the art. The AbM definition of the CDR is a compromise between Kabat and Chothia and uses Oxford Molecular’s ​​AbM antibody modeling software. The “contact” definition of a CDR is based on observed antigen contact, as illustrated in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The “conformation” definition of a CDR is based on residues that contribute enthalpy to antigen binding (see, for example, Makabe et al., 2008, J. Biol. Chem., 283:1156-1166). North identified classical CDR conformations using different preferred sets of CDR definitions (North et al., 2011, J. Mol. Biol. 406:228-256). In another approach, referred to herein as the “conformational definition” of a CDR, the position of the CDR can be identified as residues that contribute enthalpy to antigen binding (Makabe et al., 2008, J Biol. Chem. 283:1156-1166). Other CDR boundary definitions may not strictly follow any of the methods described above, but still overlap with at least a portion of the Kabat CDR, although they may be shortened or lengthened based on predictions or experimental findings that a particular residue or group of residues or even the entire CDR does not significantly affect antigen binding. As used herein, a CDR may refer to a CDR defined by any method known in the art, including combinations of methods. The methods used herein may utilize CDRs defined according to any of these methods. For any given embodiment containing more than one CDR, the CDR (or other residues of the antibody) may be defined according to any of the Kabat, Chothia, North, extended, AbM, contact, and / or conformational definitions.

[0877] "Frame" (FR) residues are antibody variable domain residues other than CDR residues. H or V L The structural domain frame contains four frame subregions, FR1, FR2, FR3 and FR4, and the CDRs are distributed in the following structure: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0878] As is known in the art, the “constant region” of an antibody refers to a single or combination of the constant regions of the antibody light chain or the constant regions of the antibody heavy chain.

[0879] As used interchangeably herein, the terms “Fc region,” “Fc domain,” and “Fc” refer to a portion of an immunoglobulin (Ig) molecule associated with a crystallizable fragment obtained by digestion of an Ig molecule with papain. As used herein, the term refers to the constant region of an antibody (excluding the first constant region immunoglobulin domain) and further to a portion of that region. Therefore, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and the N-terminus of the flexible hinge of these domains, or portions thereof. For IgA and IgM, Fc may contain a J chain.

[0880] For IgG, the Fc region comprises the immunoglobulin domains Cy2 and Cy3 (Cγ2 and Cγ3) and the hinge between Cy1 (Cγ1) and Cy2 (Cγ2). Although the boundaries of the Fc region can vary, the human IgG heavy chain Fc region is generally defined as containing residues C226 or P230 at its carboxyl terminus, numbered according to the EU index as described in Kabat et al., 1991, and Edelman et al., 1969, Proc. Natl. Acad. Sci. USA 63(1):78-85. Typically, the Fc domain comprises about 236 to about 447 amino acid residues of the constant domain of human IgG1. An exemplary amino acid sequence of the human wild-type IgG1 Fc domain is shown in SEQ ID NO:31. The Fc polypeptide may refer to the isolated region or the region in the context of an antibody or its antigen-binding moiety or an Fc fusion protein.

[0881] The heavy chain constant domain contains the Fc region and further contains the CH1 domain and hinge of the IgG heavy chain, as well as the CH2 and CH3 (and optionally the CH4 domains of IgA and IgE) domains.

[0882] In some embodiments, the antibody or antigen-binding fragment thereof described herein includes an Fc domain. The Fc domain may be derived from IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0883] "Fc fusion" proteins are proteins in which one or more polypeptides are operatively linked to an Fc polypeptide. Fc fusion products bind the Fc region of an immunoglobulin to a fusion partner.

[0884] An epitope is a region or area of ​​an antigen that an antibody specifically binds to, such as a region or area containing residues that interact with the antibody. Epitopes can be linear or conformational.

[0885] At the most detailed level, an epitope of the Ag-Ab interaction can be defined by defining the spatial coordinates of the atomic contacts present in the Ag-Ab interaction and information about their relative contributions to binding thermodynamics. At a less detailed level, an epitope can be characterized by defining the spatial coordinates of the atomic contacts between Ag and Ab. At an even less detailed level, an epitope can be characterized by the amino acid residues it contains, as defined by specific criteria, such as the distance between atoms (e.g., heavy atoms, i.e., non-hydrogen atoms) in Ab and Ag. At an even less detailed level, an epitope can be characterized by its function, such as by its competitive binding with other antibodies. An epitope can also be defined more generally as containing amino acid residues, where substitution with another amino acid would alter the characteristics of the interaction between Ab and Ag (e.g., using an alanine scan).

[0886] Based on the fact that epitopes are described and defined at different levels of detail (depending on the epitope mapping method used), it can be concluded that comparisons of epitopes of different Abs on the same Ag can be similarly performed at different levels of detail.

[0887] Epitopes described at the amino acid level (e.g., epitopes determined from X-ray structures) are considered identical if they contain the same set of amino acid residues. Epitopes are said to be overlapping if they share at least one amino acid residue. Epitopes are said to be independent (unique) if they do not share any amino acid residues.

[0888] Epitopes characterized by competitive binding are considered overlapping if the binding of the corresponding antibodies is mutually exclusive, meaning that the binding of one antibody excludes the simultaneous or sequential binding of another. Epitopes are considered independent (unique) if the antigen can simultaneously accommodate the binding of two corresponding antibodies.

[0889] Antibodies that “preferentially bind” or “specifically bind” (used interchangeably herein) to epitopes are well-known terms in the art, and methods for determining such specificity or preferential binding are also well-known in the art. A molecule is considered to exhibit “specific binding” or “preferential binding” if it reacts or associates with a particular cell or substance more frequently, more rapidly, for a longer duration, and / or with a greater affinity than it reacts or associates with an alternative cell or substance. An antibody is “specifically binding” or “preferentially binding” to a target if it binds to a target with greater affinity, conjugation, ease, and / or longer duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a GDF-15, PD-1, or PD-L1 epitope means that it binds to this epitope with greater affinity, conjugation, ease, and / or longer duration than it binds to other GDF-15, PD-1, or PD-L1 epitopes or non-GDF-15, PD-1, PD-L1 epitopes. Generally, but not necessarily, the mention of binding refers to preferential binding. "Specific binding" or "preferential binding" refers to compounds (e.g., proteins, nucleic acids, antibodies, etc.) that recognize and bind to specific molecules in a sample but substantially do not recognize or bind to other molecules in the sample. For example, antibodies or peptide receptors that recognize and bind to homologous ligands or binding partners in a sample (e.g., anti-GDF-15 antigen antibodies that bind to the GDF-15 antigen, molecules that bind to GDF-15, etc.) but substantially do not recognize or bind to other molecules in the sample will specifically bind to that homologous ligand or binding partner. Therefore, under specified detection conditions, a specific binding moiety (e.g., an antibody or its antigen-binding moiety, or its receptor or ligand-binding moiety) preferentially binds to a specific target molecule and does not bind extensively to other components present in the test sample.

[0890] Various assay methods can be used to select antibodies or peptides that specifically bind to the target molecule. Examples include solid-phase ELISA, immunoprecipitation, and BIAcore. TM (GE Healthcare, Piscatave, New Jersey), Fluorescence-activated Cell Sorting (FACS), Octet TM (ForteDo, Inc., Menlo Park, California) and various detection methods such as Western blotting can be used to identify antibodies that specifically react with the binding site of an antigen or receptor or its ligand, specifically binding to a homologous ligand or binding partner. Typically, the signal or noise of a specific or selective reaction is at least twice the background signal, more typically more than 10 times the background. More specifically, when the equilibrium dissociation constant (K... D When the value is 1 pM, 100 nM, greater than 10 nM, even greater than 100 pM, even greater than 10 pM, and even greater than 1 pM, the antibody is considered to "specifically bind" to the antigen.

[0891] As used in this article regarding antibodies, the term "competition" means that the binding of a first antibody or its antigen-binding moiety to an antigen reduces the subsequent binding of a second antibody or its antigen-binding moiety to the same antigen. Typically, the binding of the first antibody results in steric hindrance, conformational changes, or binding to a common epitope (or a portion thereof), which reduces the binding of the second antibody to the same antigen. Standard competition assays can be used to determine whether two antibodies compete with each other. A suitable antibody competition assay involves using Biacore technology, which can use surface plasmon resonance (SPR) technology, typically using biosensor systems such as the BIACORE system, to measure the degree of interaction. For example, SPR can be used in in vitro competitive binding inhibition assays to determine the ability of one antibody to inhibit the binding of a second antibody. Another assay for measuring antibody competition uses ELISA-based methods.

[0892] The antibodies of this invention further include antibody variants thereof. Variant antibodies may contain 1, 2, 3, 4, 5, up to 10, 20, 30 or more amino acid substitutions and / or deletions and / or insertions of the specific sequences and fragments discussed above. "Deletion" variants may contain the deletion of a single amino acid, such as the deletion of a small group of 2, 3, 4 or 5 amino acids, or the deletion of a larger amino acid region, such as the deletion of a specific amino acid domain or other features. "Insertion" variants may contain the insertion of a single amino acid, such as the insertion of a small group of 2, 3, 4 or 5 amino acids, or the insertion of a larger amino acid region, such as the insertion of a specific amino acid domain or other features. "Substitution" variants involve replacing one or more amino acids with the same number of amino acids and performing conserved amino acid substitutions. For example, the amino acid may be replaced by a substitute amino acid with similar properties, such as another basic amino acid, another acidic amino acid, another neutral amino acid, another charged amino acid, another hydrophilic amino acid, another hydrophobic amino acid, another polar amino acid, another aromatic amino acid, or another aliphatic amino acid. Some properties of the 20 major amino acids that can be used to select suitable substitutions are as follows.

[0893] In the process known as "phylogeny", V H and V L Certain amino acids in the sequence can be mutated to match lineage V. H and V L The naturally occurring amino acids in the sequence. Specifically, V H and V LThe amino acid sequence of the frame region in an antibody can be mutated to match the germline sequence, thereby reducing the risk of immunogenicity when administering the antibody. As used herein, the term "germline" refers to the nucleotide and amino acid sequence of the antibody gene and gene fragment as they are passed from parent to offspring via germ cells. This germline sequence differs from the nucleotide sequence encoding the antibody in mature B cells, which is altered during B cell maturation due to recombination and hypermutation events. Antibodies "utilizing" a specific germline have a nucleotide or amino acid sequence that most closely aligns to that germline nucleotide sequence or its designated amino acid sequence. Such antibodies are frequently mutated compared to the germline sequence. Human V H and V L The germline DNA sequence of the gene is known in the art.

[0894] All publications, patents, and published patent applications listed herein are incorporated herein by reference, including but not limited to U.S. Patent No. 9,534,018, U.S. Patent Application No. 16 / 541,817, and WIPO International Application No. PCT / IB2021 / 054970.

[0895] Composition

[0896] The present invention comprises a composition having: (i) a first compound having a primary therapeutic effect, and (ii) a second compound, each having a secondary therapeutic effect, and / or (iii) a third compound. The first compound may comprise a non-naturally occurring melanocortin analogue. The second compound may comprise a spirocyclic compound. The third compound may comprise an antibody or an antigen-binding fragment thereof.

[0897] First compound: A non-natural melanocortin analogue

[0898] The first compound of this invention may comprise a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin 3 receptor (MC3R) and / or melanocortin 4 receptor (MC4R) antagonist, agonist, or inverse agonist. The first compound may exert a therapeutic effect after antagonizing MC3R and / or MC4R. The non-naturally occurring melanocortin analog consists of...

[0899] In some embodiments, the first compound present in the composition of the present invention comprises a non-naturally occurring melanocortin analogue, which comprises the sequence according to formula (I).

[0900] X 1 X 2 X 3 R 1 R 2 R 3 R 4R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I)

[0901] in:

[0902] R 1 The group consisting of the following is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, methylated D-phenylalanine, succinic acid, phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, aspartic acid Amines, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Ac-Tle), acetylated D-tertiary leucine (dTle), acetylated normal valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0903] R 2 The following groups are absent or selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0904] R 3The group consisting of the following is absent or selected: histidine, histidine methylated at position 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, tryptophan, arginine, 4-amino-1-yl 2,4,5-Tetrahydro-2-benzozazepine-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0905] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0906] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0907] R 6 The group consisting of the following items is absent or selected: D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), 4-amino-1,4,5,6-tetrahydroaza-diazopheno-(4,3-b)indol-3(2H)-one (Aia), phenylalanine, tyrosine, Pen, dPen, and alanine;

[0908] R 7 The group consisting of the following is absent or selected: glycine, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic).

[0909] R 8 It is absent or contains lysine or arginine;

[0910] R 9 It is absent or contains tryptophan;

[0911] R 10 It is absent or contains lysine;

[0912] R 11 To R 20 The following groups are not present independently or are selected from: cysteine, leucine, tyrosine, aspartic acid, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, prolylglycine (Pro-Gly), D-Nal (2'), L-Nal (2'), Bip, ornithine, and tryptophan;

[0913] Where R 2 If it is a n-valeryl group or a n-hexanoyl group, then R 1 X 1 X 2 and X 3 It does not exist;

[0914] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0915] X 2 The following groups are not present or are selected: D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0916] X 3The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0917] Y 1 Choose the group consisting of the following: D-alanine, L-alanine, β-alanine, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, L-proline, D-proline, β-homoproline, piperazine-2-one ring, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0918] Y 2 The group consisting of or not present in the following groups is selected: D-proline, L-proline, β-homoproline, piperazine-2-one ring, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, Hyp, dHyp, D-alanine, L-alanine, β-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0919] Y 3 The group consisting of the following is absent or selected: D-threonine, L-threonine, D-alanine, L-alanine, D-proline, L-proline, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, and piperazine-2-one ring;

[0920] Y 4 It is absent or is either D-proline or D-valine;

[0921] Y 5 It is absent or is either D-proline or D-valine;

[0922] Y 6 It is absent or is either D-proline or D-valine;

[0923] Y 7 It is absent or is either D-proline or D-valine;

[0924] Y 8 It is absent or is either D-proline or D-valine;

[0925] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0926] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0927] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0928] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0929] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0930] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is glycine, proline or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0931] When R 2 It is glutamic acid or aspartic acid and R 10When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0932] When R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The closure of the lactam between them; and

[0933] When R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 With R 7 The lactam closure between them;

[0934] X 1 X 2 X 3 Indicates the presence of an arbitrarily existing N-terminus; and

[0935] Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Indicates the C-terminus.

[0936] In some embodiments of equation (I):

[0937] R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, methylated D-phenylalanine, succinic acid, phthalic acid, tyrosine, aspartic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid. Asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated normal valine (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0938] R 2The following groups are absent or selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, valeryl group, hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[0939] R 3 The group consisting of the following is absent or selected: histidine, histidine methylated at position 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, tryptophan, arginine, 4-amino-1-yl 2,4,5-Tetrahydro-2-benzozazepine-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0940] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0941] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0942] R 6 The group consisting of the following items is absent or selected: D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0943] R7 The following groups are not present or are selected: glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diaminopropionic acid, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic).

[0944] R 8 It is absent or contains lysine or arginine;

[0945] R 9 It is absent or contains tryptophan;

[0946] R 10 It is absent or contains lysine;

[0947] R 11 To R 20 The following groups are not present independently or are selected from: cysteine, leucine, tyrosine, aspartic acid, leucine, isoleucine, valine, valine, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, prolylglycine (Pro-Gly), D-Nal (2'), L-Nal (2'), Bip, ornithine, and tryptophan;

[0948] Where R 2 If it is a n-valeryl group or a n-hexanoyl group, then R 1 X 1 X 2 and X 3 It does not exist;

[0949] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0950] X 2The following groups are not present or are selected: D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0951] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazine-2-one ring, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0952] Y 1 Choose the group consisting of the following: D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0953] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0954] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0955] Y 4 It is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;

[0956] Y 5 It is absent or is either D-proline or D-valine;

[0957] Y 6 It is absent or is either D-proline or D-valine;

[0958] Y 7 It is absent or is either D-proline or D-valine;

[0959] Y 8 It is absent or is either D-proline or D-valine;

[0960] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0961] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0962] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0963] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0964] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[0965] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0966] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R4 With R 10 Side-chain lactam bridges between them;

[0967] When R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The closure of the lactam between them; and

[0968] When R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 With R 7 The lactam closure between them.

[0969] In some embodiments of equation (I):

[0970] R 1 The group consisting of the following is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, tyrosine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[0971] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen).

[0972] R 3The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro -2-Benzazapyro-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[0973] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[0974] R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[0975] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[0976] R 7 The following groups are not present or are selected: glycine, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[0977] R 8 It is absent or contains lysine or arginine;

[0978] R 9It is absent or contains tryptophan;

[0979] R 10 It is absent or contains lysine;

[0980] R 11 To R 20 It does not exist;

[0981] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[0982] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0983] X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[0984] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[0985] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;

[0986] Y 3 The group consisting of the following is absent or selected: D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;

[0987] Y 4 It is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;

[0988] Y 5 It is absent or is either D-proline or D-valine;

[0989] Y 6 It is absent or is either D-proline or D-valine;

[0990] Y 7 It is absent or is either D-proline or D-valine;

[0991] Y 8 It is absent or is either D-proline or D-valine;

[0992] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[0993] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 Disulfide bonds between them;

[0994] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[0995] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[0996] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R7 Side-chain lactam bridges between them;

[0997] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[0998] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[0999] The conditions are:

[1000] When R 2 When it is dAsp, then R 7 Not for dLys;

[1001] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and

[1002] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified.

[1003] In some embodiments, non-natural melanocortin analogues comprise the sequence of formula (I), wherein:

[1004] R 1The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;

[1005] R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);

[1006] R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe);

[1007] R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe);

[1008] R5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe.

[1009] R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine;

[1010] R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic);

[1011] R 8 It is absent or contains lysine or arginine;

[1012] R 9 It is absent or contains tryptophan;

[1013] R 10 It is absent or contains lysine;

[1014] R 11 To R 20 It does not exist;

[1015] X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine;

[1016] X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[1017] X3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine;

[1018] Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;

[1019] Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine.

[1020] Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine;

[1021] Y 4 It is absent or is either D-proline or D-valine;

[1022] Y 5 It is absent or is either D-proline or D-valine;

[1023] Y 6 It is absent or is either D-proline or D-valine;

[1024] Y 7 It is absent or is either D-proline or D-valine;

[1025] Y 8 It is absent or is either D-proline or D-valine;

[1026] This non-natural melanocortin analogue is optionally partially cyclized by a group consisting of:

[1027] When R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R2 With R 7 or X 1 Disulfide bonds between them;

[1028] When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them;

[1029] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them;

[1030] When R 1 or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 or R 2 With R 7 Side-chain lactam bridges between them;

[1031] When R 1 or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 or R 2 With R 8 Side-chain lactam bridges between them;

[1032] When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With R 10 Side-chain lactam bridges between them;

[1033] The conditions are:

[1034] When R 2 When it is dAsp, then R 7 Not for dLys;

[1035] When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7Not Arg-Trp-Lys; and

[1036] When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified;

[1037] When R 7 When it is Aia, R 4 dNal(2');

[1038] When R 4 p(I)dPhe and this non-natural melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His;

[1039] When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal;

[1040] When this non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and

[1041] When this non-natural melanocortin analogue is linear, R 2 It does not not exist.

[1042] In some embodiments, non-naturally occurring melanocortin analogs have one or more β-hairpin (β-hairpin) and / or β-turn (β-turn) structures. In some embodiments, R according to the sequence of formula (I) 3 (It can be hydroxyproline, hydroxy-D-proline, D-alanine, D-methionine, D-valine, prolylglycine (Pro-Gly), glycine) provides a β-hairpin and / or β-turn structure for non-naturally occurring melanocortin analogs. In some embodiments, if present, disulfide bonds according to the sequence of formula (I) provide a β-hairpin and / or β-turn structure for non-naturally occurring melanocortin analogs.

[1043] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

[1044] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an acyl group. In some embodiments, the acyl group is an acetyl group (e.g., In some embodiments, the acyl group is a formyl group (e.g., ).

[1045] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an imine group.

[1046] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an amide group. In some embodiments, the amide group is a pyroglutamyl (pGlu) group (e.g., In some embodiments, the amide group is derived from a fatty acid (e.g., ).

[1047] Other examples of N-terminal modifications include, but are not limited to, (urea group), (carbamate group) (Sulfanamide group) (alkylamine group).

[1048] In some embodiments, if present, the N-terminus of the non-naturally occurring melanocortin analogue is not modified.

[1049] As discussed above, Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 The C-terminus represents a non-naturally occurring melanocortin analogue. In some embodiments, Y... 1 To Y 8 It does not exist. In some embodiments, Y 1 Existence and Y 2 To Y 8 It does not exist.

[1050] In some embodiments, Y 3 To Y 8 It does not exist. In some embodiments, Y 3 To Y 8 It does not exist, and Y1 It is D-valine and Y 2 It is D-proline, or Y-proline. 1 It is D-proline and Y 2 It is D-valine.

[1051] In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist. In some embodiments, Y 3 Existence and Y 4 To Y 8 It does not exist, and (i)Y 1 (ii)Y is D-valine or D-proline. 2 It is D-valine or D-proline, and / or (iii) Y 3 It is D-valine or D-proline. In some embodiments, Y... 3 Existence and Y 4 To Y 8 It does not exist, and (i)Y 1 For D-valine, Y 2 It is D-valine and Y 3 For D-proline, (ii)Y 1 For D-proline, Y 2 It is D-valine and Y 3 For D-valine, or (iii)Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine.

[1052] In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist. In some embodiments, Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist, and (i)Y 1 (ii)Y is D-valine or D-proline. 2 It is D-valine or D-proline, (iii)Y 3 It is D-valine or D-proline, and / or (iv) Y 4 It is D-valine or D-proline. In some embodiments, Y... 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist, and (i)Y 1For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-proline, (ii)Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 For D-valine, (iii)Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4为D- Valine, or (iv)Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine.

[1053] In some embodiments, the C-terminus includes additional derivatives to extend the length of the C-terminus of non-naturally occurring melanocortin analogs. Exemplary additional C-termini include, but are not limited to, Y... 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y12 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 1 4 AND 15 AND 16 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND12 AND 13 AND 14 AND 15 AND 16 AND 17 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 AND 19 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND 9 AND 10 AND 11 AND 12 AND 13 AND 14 AND 15 AND 16 AND 17 AND 18 AND 19 AND 20 ,AND 1 AND 2 AND 3 AND 4 AND 5 AND 6 AND 7 AND 8 AND9 Y 10 Y 11 Y 12 Y 13 Y 14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 、Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 Y 9 Y 10 Y 11 Y 12 Y 13 Y 14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 Y​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​14 Y 15 Y 16 Y 17 Y 18 Y 19 Y 20 Y 21 Y 22 Y 23 Y 24 etc., where Y exists. 9 To Y 24 Each is independently either D-proline or D-valine.

[1054] In some embodiments, if present, the C-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

[1055] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is fitted with an amide group (e.g., Modification. In some embodiments, the amide group is an N-alkylamide group (e.g., ) or N-arylamide group. In some embodiments, the N-arylamide group is a p-nitroaniline group (pNA) (e.g., ) or 7-amino-4-methylcoumarin (AMC) (e.g., ).

[1056] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is bound with an ester group (e.g., Modification.

[1057] In some embodiments, if present, the C-terminus of a non-naturally occurring melanocortin analogue is replaced with an aldehyde (e.g., Modification.

[1058] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analogue is unmodified. In some embodiments, the C-terminus of the non-naturally occurring melanocortin analogue is unmodified, and the sequence of formula (I) is Ac-Nle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 305; B07a).

[1059] In some embodiments, R 1 It does not exist, and R 2 It is D-aspartic acid. In some embodiments, R 1 It is acetylated leucine, and R 2 It is D-aspartic acid.

[1060] In some embodiments, X 1 X 2 and X 3 It does not exist. In some embodiments, X 1 Existence and X 2 and X 3 It does not exist.

[1061] In some embodiments, R 4 Not D-phenylalanine. In some embodiments, R 4 It is D-Nal(2').

[1062] In some embodiments, the non-naturally occurring melanocortin analogues described herein are cyclized. For example, non-naturally occurring melanocortin analogues can be partially cyclized by selecting from the group consisting of: when R 1 or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 or R 2 With R 7 or X 1 disulfide bonds between; when R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; when R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between; when R 1 It is aspartic acid and R 5-8 When either of them is lysine, R 1 With R 5-8 Any of the side chain lactam bridges in R; 1 For lysine and R 6 When it is aspartic acid, R 1 With R 6 The side-chain lactam bridge between; when R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 2 With R 7 The side-chain lactam bridge between; when R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7When it is glycine, proline, or tryptophan, R 2 With R 8 The side-chain lactam bridge between; when R 2 or R 4 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 or R 4 With any R 10 The side-chain lactam bridge between; when R 1 It is succinic acid or phthalic acid and R 7 When it is lysine, R 1 With R 7 The lactam closure between; and / or when R 2 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 With R 7 The lactam closure between them. Cycloning can also begin from any X residue (optionally a stable N-terminal residue). For example, X 2 It can be aspartic acid, which can be used for cyclization.

[1063] In some embodiments, R 1 R 2 and R 7 Existence and R 8 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 7 Via lactam cyclization. In some embodiments, R 1 It is acetylated leucine, R 2 It is aspartic acid, R 3 Select the group consisting of proline, hydroxyproline, and hydroxy-D-proline, R 4 For dNal(2'), R 5 For arginine, R 6 For D-tryptophan or L-tryptophan, R 7 For lysine, Y 1 It is D-valine and / or Y 2 It is D-proline.

[1064] In some embodiments, the sequence of equation (I) is: Ac-Nle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 306; B07) or Ac-Nle- c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:307; D3), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

[1065] In some embodiments, R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 8 Via lactam cyclization. In some embodiments, R 1 It is acetylated leucine, R 2 It is aspartic acid, R 3 Select the group consisting of proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine, R 4 For histidine or dNal(2'), R 5 For dNal(2') or arginine, R 6 Select the group consisting of free arginine, D-tryptophan, and L-tryptophan, R 7 For tryptophan or proline, R 8 For lysine, Y 1 Select the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y 2 It is D-proline.

[1066] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[1067] Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 308; D1);

[1068] Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 309; D1γ);

[1069] Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 310; D1δ);

[1070] Ac-Nle- c (Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO:311;D2;and

[1071] Ac-Nle- c (Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 312; D4),

[1072] Where c represents through R 2 and R 8 Cyclation via lactam bonds.

[1073] In some embodiments, R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 2 and R 10 Cyclation via lactam bonds. In some embodiments, the sequence of formula (I) is Ac-Nle- c (Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:313; D1α), where c represents the result of passing through R 2 and R 10 Via lactam cyclization. In some embodiments, R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) passes through R. 4 and R 10 Cyclation via a lactam bond. In some embodiments, the sequence of formula (I) is Ac-Nle-Phe-Phe- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:314; D1β), where c represents the result of R 4 and R 10 Cyclation via lactam bonds.

[1074] In some embodiments, the sequence of formula (I) is linear. In some embodiments, the sequence of formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO:315; A1).

[1075] In some embodiments of the sequence of equation (I), R 1 It is acetylated leucine. Alternatively, in some embodiments, R 1 R is an acetylated amino acid other than acetylated leucine. In some embodiments, R 1 These are non-acetylated amino acids. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[1076] Ac-dArg- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 316);

[1077] Ac-dMet- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 317);

[1078] Ac-dIle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 318);

[1079] Ac-dLeu- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 319);

[1080] Ac-dVal- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 320);

[1081] Ac-dAla- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 321);

[1082] Ac-Ala- c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:322);

[1083] Ac-Tle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:323);

[1084] Ac-dTle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:324);

[1085] Ac-dNle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:325);

[1086] Ac-Nva- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:326);

[1087] Ac-Gly- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:327);

[1088] Ac-dPro- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:328);

[1089] Ac-dCys- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:329);

[1090] Ac-dPhe- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:330);

[1091] Ac-dTyr- c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 331);

[1092] Ac-dGln- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 332); and

[1093] Ac-dAsn- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:333), where c represents through 2 and R 7 Cyclation via lactam bonds.

[1094] In some embodiments, when the sequence of equation (I) is passed through R 2 and R 7 When cyclized, then R 2 For Asp and R 7 For Lys. Alternatively, in some embodiments, when the sequence of equation (I) is passed through R 2 and R 7 When cyclized, then R 2 For those other than Asp that can interact with R 7 The amino acid that forms a bond with the residue and R 7 For those other than Lys that can interact with R 2 Amino acids that form bonds with residues at a certain point. For example, when R... 2 It consists of amino acids other than Arg and R 7 When R is an amino acid other than Lys, 2 The residues at that position can interact with R 7 The residues at the position form bonds, such as lactam bonds or disulfide bonds. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[1095] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 334);

[1096] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 335);

[1097] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:336);

[1098] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:337);

[1099] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:338);

[1100] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:339);

[1101] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:340);

[1102] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:341);

[1103] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:342);

[1104] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:343);

[1105] Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:344);

[1106] Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:345);

[1107] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:346);

[1108] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:347);

[1109] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:348);

[1110] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:349);

[1111] Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:350);

[1112] Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:351);

[1113] Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:352);

[1114] Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:353);

[1115] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:354);

[1116] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:355);

[1117] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:356);

[1118] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 357);

[1119] Ac-Nle-c(dPen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 358);

[1120] Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 359);

[1121] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 360);

[1122] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 361);

[1123] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 362); and

[1124] Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO:363),

[1125] Where c represents through R 2 and R 6 or R 7 Cycling via lactam bonds or disulfide bonds.

[1126] In some embodiments of the sequence of equation (I), R 3 For Pro. Alternatively, in some embodiments, R 3 The amino acid is absent or is not Pro. In some embodiments, the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:364);

[1127] Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 365);

[1128] Ac-Nle-c(Asp-dPro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366);

[1129] Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 367);

[1130] Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368);

[1131] Ac-Nle-c(Asp-Pro-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 369);

[1132] Ac-Nle-c(Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 370);

[1133] Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 371);

[1134] Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372);

[1135] Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 373); and

[1136] Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:374), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

[1137] In some embodiments of the sequence of equation (I), R 5 For Arg. Alternatively, in some embodiments, R 5 The amino acid is absent or consists of an amino acid other than Arg. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[1138] Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375);

[1139] Ac-Nle-c(Asp-Pro-dNal(2')-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376);

[1140] Ac-Nle-c(Asp-Pro-dNal(2')-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377);

[1141] Ac-Nle-c(Asp-Pro-dNal(2')-dArg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 378);

[1142] Ac-Nle-c(Asp-Pro-dNal(2')-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379);

[1143] Ac-Nle-c(Asp-Pro-dNal(2')-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 380);

[1144] Ac-Nle-c(Asp-Pro-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381);

[1145] Ac-Nle-c(Asp-Pro-dNal(2')-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382);

[1146] Ac-Nle-c(Asp-Pro-dNal(2')-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383);

[1147] Ac-Nle-c(Asp-Pro-dNal(2')-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); and

[1148] Ac-Nle-c(Asp-Pro-dNal(2')-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:385),

[1149] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[1150] In some embodiments of the sequence of equation (I), R 6 For Trp. Alternatively, in some embodiments, R 6 The amino acid is absent or is an amino acid other than Trp. In some embodiments, the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH2(SEQ ID NO:386);

[1151] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Nal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387);

[1152] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 388);

[1153] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389);

[1154] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 390);

[1155] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and

[1156] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ala-Lys)-dVal-dPro-NH2(SEQ ID NO:392), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

[1157] In some embodiments of the sequence of equation (I), R 4 For dNal(2'). Alternatively, in some embodiments, R 4 Amino acids other than dNal(2'). For example, in some embodiments, when R 4 When R is an amino acid other than dNal(2'), 4 For Bip. In some embodiments, the sequence of equation (I) is:

[1158] Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:393), where c represents the expression via R 2 and R 7 Cyclation via lactam bonds.

[1159] In some embodiments of the sequence of equation (I), Y 1 For dVal and Y 2 For dPro. Alternatively, in some embodiments, Y 1 It consists of amino acids other than dVal, and Y 2 These are amino acids other than dPro. In some embodiments, Y 1 For dVal and Y 2 These are amino acids other than dPro. In some embodiments, Y 1 It consists of amino acids other than dVal and Y 2 For dPro.

[1160] In some embodiments, Y 1 For dVal, Y 2 It is dPro, and the C-terminus is modified with NH2. In some embodiments, Y 1 Y consists of amino acids other than dVal. 2 It consists of amino acids other than dPro, and its C-terminus is modified with NH2. In some embodiments, Y 1 For dVal, Y 2 It consists of amino acids other than dPro, and its C-terminus is modified with NH2. In some embodiments, Y 1 Y consists of amino acids other than dVal. 2It is dPro, and the C-terminus is modified with NH2. In some embodiments, Y 1 For dVal, Y 2 It is dPro, and the C-terminus is not modified.

[1161] In the embodiment of formula (I), when Y 1 When Y is an amino acid other than dVal, then 1 Selected from dPro, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, and dLys. In the embodiment of formula (I), when Y 2 When Y is an amino acid other than dPro, then 2 Alternatively, it may be selected from dVal, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, and dAsn. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[1162] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ ID NO: 394);

[1163] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 395);

[1164] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 396);

[1165] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 397);

[1166] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 398);

[1167] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2 (SEQ ID NO: 399);

[1168] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH2(SEQ ID NO:400);

[1169] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO:401);

[1170] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH2(SEQ ID NO:402);

[1171] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO:403);

[1172] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO:404);

[1173] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO:405);

[1174] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO:406);

[1175] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO:407);

[1176] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2(SEQ ID NO:408);

[1177] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH2(SEQ ID NO:409);

[1178] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO:410);

[1179] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO:411);

[1180] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH2(SEQ ID NO:412);

[1181] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO:413);

[1182] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO:414);

[1183] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO:415);

[1184] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO:416);

[1185] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO:417);

[1186] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO:418);

[1187] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO:419);

[1188] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH2(SEQ ID NO:420);

[1189] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH2(SEQ ID NO:421);

[1190] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ ID NO:422);

[1191] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO:423);

[1192] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO:424);

[1193] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO:425);

[1194] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH2(SEQ ID NO:426);

[1195] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO:427);

[1196] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO:428);

[1197] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO:429);

[1198] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO:430);

[1199] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO:431);

[1200] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO:432);

[1201] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO:433);

[1202] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO:434);

[1203] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO:435);

[1204] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Pro-Val-NH2(SEQ ID NO:436);

[1205] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-dVal-NH2(SEQ ID NO:437);

[1206] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO:438);

[1207] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO:439);

[1208] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO:440);

[1209] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO:441);

[1210] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO:442);

[1211] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 443);

[1212] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 444);

[1213] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 445);

[1214] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 446);

[1215] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 447);

[1216] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 448); and

[1217] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO:449),

[1218] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[1219] In some embodiments of the sequence of equation (I), when Y 3 Existence and Y 4-8 If it does not exist, then Y 1 Y 2 and Y 3 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 and Y 4 Existence and Y 5-8 If it does not exist, then Y 1 Y 2 Y 3 and Y4 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 To Y 5 Existence and Y 6-8 If it does not exist, then Y 1 To Y 5 Either dVal or dPro can be chosen independently. In some embodiments of the sequence of equation (I), when Y 3 To Y 6 Existence and Y 7-8 If it does not exist, then Y 1 To Y 6 Either dVal or dPro can be chosen independently. In some embodiments of the sequence of equation (I), when Y 3 To Y 7 Existence and Y 8 If it does not exist, then Y 1 To Y 7 Each of these is independently selected from dVal and dPro. In some embodiments of the sequence of equation (I), when Y 3 To Y 8 If it exists, then Y 1 To Y 8 Each of these is independently selected from dVal and dPro. In some embodiments, the sequence of equation (I) is selected from the group consisting of:

[1220] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 450);

[1221] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 451);

[1222] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ IDNO: 452);

[1223] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 453); and

[1224] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 454),

[1225] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[1226] In some embodiments, X 1 It exists and is acetylated leucine, and R 1 It is present and is leucine. In some embodiments, X... 2 It is present and is leucine. In some embodiments, X... 3 It is present and is leucine. In some embodiments, the sequence of formula (I) is selected from the group consisting of:

[1227] Ac-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 455);

[1228] Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 456); and

[1229] Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 457),

[1230] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[1231] As described above, some non-natural melanocortin analogs containing the sequence of formula (I) can bind to melanocortin 3 and melanocortin 4 receptors with the same or generally similar affinity. Other melanocortin analogs containing the sequence of formula (I) can bind to melanocortin 3 receptors with a greater affinity than melanocortin 4 receptors. In some embodiments, when the non-natural melanocortin analogs of the present invention bind to melanocortin 3 receptors with a greater affinity than melanocortin 4 receptors, the sequence of formula (I) is selected from the group consisting of:

[1232] Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 458);

[1233] Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 459);

[1234] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 460);

[1235] c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ IDNO: 461);

[1236] Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 462);

[1237] Ac-Nle-c(Asp-β-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 463);

[1238] Ac-Nle-c(Asp-Mamb-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 464);

[1239] Ac-Nle-c(Asp-Acpc-dNal(2')Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 465);

[1240] Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO:466); and

[1241] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH2(SEQ ID NO:467), where c represents the result of passing through R 1 or R 2 and R 7 or R 8 via lactam bond or through R 2 and R5 Cycling via disulfide bonds.

[1242] Some melanocortin analogs containing the sequence of formula (I) can bind to the melanocortin 4 receptor with a greater affinity than the melanocortin 3 receptor. In some embodiments, when a non-naturally occurring melanocortin analog binds to the melanocortin 4 receptor with a greater affinity than the melanocortin 3 receptor, the sequence of formula (I) is:

[1243] Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:468); or

[1244] Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:469),

[1245] Where c represents through R 2 and R 7 Cyclation via lactam bonds.

[1246] In some embodiments of the sequence of equation (I), when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 5-8 Cycling of either the lactam bond or disulfide bond between them. In some embodiments, when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 6 Cyclation of the lactam bond between them. In some embodiments, when X 1 Existence and X 2 and X 3 When it does not exist, the sequence of equation (I) is passed through R. 1 With R 7 Cyclation of lactam bonds between them. In some embodiments, Y 1 and Y 2 They exist and are respectively dVal and dPro, and Y 3 To Y 8 It does not exist. In some embodiments, Y 1 To Y 8 It does not exist.

[1247] Alternatively, in some embodiments, the non-naturally occurring melanocortin analogue comprises a sequence selected from the group consisting of:

[1248] Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2(SEQ ID NO:470);

[1249] Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:471);

[1250] Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:472);

[1251] Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:473);

[1252] Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:474);

[1253] Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:475);

[1254] Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:476);

[1255] Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:478);

[1256] Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:479);

[1257] Ac-Nle-c(Asp-Pro-dPhe-Arg-dTrp-Lys)-dVal-dPro-NH2(SEQ ID NO:480);

[1258] Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 481);

[1259] Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 482);

[1260] Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 483);

[1261] Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:484),

[1262] Where c represents through R 1 or R 2 and R 7 Cyclation via lactam bonds.

[1263] In some embodiments, the sequence of equation (I) is selected from the group consisting of the following:

[1264] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 485);

[1265] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 486);

[1266] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 487);

[1267] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 488);

[1268] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 489);

[1269] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:490);

[1270] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO:491);

[1271] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2(SEQ ID NO:492);

[1272] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:306);

[1273] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:493);

[1274] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:494);

[1275] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO:495);

[1276] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO:496);

[1277] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO:497);

[1278] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO:498);

[1279] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO:499);

[1280] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO:500);

[1281] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO:501);

[1282] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Pro-NH2(SEQ ID NO:502);

[1283] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Pro-NH2(SEQ ID NO:503);

[1284] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO:504);

[1285] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Pro-NH2(SEQ ID NO:505);

[1286] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Pro-NH2(SEQ ID NO:506);

[1287] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Pro-NH2(SEQ ID NO:507);

[1288] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO:508);

[1289] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO:509);

[1290] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Val-NH2(SEQ ID NO:510);

[1291] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Val-NH2(SEQ ID NO:511);

[1292] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO:512);

[1293] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO:513);

[1294] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO:514);

[1295] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO:515);

[1296] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO:516);

[1297] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO:517);

[1298] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO:518);

[1299] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO:519);

[1300] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:520);

[1301] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:521);

[1302] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:522);

[1303] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO:523);

[1304] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:524);

[1305] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:525);

[1306] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO:526);

[1307] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO:527);

[1308] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO:528);

[1309] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:529);

[1310] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:530);

[1311] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO:531);

[1312] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO:532);

[1313] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Ala-NH2(SEQ ID NO:533);

[1314] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO:534);

[1315] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Ala-NH2(SEQ ID NO:535);

[1316] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO:536);

[1317] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO:537);

[1318] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Ala-β-Pro-NH2(SEQ ID NO:538);

[1319] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Ala-β-Pro-NH2 (SEQ ID NO:539);

[1320] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO:540);

[1321] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO:541);

[1322] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO:542);

[1323] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO:543);

[1324] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:544);

[1325] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:545);

[1326] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:546);

[1327] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:547)

[1328] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:548);

[1329] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO:549);

[1330] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO:550);

[1331] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO:551);

[1332] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO:552);

[1333] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO:553);

[1334] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO:554);

[1335] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO:555);

[1336] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:556);

[1337] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:557);

[1338] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:558);

[1339] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO:559);

[1340] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO:560);

[1341] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO:561);

[1342] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO:562);

[1343] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO:563);

[1344] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO:564);

[1345] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO:565);

[1346] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO:566);

[1347] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO:567);

[1348] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO:568);

[1349] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 569);

[1350] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQID NO:570); and

[1351] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 571),

[1352] Where c represents through R 1 and R 7 Cyclation via lactam bonds.

[1353] Alternatively, in some embodiments, the non-naturally occurring melanocortin analogue comprises a sequence selected from the group consisting of:

[1354] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 572);

[1355] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 573);

[1356] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dThr-dPro-dThr (SEQ ID NO: 574);

[1357] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-Dlys)-dThr-dPro-dThr (SEQ ID NO: 575);

[1358] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 576);

[1359] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dVal-NH2 (SEQ ID NO: 577);

[1360] Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:578);

[1361] Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO:579);

[1362] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:580);

[1363] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:581);

[1364] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dVal-dPro-NH2(SEQ ID NO:582);

[1365] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-DLys)-dVal-dPro-NH2(SEQ ID NO:583);

[1366] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO:584);

[1367] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2(SEQ ID NO:585);

[1368] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2(SEQ ID NO:586);

[1369] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2(SEQ ID NO:587);

[1370] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO:588);

[1371] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO:589);

[1372] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βPro-NH2(SEQ ID NO:590);

[1373] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-DLys)-βVal-βPro-NH2(SEQ ID NO:591);

[1374] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO:592);

[1375] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2(SEQ ID NO:593);

[1376] Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-DLys)-βPro-βPro-NH2(SEQ ID NO:594);

[1377] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-DLys)-βPro-βPro-NH2(SEQ ID NO:595);

[1378] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO:596);

[1379] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO:597);

[1380] Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-DLys)-βVal-βVal-NH2(SEQ ID NO:598);

[1381] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βVal-NH2(SEQ ID NO:599);

[1382] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:600);

[1383] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:601);

[1384] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:602);

[1385] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO:603);

[1386] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:604);

[1387] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:605);

[1388] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:606);

[1389] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2 (SEQ ID NO:607);

[1390] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO:608);

[1391] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO:609);

[1392] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr(SEQ ID NO:610);

[1393] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr(SEQ ID NO:611);

[1394] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO:612);

[1395] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO:613);

[1396] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2(SEQ ID NO:614);

[1397] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2(SEQ ID NO:615);

[1398] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:616);

[1399] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO:617);

[1400] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2(SEQ ID NO:618);

[1401] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2(SEQ ID NO:619);

[1402] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO:620);

[1403] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2(SEQ ID NO:621);

[1404] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2(SEQ ID NO:622);

[1405] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2(SEQ ID NO:623);

[1406] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2(SEQ ID NO:624);

[1407] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2(SEQ ID NO:625);

[1408] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2(SEQ ID NO:626);

[1409] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2(SEQ ID NO:627);

[1410] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO:628);

[1411] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2(SEQ ID NO:629);

[1412] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2(SEQ ID NO:630);

[1413] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2(SEQ ID NO:631);

[1414] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO:632);

[1415] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO:633);

[1416] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO:634);

[1417] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO:635);

[1418] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:636);

[1419] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:637);

[1420] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO:638);

[1421] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO:639);

[1422] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:640);

[1423] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO:641);

[1424] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO:642);

[1425] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO:643);

[1426] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:644);

[1427] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO:645);

[1428] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:646);

[1429] Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO:647);

[1430] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:648);

[1431] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO:649);

[1432] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:650);

[1433] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO:651);

[1434] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO:652);

[1435] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 653);

[1436] Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 654);

[1437] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 655);

[1438] Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 656);

[1439] Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 657);

[1440] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 658); and

[1441] Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ IDNO: 659),

[1442] Where c represents through R 1 and R 7 Cyclation via lactam bonds.

[1443] In some embodiments, the non-naturally occurring melanocortin analogue is a melanocortin receptor antagonist, such as a melanocortin 3 receptor and / or melanocortin 4 receptor antagonist. In some embodiments, the non-naturally occurring melanocortin analogue is a melanocortin receptor agonist, such as a melanocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, and / or melanocortin 5 receptor agonist. For example, in some embodiments, the melanocortin analogue has agonist activity against melanocortin 3 and / or melanocortin 4 receptors, as well as against melanocortin 1 and melanocortin 5 receptors. In other embodiments, the melanocortin analogue has antagonist activity against melanocortin 3 and / or melanocortin 4 receptors, and agonist activity against melanocortin 1 and melanocortin 5 receptors.

[1444] In some embodiments, the non-naturally occurring melanocortin analogue comprises any one of the sequences of SEQ ID NO: 305 to 659. In some embodiments, the non-naturally occurring melanocortin analogue comprises any one of the sequences of SEQ ID No: 305 to 469, 481 to 483, and 485 to 571. In some embodiments, the non-naturally occurring melanocortin analogue comprises any one of the sequences of SEQ ID No: 305 to 469 and 481 to 483. In some embodiments, the non-naturally occurring melanocortin analogue comprises any one of the sequences of SEQ ID No: 306, 428, 481 to 483, 493 to 495, 528 to 531, and 552 to 555.

[1445] In some embodiments, the non-naturally occurring melanocortin analogue comprises the sequence of SEQ ID NO:306 (TCMCB07). The structure of TCMCB07 (“B07”), which comprises Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2, is shown below:

[1446]

[1447] TCMCB07 (SEQ ID NO:306).

[1448] Further examples of melanocortin analogues

[1449] Further aspects of melanocortin analogues that can be used in the composition are described below.

[1450] Non-naturally occurring melanocortin analogues are represented by formula (I) as shown above, and comprise non-naturally occurring melanocortin analogues coupled with degradation-resistant C-terminal extensions and optional N-terminal extensions.

[1451] In summary, R1 To R 20 It can be one of several known melanocortin analogs, each of which has seven residues that are independently an amino acid or peptide mimic. Some melanocortin analogs have fewer than seven residues. In summary, in one respect, R 1 To R 7 This indicates α-melanocortin analogues. In summary, on the other hand, R... 1 To R 7 This refers to melanocortin analogues, which bind to MC3, MC4, and / or MC5 receptors as agonists, inverse agonists, or antagonists.

[1452] The presence of C-terminal extensions on non-naturally occurring melanocortin analogs of the present invention can confer resistance to degradation of the sequence, prevent exposure of RF amide sequences, and / or promote transepithelial transport.

[1453] In some embodiments, a proline mimic (piperazine-2-one ring) replaces the D-Pro at the C-terminal extension. On one hand, proline mimics are synthesized as described in Teixido et al., Brain Res Bull, 2007, 73(1-3):103-107. The piperazine-2-one ring is also discussed in Bhatt and Just, Helvetica Chimica Acta 83:722-727 (2000). To replace proline with a piperazine-2-one ring, an ethylene bridge is incorporated between the nitrogen molecules of two adjacent α-amino groups. This produces a six-membered ring containing two nitrogen atoms and four carbon atoms, structurally similar to the proline ring between the functional groups of two adjacent amino acid residues (albeit a six-membered ring).

[1454] The C-terminal extensions of non-naturally occurring melanocortin analogs resist significant degradation before the peptide is cleared from the bloodstream in humans or animals. Furthermore, the C-terminal extensions possess sufficient stability to ensure that non-naturally occurring melanocortin analogs, when administered to humans or animals, do not induce or minimize cardiovascular effects. Due to the wide range of stability differences among peptides, amino acids, and small molecules, the melanocortin analogs described herein possess variable-length C-terminal extensions in the extracellular physiological environment. These C-terminal extensions possess sufficient stability (e.g., length, spatial structure) to ensure that any degradation in the body before clearance from the bloodstream does not re-expose the cardiovascular (RF amide) pharmacophore for its intended effect.

[1455] Cycloned variants

[1456] Cyclated melanocortin analogues have shown improved efficacy and stability. See Balse-Srinivasan et al., J. Med. Chem. 46(17):3728-3733 (2003) and Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001); Kavarana et al., J. Med. Chem. 45(12):2644-2650 (2002). In one respect, non-naturally occurring melanocortin analogues represented by formula (I) are cyclized. The following is a list of non-limiting examples of how non-naturally occurring melanocortin analogues represented by formula (I) can be cyclized:

[1457] In equation (I), when R 1 or R 2 For cysteine ​​and R 7 Or Y 1 When it is cysteine, R 1 or R 2 With R 7 Or Y 1 The disulfide bond between them, as described in Balse-Srinivasan et al., J. Med. Chem., 2003, 46(23):4965-4973. When Y 1 When it is cysteine, Y 2 It does not not exist, but it is selected from the group consisting of the following: D-threonine, L-threonine, D-proline, L-proline, and piperazine-2-one ring.

[1458] When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 Lactam bridges between them, such as Mayorov et al. J.Med.Chem.49:1946-1952 (2006) and Bednarek et al., Biochem.Biophys.Res.Com.286(3):641-645 (2001).

[1459] When R 2 It is glutamic acid or aspartic acid and R 7 When it is lysine, R 2 With R 7 The side-chain lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001).

[1460] When R 1 It is succinic acid or phthalic acid and R7 When it is lysine, R 1 With R 7 Lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001) and Kavarana et al., J. Med. Chem. 45(12):2644-2650 (2002).

[1461] When R 2 or R 3 It is succinic acid and R 7 When it is 2,3-diamino-propionic acid, R 2 or R 3 With R 7 Lactam bridges between them, such as Bednarek et al., Biochem. Biophys. Res. Com. 286(3):641-645 (2001).

[1462] The “backbone” cyclic peptide is formed by covalent bonding between the C-terminus and / or N-terminus of the target linear peptide. This example is described as the bridging of two amide nitrogens via a alkyl group and an amide, as described in Hess et al., J. Med. Chem. 50:6201-6211 (2007).

[1463] Amino acid isomers and non-standard amino acids

[1464] In some embodiments, the amino acid residues of the non-naturally occurring melanocortin analogs provided herein for use in the present invention may be D-amino acids or L-amino acids, or may be substituted with their non-standard isomer counterparts. For example, α-amino acids may be substituted with β-amino acids, and L-amino acids may be substituted with D-amino acids. Amino acids not specified as D- or L-isomers in the present invention may be any isomer. Unless specifically indicated as β-amino acids, all amino acids are α-amino acids. Unless specifically specified, β-amino acids may be β-amino acids. 2 - amino acids or β 3 - amino acids, or in some cases, β. 2 and β 3 Both.

[1465] Receptor agonists and antagonists

[1466] In some embodiments, non-natural melanocortin analogues are MC4 receptor agonists, MC4 receptor antagonists, MC3 receptor agonists, MC3 receptor antagonists, and / or MC5 receptor agonists with the α-melanocyte stimulating hormone (MSH) group.

[1467] In some embodiments, non-natural melanocortin analogues are MC3 receptor antagonists of the γ-melanocyte stimulating hormone group.

[1468] In some embodiments, non-natural melanocortin analogues are MC3 receptor agonists of the γ-melanocyte stimulating hormone group.

[1469] peptide synthesis

[1470] The non-natural melanocortin analogues described herein can be readily synthesized using any known conventional procedure for forming peptide bonds between amino acids. Such conventional procedures include, for example, any solution-phase procedure that allows condensation between a free α-amino group of an amino acid or residue thereof having a protected carboxyl group or other reactive group and a free primary carboxyl group of another amino acid or residue thereof having a protected amino group or other reactive group. In an exemplary procedure, the peptides described herein can be synthesized by solid-phase synthesis and purified according to methods known in the art. The peptides described herein can be prepared using any of a variety of well-known methods, utilizing various resins and reagents.

[1471] Peptide synthesis can be performed by sequentially adding each amino acid in the desired sequence to another amino acid or residue thereof; or by first conventionally synthesizing a peptide fragment having the desired amino acid sequence, then condensing it to provide the desired peptide. The resulting peptide is then cyclized to produce a cyclic peptide.

[1472] Solid-phase peptide synthesis methods are well-known and practiced in the art. In such methods, peptide synthesis is carried out by sequentially incorporating desired amino acid residues one by one into a growing peptide chain, according to the general principles of solid-phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem. 24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., eds., Academic Press 1-284 (1980).

[1473] In the chemical synthesis of peptides, reactive side chain groups of various amino acid residues are protected with appropriate protecting groups to prevent chemical reactions at that site until the protecting groups are removed. Another common approach is to protect the α-amino group of the entity when the amino acid residue or fragment reacts at the carboxyl group, and then selectively remove the α-amino protecting group to allow subsequent reactions to occur at that site. Specific protecting groups used in solid-phase and solution-phase synthesis methods are known to those skilled in the art.

[1474] The α-amino group can be protected by suitable protecting groups, including urethane protecting groups such as benzyloxycarbonyl (Z); and substituted benzyloxycarbonyl groups such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc), and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane protecting groups such as tert-butoxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc can be used for α-amino group protection.

[1475] The guanidino group can be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylsaturonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), and Boc. Pmc is a useful protecting group for Arg.

[1476] Solid-phase synthesis begins at the C-terminus of the peptide by coupling the protected α-amino acid to a suitable resin. Such starting materials are prepared by attaching the α-amino-protected amino acid to a p-benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotriphenylmethyl chloride resin via an ester bond, or via an Fmoc-linker, such as an amide bond between p-((R,S)-α-(1-(9H-fluoro-en-9-yl)-methoxyformamido)-2,4-dimethyloxybenzyl)-phenoxyacetic acid (Rink linker) and a diphenylmethylamine (BHA) resin, or by other methods known in the art. Fmoc-linker-BHA resin supports are commercially available and are typically used where feasible. The resin is repeatedly cycled as needed to sequentially add amino acids. The α-amino Fmoc protecting group is removed under alkaline conditions. For this purpose, piperidine, piperazine, diethylamine, or morpholine (20% to 40% v / v) in N,N-dimethylformamide (DMF) can be used.

[1477] After removing the α-amino protecting group, the subsequent protected amino acids are sequentially coupled to obtain the intermediate, i.e., the protected peptide resin. Activating agents used for amino acid coupling in solid-phase peptide synthesis are well known in the art. After peptide synthesis, if desired, orthogonally protected side-chain protecting groups can be removed using methods well known in the art for further peptide derivatization.

[1478] The reactive groups in a peptide can be selectively modified during solid-phase synthesis or after removal from the resin. For example, a peptide can be modified on the resin to obtain an N-terminal modification, such as acetylation, or it can be modified after removal from the resin using a cleavage reagent. Methods for N-terminal modifications (such as acetylation) and C-terminal modifications (such as amidation) are known in the art. Similarly, methods for modifying amino acid side chains are well known to those skilled in the art of peptide synthesis. The choice of modification for the reactive groups present on the peptide will depend in part on the desired characteristics of the peptide.

[1479] Peptides can be cyclized before cleavage from a peptide resin. For cyclization via reactive side chains, the desired side chain is deprotected, the peptide is suspended in a suitable solvent, and a cyclic coupling agent is added. Suitable solvents include, for example, DMF, dichloromethane (DCM), or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling agents include, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate (HBTU), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(pyrrolidone)-phosphonium hexafluorophosphate, etc. The coupling is initiated using pyrophosphonium hexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TATU), 2-(2-oxo-1(2H)-pyridyl)-1,1,3,3-tetramethylureon tetrafluoroborate (TPTU), or N,N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole (DCCl / HOBt). Coupling is initially initiated using a suitable base (such as N,N-diisopropylethylamine (DIPEA), symmetrical chloromethol, or N-methylmorpholine (NMM)).

[1480] After peptide synthesis, the peptide can be cleaved from the solid phase using various methods (such as using a suitable column, such as C). 18 The peptide is purified by reversed-phase high-performance liquid chromatography (RP-HPLC) using a column. Other separation or purification methods, such as those based on peptide size or charge, can also be used. Once purified, the peptide can be characterized using various methods, such as HPLC, amino acid analysis, and mass spectrometry.

[1481] Salt form of peptide

[1482] The non-natural melanocortin analog peptides described herein can be in the form of any pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable nontoxic base or acid (including inorganic or organic bases and inorganic or organic acids). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Exemplary salts include ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and salts of basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[1483] When the peptides described herein are basic, acid addition salts can be prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carboxylic acids, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, malonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. The acid addition salts of the peptides described herein are prepared in a suitable solvent from the peptide and an excess of an acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, citric acid, tartaric acid, maleic acid, succinic acid, or methanesulfonic acid). The acetate form is particularly suitable. When the peptides described herein contain an acidic portion, suitable pharmaceutically acceptable salts may include alkali metal salts (such as sodium or potassium salts) or alkaline earth metal salts (such as calcium or magnesium salts).

[1484] Second compound: Spirocyclic compound

[1485] The second compound of this invention may comprise a spirocyclic compound. In some embodiments, the spirocyclic compound is an MC4R antagonist. The second compound can exert a therapeutic effect after antagonizing MC4R.

[1486] The spirocyclic compound can be a compound of formula (X) of the present invention, for example, (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, or a pharmaceutically acceptable salt thereof.

[1487] As used herein, compounds of formula X as described herein include optional substituents and variables. It should be understood that the normal valence state of each specified (optionally substituted) atom or part does not exceed its normal valence state, and any optional substituent will produce a stable compound. It should also be understood that combinations of optional substituents and / or variables are permitted only if such combinations produce a stable compound.

[1488] As used herein, unless otherwise specified, the attachment site of a substituent may be from any suitable position of that substituent. For example, the piperidinyl group may be piperidin-1-yl (attached via the N atom of the piperidinyl group), piperidin-2-yl (attached via the C atom at position 2 of the piperidinyl group), piperidin-3-yl (attached via the C atom at position 3 of the piperidinyl group), or piperidin-4-yl (attached via the atom at position 4 of the piperidinyl group). In another example, the pyridinyl group (or pyridyl group) may be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

[1489] As used herein, the attachment point of a substituent can specifically indicate the location where the substituent is attached to another part. For example, "(C3-4 cycloalkyl)-C1-4 alkyl-" means the attachment point generated at the "C1-4 alkyl" part of "(C3-4 cycloalkyl)-C1-4 alkyl-".

[1490] When describing a substituted or optionally substituted portion, if it is not specified which atom of the portion is bonded to the substituent, then the substituent may be bonded to any suitable atom of that portion. For example, in the substituted "(C3-4 cycloalkyl)-C1-4 alkyl-", the substituent on the cycloalkyl group (i.e., (C3-4 cycloalkyl)-C1-4 alkyl-) may be bonded to the alkyl portion of the cycloalkyl group or to any carbon atom on the cycloalkyl group. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[1491] As used herein, when describing the relative positions of two substituents in a ring structure, the term "adjacent" refers to two substituents that are attached to two cyclic atoms of the same ring, which are directly connected by chemical bonds.

[1492] Spirocyclic compounds of formula (X)

[1493] In some embodiments, the composition of the present invention comprises a second compound, the second compound comprising a structure according to formula (X):

[1494]

[1495] Or its pharmaceutically acceptable salt, wherein:

[1496] Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a , of which C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[1497] Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 1-4 alkyl-, where C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[1498] Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[1499] Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups;

[1500] Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from hal...

Claims

1. A composition comprising: A first compound comprising a non-naturally occurring melanocortin analogue, said non-naturally occurring melanocortin analogue comprising the sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) in: R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe); R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe. R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine; R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It is absent or contains lysine or arginine; R 9 It is absent or contains tryptophan; R 10 It is absent or contains lysine; R 11 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine; X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine. Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-proline or D-valine; Y 5 It is absent or is either D-proline or D-valine; Y 6 It is absent or is either D-proline or D-valine; Y 7 It is absent or is either D-proline or D-valine; Y 8 It is absent or is either D-proline or D-valine; The non-natural melanocortin analogues are optionally partially cyclized from the group consisting of: When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between them; When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 Or R 2 With R 7 Side-chain lactam bridges between them; When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 Side-chain lactam bridges between them; When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 Side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 7 When it is Aia, R 4 dNal(2'); When R 4 p(I)dPhe and the non-naturally occurring melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO:661), then Y 1 To Y 2 Not dPro-dVal; When the aforementioned non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and When the non-natural melanocortin analogue is linear, R 2 It does not not exist. and Second compound and / or third compound, The second compound comprises a structure according to formula (X). Or its pharmaceutically acceptable salt, wherein: Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a Wherein C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx. B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 atoms independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form optional groups of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl; Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 Alkyl; and Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N, and The third compound comprises an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), wherein the antibody or antigen-binding fragment thereof comprises at least one of the following: a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52; b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184; c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185; d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186; e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179; f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180; g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181; h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:

163. i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039. j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

163. L ); k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ; l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162; m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; and GDF-15 n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

2. A composition comprising: A first compound comprising a non-naturally occurring melanocortin analogue, said non-naturally occurring melanocortin analogue comprising the sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe); R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe. R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine; R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It is absent or contains lysine or arginine; R 9 It is absent or contains tryptophan; R 10 It is absent or contains lysine; R 11 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine; X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine. Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-proline or D-valine; Y 5 It is absent or is either D-proline or D-valine; Y 6 It is absent or is either D-proline or D-valine; Y 7 It is absent or is either D-proline or D-valine; Y 8 It is absent or is either D-proline or D-valine; The non-natural melanocortin analogues are optionally partially cyclized from the group consisting of: When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between them; When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 Or R 2 With R 7 Side-chain lactam bridges between them; When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 Side-chain lactam bridges between them; When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 Side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 7 When it is Aia, R 4 dNal(2'); When R 4 p(I)dPhe and the non-naturally occurring melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal; When the aforementioned non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and When the non-natural melanocortin analogue is linear, R 2 It does not not exist, and A second compound comprising the structure according to formula (X) Or its pharmaceutically acceptable salt, wherein: Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a Wherein C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx. B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 atoms independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C) 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form optional groups of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl; Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 Alkyl; and Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N.

3. A composition comprising: A first compound comprising a non-naturally occurring melanocortin analogue, said non-naturally occurring melanocortin analogue comprising the sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) in: R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe); R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe. R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine; R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It is absent or contains lysine or arginine; R 9 It is absent or contains tryptophan; R 10 It is absent or contains lysine; R 11 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine; X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine. Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-proline or D-valine; Y 5 It is absent or is either D-proline or D-valine; Y 6 It is absent or is either D-proline or D-valine; Y 7 It is absent or is either D-proline or D-valine; Y 8 It is absent or is either D-proline or D-valine; The non-natural melanocortin analogues are optionally partially cyclized from the group consisting of: When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between them; When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 Or R 2 With R 7 Side-chain lactam bridges between them; When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 Side-chain lactam bridges between them; When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 Side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 7 When it is Aia, R 4 dNal(2'); When R 4 p(I)dPhe and the non-naturally occurring melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal; When the aforementioned non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and When the non-natural melanocortin analogue is linear, R 2 It does not not exist, and A third compound comprising an antibody or an antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), said antibody or antigen-binding fragment thereof comprising at least one of the following: a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52; b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184; c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185; d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186; e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179; f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180; g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181; h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:

163. i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039. j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

163. L ); k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ; l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162; m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; and n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

4. A composition comprising: A first compound comprising a non-naturally occurring melanocortin analogue, said non-naturally occurring melanocortin analogue comprising the sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) in: R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe); R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe. R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine; R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It is absent or contains lysine or arginine; R 9 It is absent or contains tryptophan; R 10 It is absent or contains lysine; R 11 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine; X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine. Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-proline or D-valine; Y 5 It is absent or is either D-proline or D-valine; Y 6 It is absent or is either D-proline or D-valine; Y 7 It is absent or is either D-proline or D-valine; Y 8 It is absent or is either D-proline or D-valine; The non-natural melanocortin analogues are optionally partially cyclized from the group consisting of: When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between them; When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 Or R 2 With R 7 Side-chain lactam bridges between them; When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 Side-chain lactam bridges between them; When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 Side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 7 When it is Aia, R 4 dNal(2'); When R 4 p(I)dPhe and the non-naturally occurring melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal; When the aforementioned non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and When the non-natural melanocortin analogue is linear, R 2 It does not not exist. A second compound comprising the structure according to formula (X): Or its pharmaceutically acceptable salt, wherein: Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a Wherein C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx. B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 atoms independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form optional groups of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl; Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 alkyl; Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N, and A third compound comprising an antibody or an antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), said antibody or antigen-binding fragment thereof comprising at least one of the following: a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52; b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184; c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185; d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186; e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179; f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180; g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181; h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:

163. i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039. j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

163. L ); k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ; l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162; m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; GDF-15 and n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

5. The composition according to any one of claims 1 to 4, wherein, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of: acyl groups, imine groups, amide groups, urea groups, carbamate groups, sulfonamide groups, and alkylamine groups.

6. The composition according to claim 5, wherein, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an acyl group.

7. The composition according to claim 6, wherein the acyl group is an acetyl group.

8. The composition according to claim 6, wherein the acyl group is a formyl group.

9. The composition according to claim 5, wherein, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an imine group.

10. The composition of claim 5, wherein, if present, the N-terminus of the non-naturally occurring melanocortin analog is modified with an amide group.

11. The composition according to claim 10, wherein the amide group is a pyroglutamyl (pGlu) group.

12. The composition of claim 10, wherein the amide group is derived from fatty acids.

13. The composition according to any one of claims 1 to 4, wherein, if present, the N-terminus of the non-naturally occurring melanocortin analogue is not modified.

14. The composition according to any one of claims 1 to 4, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of amide groups, ester groups, and aldehyde groups.

15. The composition of claim 14, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified with an amide group.

16. The composition according to claim 15, wherein the amide group is a -NH alkylamide group or a -NH arylamide group.

17. The composition according to claim 16, wherein the -NH arylamide group is a p-nitroaniline group or 7-amino-4-methylcoumarin.

18. The composition of claim 14, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified with an ester group.

19. The composition according to any one of claims 1 to 4, wherein the C-terminus of the non-naturally occurring melanocortin analogue is not modified.

20. The composition according to any one of claims 1 to 4, wherein R 1 It does not exist, and R 2 It is D-aspartic acid.

21. The composition according to claim 20, wherein X 1 X 2 and X 3 It does not exist.

22. The composition according to any one of claims 1 to 4, wherein R 4 It is not D-phenylalanine.

23. The composition according to any one of claims 1 to 4, wherein R 4 It is dNal(2').

24. The composition according to any one of claims 1 to 4, wherein Y 3 To Y 8 It does not exist.

25. The composition according to claim 24, wherein: Y 1 It is D-valine and Y 2 It is D-proline; or Y 1 It is D-proline and Y 2 It is D-valine.

26. The composition according to any one of claims 1 to 4, wherein Y 3 Existence and Y 4 To Y 8 It does not exist.

27. The composition according to claim 26, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is D-valine or D-proline; and / or Y 3 It is either D-valine or D-proline.

28. The composition according to claim 26, wherein: Y 1 For D-valine, Y 2 It is D-valine and Y 3 It is D-proline; Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-valine; Y 1 For D-valine, Y 2 It is D-proline and Y 3 It is D-valine; or Y 1 For D-proline, Y 2 It is D-valine and Y 3 It is D-proline.

29. The composition according to any one of claims 1 to 4, wherein Y 3 and Y 4 It exists, and Y 5 To Y 8 It does not exist.

30. The composition according to claim 29, wherein: Y 1 It is either D-valine or D-proline; Y 2 It is either D-valine or D-proline; Y 3 It is D-valine or D-proline; and / or Y 4 It is either D-valine or D-proline.

31. The composition according to claim 29, wherein: Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-proline; Y 1 For D-proline, Y 2 For D-valine, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-valine; Y 1 For D-valine, Y 2 For D-valine, Y 3 It is D-proline and Y 4 It is D-valine; or Y 1 For D-valine, Y 2 For D-proline, Y 3 It is D-valine and Y 4 It is D-proline.

32. The composition according to any one of claims 1 to 4, wherein R 1 R 2 and R 7 Existence and R 8 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 7 Cyclation via lactam bonds.

33. The composition according to claim 32, wherein: R 1 It is acetylated leucine; R 2 It is aspartic acid; R 3 Choose the group consisting of the following: proline, hydroxyproline, and hydroxy-D-proline; R 4 For D-Nal(2'); R 5 It is arginine; R 6 It is either D-tryptophan or L-tryptophan; R 7 It is lysine; Y 1 It is D-valine; and / or Y 2 It is D-proline.

34. The composition according to claim 32, wherein the sequence of formula (I) is: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 306; B07) or Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:307; D3), where c represents the result of passing through R 2 and R 7 Cyclation via lactam bonds.

35. The composition according to any one of claims 1 to 4, wherein R 1 R 2 R 7 and R 8 Existence and R 9 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 8 Cyclation via lactam bonds.

36. The composition according to claim 35, wherein: R 1 It is acetylated leucine; R 2 It is aspartic acid; R 3 Choose the group consisting of the following: proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine; R 4 For histidine or D-Nal(2'); R 5 It is D-Nal(2') or arginine; R 6 Choose the group consisting of the following: arginine, D-tryptophan, and L-tryptophan; R 7 It is tryptophan or proline; R 8 It is lysine; Y 1 Choose the group consisting of: D-valine, D-leucine, and D-isoleucine; and / or Y 2 It is D-proline.

37. The composition according to claim 35, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle- c (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:308;D1); Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO:309;D1γ); Ac-Nle- c (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2(SEQ ID NO:310;D1δ); Ac-Nle- c (Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 311; D2); and Ac-Nle- c (Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO:312; D4), where c represents through R 2 and R 8 Cyclation via lactam bonds.

38. The composition according to any one of claims 1 to 4, wherein R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 2 and R 10 Cyclation via lactam bonds.

39. The composition according to claim 38, wherein the sequence of formula (I) is Ac-Nle- c (Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:313; D1α), where c represents the result of passing through R 2 and R 10 Cyclation via lactam bonds.

40. The composition according to any one of claims 1 to 4, wherein R 1 To R 2 and R 7 To R 10 Existence and R 11 To R 20 It does not exist, and the sequence of equation (I) is passed through R. 4 and R 10 Cyclation via lactam bonds.

41. The composition according to claim 40, wherein the sequence of formula (I) is Ac-Nle-Phe-Phe-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:314; D1β), where c represents R 4 and R 10 Cyclation via lactam bonds.

42. The composition according to claim 19, wherein the sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO:305; B07a), where c represents R 2 and R 7 Cyclation via lactam bonds.

43. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is linear.

44. The composition according to claim 43, wherein the sequence of formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO:315; A1).

45. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-dArg- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:316); Ac-dMet- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:317); Ac-dIle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:318); Ac-dLeu- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:319); Ac-dVal- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:320); Ac-dAla- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:321); Ac-Ala- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:322); Ac-Tle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:323); Ac-dTle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:324); Ac-dNle- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:325); Ac-Nva- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:326); Ac-Gly- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:327); Ac-dPro- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:328); Ac-dCys- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:329); Ac-dPhe- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:330); Ac-dTyr- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:331); Ac-dGln- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:332); and Ac-dAsn- c (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO:333), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

46. ​​The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 341); Ac-Nle-c(Cys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c(dCys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:343); Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:344); Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:345); Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:346); Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:347); Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:348); Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:349); Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:350); Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO:351); Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:352); Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:353); Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO:354); Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO:355); Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO:356); Ac-Nle-c(dPen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 357); Ac-Nle-c(dPen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 359); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 360); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 361); Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 362); and Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO:363), Where c represents through R 2 and R 6 Or R 7 Cycling via lactam bonds or disulfide bonds.

47. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 364); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c(Asp-dPro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 367); Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c(Asp-Pro-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 369); Ac-Nle-c(Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 371); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 373); and Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:374), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

48. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375); Ac-Nle-c(Asp-Pro-dNal(2')-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-Nle-c(Asp-Pro-dNal(2')-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-dNal(2')-dArg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-Nle-c(Asp-Pro-dNal(2')-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c(Asp-Pro-dNal(2')-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 380); Ac-Nle-c(Asp-Pro-dNal(2')-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381); Ac-Nle-c(Asp-Pro-dNal(2')-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c(Asp-Pro-dNal(2')-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383); Ac-Nle-c(Asp-Pro-dNal(2')-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); and Ac-Nle-c(Asp-Pro-dNal(2')-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:385), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

49. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH2 (SEQ ID NO: 386); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Nal(1')-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 388); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO:392), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

50. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:393), wherein c represents the sequence of R. 2 and R 7 Cyclation via lactam bonds.

51. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2(SEQ ID NO:394);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH(SEQ ID NO:395);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-OH(SEQ ID NO:396);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO:397);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH2(SEQ ID NO:398);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO:399);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH2(SEQID NO:400);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO:401);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH2(SEQ ID NO:402);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO:403);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO:404);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO:405);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO:406);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO:407); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH2(SEQ ID NO:408); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH2(SEQ ID NO:409); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO:410); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO:411); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH2(SEQ ID NO:412); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO:413); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO:414); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO:415);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO:416);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO:417);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO:418);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO:419);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH2(SEQ ID NO:420);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH2(SEQ ID NO:421);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ IDNO:422);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO:423);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO:424);Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO:425); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH2(SEQ ID NO:426); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO:427); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO:428); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO:429); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO:430); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO:431); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO:432); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO:433); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO:434); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO:435); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Pro-Val-NH2(SEQ ID NO:436); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-dVal-NH2(SEQ ID NO:437); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO:438); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO:439); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO:440); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO:441); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO:442); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 444); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 445); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 448); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO:449), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

52. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 452); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 453); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO:454), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

53. The composition according to any one of claims 1 to 4, wherein X 1 It exists and is acetylated leucine, and R 1 It exists and is leucine.

54. The composition according to claim 53, wherein X 2 It exists and is leucine.

55. The composition according to claim 53, wherein X 3 It exists and is leucine.

56. The composition according to claim 53, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 455); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 456); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ IDNO:457), Where c represents through R 2 and R 7 Cyclation via lactam bonds.

57. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 458); Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 460); c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-Nle-c(Asp-β-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Nle-c(Asp-Mamb-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Nle-c(Asp-Acpc-dNal(2')Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO:466); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO:467), Where c represents through R 2 and R 7 Or R 8 via lactam cyclization or through R 2 and R 5 Cycling via disulfide bonds.

58. The composition according to any one of claims 1 to 4, wherein the sequence of formula (I) is: Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 468); or Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:469), Where c represents through R 2 and R 7 Or R 8 Cyclation via lactam bonds.

59. The composition according to any one of claims 1 to 4, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NO: 306, 428, 481 to 483, 493 to 495, 528 to 531 and 552 to 555.

60. The composition according to any one of claims 1 to 4, wherein the non-naturally occurring melanocortin analog comprises the sequence of SEQ ID NO:

306.

61. The composition according to any one of claims 1 to 2 and 4 to 60, wherein the second compound is a compound of formula (Xi): Or its pharmaceutically acceptable salt.

62. The composition according to any one of claims 1 to 2 and 4 to 61, wherein the second compound is a compound of formula (Xii): Or its pharmaceutically acceptable salt.

63. The composition according to any one of claims 1 to 2 and 4 to 62, wherein: Rx 1 For Rx 1a And Rx 1a Rx can be optionally selected independently by 1, 2, 3 or 4 A Substituted 6-membered heteroaryl group, where each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 14 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C3-C4 cycloalkyl or (C 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 alkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Or two adjacent Rx A Together with the two ring atoms of the 6-membered heteroaryl group to which they are attached, they form a fused benzene ring or a fused 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 14 Substituents of haloalkoxy groups.

64. The composition according to claim 63, wherein Rx 1a Rx can be optionally selected independently by 1, 2 or 3 A Substituted pyrimidine groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy or C 3-4 Cycloalkyl.

65. The composition according to claim 64, wherein Rx 1a It is pyrimidin-2-yl.

66. The composition according to any one of claims 1 to 2, 4 to 61, and 63 to 65, wherein Xx 1 It is CH2.

67. The composition according to any one of claims 1 to 2 and 4 to 66, wherein Rx 2 and Rx 3 Each of them is independently H, F, or C. 1-4 alkyl.

68. The composition according to any one of claims 1 to 2 and 4 to 67, wherein Rx 2 It is methyl and Rx 3 For H.

69. The composition according to any one of claims 1 to 2 and 4 to 68, wherein Yx 3 Let N be the number of elements, and Yx be the number of elements. 1 Yx 2 Yx 4 and Yx 5 Each of them is independently CRx 4 .

70. The composition according to claim 69, wherein Rx 4 Independent of H, halogen or C 1-2 Alkyl group.

71. The composition according to any one of claims 1 to 2 and 4, wherein the second compound is selected from: (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1; 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1; 2-(6-(difluoromethoxy)pyridin-3-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-2; 1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)-2-(4-(trifluoromethyl)phenyl)prop-1-one, DIAST-1; 1-(4,7-dimethyl-3,4-dihydro-1H-spiro(1,8-naphthid-2,3'-pyrrolidine)-1'-yl)-2-(4-fluorophenyl)ethyl-1-one, DIAST-1; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one; (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, DIAST-1; and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-((4,6- 2 H2)pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl}prop-1-one, Or its pharmaceutically acceptable salt.

72. The composition according to any one of claims 1 to 2 and 4, wherein the second compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one, or a pharmaceutically acceptable salt thereof.

73. The composition according to any one of claims 1 to 2 and 4, wherein the second compound is in the crystalline form of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidin-2,3'-pyrrolidine)-1'-yl)prop-1-one.

74. The composition according to any one of claims 1 to 73, wherein the antibody or its antigen-binding fragment comprises a human Fc domain selected from the group consisting of: IgA1, IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3 or IgG4.

75. The composition according to any one of claims 1 to 74, wherein the antibody or its antigen-binding fragment has a K value of about or less than the value selected from the group consisting of the following. D Combined with human or cynomolgus monkey GDF-15: approximately 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, and 10 pM.

76. The composition according to any one of claims 1 to 75, wherein the antibody or its antigen-binding fragment comprises an anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences, said one or more amino acid sequences being selected from the group consisting of amino acid sequences of the following: SEQ ID NO: 32, 165, 52, 25, 166, 22, 23, 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

77. The composition according to any one of claims 1 to 76, further comprising an anticancer agent.

78. The composition according to claim 77, wherein the anticancer agent is at least one chemotherapeutic agent.

79. The composition of claim 78, wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of platinum coordination complexes, antimetabolites, microtubule binders, alkylated antitumor agents, and cytotoxic antibiotics.

80. The composition according to claim 79, wherein the platinum coordination complex is cisplatin.

81. The composition according to claim 79, wherein the antimetabolite is 5-fluorouracil (5-FU).

82. The composition according to claim 79, wherein the microtubule binding agent is vincristine.

83. The composition according to claim 79, wherein the alkylated antitumor agent is cyclophosphamide.

84. The composition according to claim 79, wherein the cytotoxic antibiotic is doxorubicin.

85. The composition according to any one of claims 1 to 2 and 4, wherein the first compound and the second compound are present in a single pharmaceutical composition.

86. The composition according to any one of claims 1 and 3 to 4, wherein the first compound and the third compound are present in a single pharmaceutical composition.

87. The composition according to claim 1 or 4, wherein, if present, the first compound, the second compound, and the third compound are present in a single pharmaceutical composition.

88. The composition according to any one of claims 85 to 87, wherein the single pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intraventricular or oral administration.

89. The composition according to any one of claims 85 to 87, wherein the single pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

90. The composition according to any one of claims 85 to 89, wherein the first compound is present in the single pharmaceutical composition at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the single pharmaceutical composition.

91. The composition according to any one of claims 1 to 2 and 4, wherein: The first compound is present in the first pharmaceutical composition; and The second compound is present in the second pharmaceutical composition.

92. The composition according to any one of claims 1 and 3 to 4, wherein: The first compound is present in the first pharmaceutical composition; and The third compound is present in the third pharmaceutical composition.

93. The composition according to claim 1 or 4, wherein: The first compound is present in the first pharmaceutical composition; The second compound is present in the second pharmaceutical composition; and The third compound is present in the third pharmaceutical composition.

94. The composition according to any one of claims 91 to 93, wherein the first pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intraventricular or oral administration.

95. The composition according to any one of claims 91 to 94, wherein the first pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

96. The composition according to any one of claims 91 to 95, wherein the first compound is present in the first pharmaceutical composition at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the first pharmaceutical composition.

97. A composition comprising: The first compound with primary therapeutic effects; and Second and / or third compounds, each possessing secondary therapeutic effects, The first compound is a non-natural melanocortin analogue, the second compound is a spirocyclic compound, and the third compound is an antibody or its antigen-binding fragment.

98. The composition of claim 97, wherein the non-naturally occurring melanocortin analogue is a melanocortin 3 receptor (MC3R) agonist and a melanocortin 4 receptor (MC4R) agonist.

99. The composition according to claim 97 or 98, wherein the primary therapeutic effect occurs after activation of the MC3R and / or the MC4R.

100. The composition according to any one of claims 97 to 99, wherein the non-naturally occurring melanocortin analog comprises the sequence according to formula (I), X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) in: R 1 The group consisting of the following items is absent or selected: cysteine, leucine (Nle), acetylated leucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, valine (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertiary leucine (Tle), acetylated D-tertiary leucine (dTle), acetylated valine (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R 2 The following groups are not present or are selected: proline, aspartic acid, D-aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, leucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3 The group consisting of the following is absent or selected: histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D-methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzo[a] Azazo-3-one (Aba), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetrahydronaphthalene-2-carboxylic acid (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindanone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentanecarboxylic acid (Cpe); R 4 Choose the group consisting of the following: histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, p-chloro-D-phenylalanine (p(Cl)dPhe), p-bromo-D-phenylalanine (p(Br)dPhe), and p-iodo-D-phenylalanine (p(I)dPhe); R 5 The following groups are not present or are selected: arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe. R 6 The group consisting of the following items is absent or selected: L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, Nal(1'), Aia, phenylalanine, tyrosine, Pen, dPen and alanine; R 7 The following groups are not present or are selected: aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2'), ornithine, Pen, dPen and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R 8 It is absent or contains lysine or arginine; R 9 It is absent or contains tryptophan; R 10 It is absent or contains lysine; R 11 To R 20 It does not exist; X 1 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, n-valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated n-leucine; X 2 The group consisting of the following is absent or selected: D-threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; X 3 The group consisting of the following is absent or selected: D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, valine, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and leucine; Y 1 The group consisting of the following items is absent or selected: D-alanine, L-alanine, D-valine, L-valine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y 2 The group consisting of the following items is absent or selected: D-proline, L-proline, D-valine, L-valine, L-tert-leucine, ortholeucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine. Y 3 The group consisting of the following is absent or selected: D-proline, L-proline, D-valine, and L-valine; Y 4 It is absent or is either D-proline or D-valine; Y 5 It is absent or is either D-proline or D-valine; Y 6 It is absent or is either D-proline or D-valine; Y 7 It is absent or is either D-proline or D-valine; Y 8 It is absent or is either D-proline or D-valine; The non-natural melanocortin analogues are optionally partially cyclized from the group consisting of: When R 1 Or R 2 For cysteine ​​and R 7 or X 1 When it is cysteine, R 1 Or R 2 With R 7 or X 1 disulfide bonds between them; When R 2 and R 5 To R 20 When any one of the components is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 With R 5 To R 20 Disulfide bonds between any of them; When R 1 It is leucine and R 7 When it is glutamic acid, R 1 With R 7 The lactam bridge between them; When R 1 Or R 2 It is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO and R 7 When it is lysine or ornithine, R 1 Or R 2 With R 7 Side-chain lactam bridges between them; When R 1 Or R 2 It is either glutamic acid or aspartic acid, R 8 For lysine and R 7 When it is proline, glycine, or tryptophan, R 1 Or R 2 With R 8 Side-chain lactam bridges between them; When R 2 It is glutamic acid or aspartic acid and R 10 When it is lysine, R 2 Or R 4 With R 10 Side-chain lactam bridges between them; The conditions are: When R 2 When it is dAsp, then R 7 Not for dLys; When R 2 To R 4 When R is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then 5 To R 7 Not Arg-Trp-Lys; and When Y 1 For dPro, Y 2 For dVal and Y 3 To Y 8 If it does not exist, then R 4 Not dNal(2') or R 4 It is dNal(2') and the C-terminus is not modified; When R 7 When it is Aia, R 4 dNal(2'); When R 4 p(I)dPhe and the non-naturally occurring melanocortin analogue via R 1 With R 7 When the lactam bond between them is cyclized, then R 2 For His; When R 2 To R 7 When it is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 To Y 2 Not dPro-dVal; When the aforementioned non-natural melanocortin analogue is administered via R 2 With R 8 Cyclication of the lactam bond between and R 3 When it is Pro, then R 7 Not for Pro and Y 1 Not for dPro; and When the non-natural melanocortin analogue is linear, R 2 It does not not exist.

101. The composition of claim 100, wherein the non-naturally occurring melanocortin analog comprises the sequence of SEQ ID NO:

306.

102. The composition according to any one of claims 97 to 101, wherein the spirocyclic compound is an MC4R antagonist.

103. The composition according to any one of claims 97 to 102, wherein the secondary therapeutic effect occurs after the MC4R antagonism.

104. The composition according to any one of claims 97 to 103, wherein the spirocyclic compound comprises a structure according to formula (X). Or its pharmaceutically acceptable salt, wherein: Rx 1 H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl or Rx 1a Wherein C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl groups is optionally represented by 1, 2, 3, or 4 independently selected C groups. 1-4 Alkyl substitution, wherein the phenyl group is optionally substituted with 1, 2, 3 or 4 independently selected Rx. B Replace, where Rx B Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl or Rx B1 ; or two adjacent Rx B Together with the two cyclic atoms of the phenyl group to which they are attached, they form fused 5- or 6-membered heteroaryl groups, each of which is optionally surrounded by 1, 2, or 3 atoms independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 1a To be optionally controlled by 1, 2, 3 or 4 independent Rx A Substituted 5- or 6-membered heteroaryl groups, wherein each Rx A Halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, -N(C) 1-4 Alkyl)2, Rx A1 or (C) 3-4 cycloalkyl)-C 14 alkyl-, wherein the C 14 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups; or two adjacent Rx groups. A Together with the two cyclic atoms of the 5- or 6-membered heteroaryl groups to which they are attached, they form fused benzene rings or fused 5- or 6-membered heteroaryl groups or fused 5- or 6-membered heterocyclic alkyl groups or fused 5- or 6-membered cycloalkyl groups, wherein each is optionally composed of 1, 2 or 3 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx A1 It is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl group, wherein each is optionally surrounded by 1, 2 or 3 independently selected from halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx B1 It is a 5- or 6-membered heteroaryl group, wherein each is optionally surrounded by 1, 2, or 3 independently selected from halogen, -OH, -CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Rx 2 and Rx 3 Each of them is independently H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 Alkyl, wherein C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally composed of 1, 2, 3, 4, or 5 independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substituents of haloalkoxy groups; Or Rx 2 and Rx 3 Together with the carbon atoms to which they are attached, they form optional groups of 1, 2, 3, 4, or 5 atoms, each independently selected from halogens, -OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 The C-substituent of the halogenated alkoxy group 3-6 cycloalkyl; Each Rx 4 Independently, it can be H, halogen, -OH, -CN, or C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -N(C) 1-2 Alkyl)2, C 3-4 cycloalkyl or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein the C 1-4 Alkyl, C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 Each of the alkyl groups is optionally selected by 1, 2, 3, 4 or 5 independently selected from halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Substitution of haloalkoxy groups Xx 1 For C(Rx) X )2, where each Rx X Independently H or C 1-4 alkyl; Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 Each of them is independently CR 4 Or N, the condition is Yx 1 Yx 2 Yx 3 Yx 4 and Yx 5 No more than 3 of them are N.

105. The composition according to claim 104, wherein the spirocyclic compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthidine-2,3'-pyrrolidine)-1'-yl)prop-1-one, or a pharmaceutically acceptable salt thereof.

106. The composition according to any one of claims 97 to 105, wherein the antibody or its antigen-binding fragment specifically binds to a portion of human growth differentiation factor 15 (GDF-15).

107. The composition according to any one of claims 97 to 106, wherein the antibody or its antigen-binding fragment binds to GDF-15, thereby preventing GDF-15 from binding to glial cell-derived neurotrophic factor family receptor α-like (GFRAL) receptors.

108. The composition according to any one of claims 97 to 107, wherein the antibody or its antigen-binding fragment comprises at least one of the following: a) Light chain complementarity-determining region 1 (LCDR-1) containing the amino acid sequence of SEQ ID NO:95, LCDR-2 containing the amino acid sequence of SEQ ID NO:28, LCDR-3 containing the amino acid sequence of SEQ ID NO:9, heavy chain complementarity-determining region 1 (HCDR-1) containing the amino acid sequence of SEQ ID NO:32, HCDR-2 containing the amino acid sequence of SEQ ID NO:165, and HCDR-3 containing the amino acid sequence of SEQ ID NO:52; b) Select the LCDR-1 amino acid sequence from the group consisting of sequences of SEQ ID NO: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174 and 184; c) Select the LCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175 and 185; d) Select the LCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 9, 29, 38, 48, 63, 76, 89, 102, 176 and 186; e) Select the HCDR-1 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171 and 179; f) Select the HCDR-2 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172 and 180; g) Select the HCDR-3 amino acid sequence from the group consisting of the sequences of SEQ ID NO: 1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173 and 181; h) The amino acid sequences of HCDR-1, HCDR-2 and HCDR-3 as shown in the amino acid sequence of SEQ ID NO:166 and the amino acid sequences of LCDR-1, LCDR-2 and LCDR-3 as shown in the amino acid sequence of SEQ ID NO:

163. i) The amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125038 and the amino acid sequence encoded by the insert of the plasmid deposited at ATCC with ATCC accession number PTA-125039. j) A heavy chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

166. H ) and a light chain variable domain (V) containing at least 90% of the same amino acid sequence as SEQ ID NO:

163. L ); k) V containing the amino acid sequence of SEQ ID NO:166 H and V containing the amino acid sequence of SEQ ID NO:163 L ; l) a heavy chain (HC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:164 and a light chain (LC) containing at least 90% of the same amino acid sequence as the sequence of SEQ ID NO:162; m) HC containing the amino acid sequence of SEQ ID NO:164 and LC containing the amino acid sequence of SEQ ID NO:162; GDF-15; and n) competes with at least one antibody from (a) to (m) above for binding to GDF-15.

109. The composition of claim 108, wherein the antibody or antigen-binding fragment thereof comprises an anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences, said one or more amino acid sequences being selected from the group consisting of amino acid sequences of the following: SEQ ID NO: 32, 165, 52, 25, 166, 22, 23, 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10 and 162.

110. The composition according to any one of claims 97 to 109, wherein the secondary therapeutic effect is a supportive therapeutic effect compared to the primary therapeutic effect.

111. The composition according to any one of claims 97 to 110, wherein the composition comprises a lower dose unit of the second compound and / or the third compound compared to a dose unit of the second compound and / or the third compound in the absence of the first compound.

112. The composition according to any one of claims 97 to 111, wherein the composition comprises a lower dose of the second compound and / or the third compound compared to a dose of the second compound in the absence of the first compound and / or a dose of the third compound.

113. The composition according to any one of claims 97 to 112, wherein the composition comprises a shorter dose of the second compound and / or the third compound compared to a dose regimen of the second compound and / or the third compound in which the first compound is absent.

114. The composition according to any one of claims 97 to 113, wherein the composition comprises a smaller dose of the second compound and / or the third compound compared to a dose of the second compound in the absence of the first compound and / or a dose of the third compound.

115. The composition according to any one of claims 97 to 114, wherein the composition has an improved net effect on MC4R compared to the effect of the second compound on MC4R in the absence of the first compound and / or the effect of the third compound on MC4R.

116. A method for increasing the appetite of a subject in need relative to a control, the method comprising: The composition according to any one of claims 1 to 115 is administered to the subject.

117. The method of claim 116, wherein, compared with the control, the subject experiences an increase in appetite, as measured by an increase in food intake of approximately 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, or 3000.

118. The method of claim 116, wherein the subject does not follow a high-carbohydrate, high-calorie (HCHC) diet.

119. The method of claim 118, wherein the HCHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from carbohydrates.

120. The method according to any one of claims 116 to 119, wherein the subject does not follow a high-fat, high-calorie (HFHC) diet.

121. The method of claim 120, wherein the HFHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from fat.

122. The method according to any one of claims 116 to 121, wherein the first compound, the second compound, and the third compound are applied simultaneously as a single composition.

123. The method according to any one of claims 116 to 122, wherein: The first compound is present in the first pharmaceutical composition; If present, the second compound is present in the second pharmaceutical composition; and If present, the third compound is present in the third pharmaceutical composition.

124. The method of claim 123, wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and are administered simultaneously but separately.

125. The method of claim 123, wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and administered sequentially.

126. The method of claim 125, wherein the first pharmaceutical composition is administered prior to the initial administration of the second pharmaceutical composition.

127. The method of claim 125, wherein the first pharmaceutical composition is administered prior to the initial administration of the third pharmaceutical composition.

128. The method of claim 125, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially over about 24 hours.

129. The method of claim 128, wherein the first pharmaceutical composition is administered in the morning and the second pharmaceutical composition is administered at night.

130. The method of claim 125, wherein the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially over about 24 hours.

131. The method of claim 130, wherein the first pharmaceutical composition is administered in the morning and the third pharmaceutical composition is administered at night.

132. The method according to any one of claims 116 to 131, wherein the first compound comprises the sequence of SEQ ID NO:

306.

133. The method according to any one of claims 116 to 132, wherein the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

134. The method according to any one of claims 116 to 133, wherein the first compound is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the weight of the subject.

135. The method according to any one of claims 116 to 134, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10% to 75% lower than the therapeutically effective amount of the second compound when administered alone.

136. The method according to any one of claims 116 to 135, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25% to 50% lower than the therapeutically effective amount of the second compound when administered alone.

137. The method according to any one of claims 116 to 136, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10% to 75% lower than the therapeutically effective amount of the third compound when administered alone.

138. The method according to any one of claims 116 to 137, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25% to 50% lower than the therapeutically effective amount of the third compound when administered alone.

139. The method according to any one of claims 116 to 138, wherein the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

140. The method according to any one of claims 116 to 138, wherein the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

141. The method according to any one of claims 116 to 140, wherein the subject experienced loss of appetite, reduced food consumption, and / or weight loss prior to the administration.

142. The method of claim 141, wherein the loss of appetite, reduced food consumption, and / or weight loss are caused by cachexia.

143. The method of claim 141 or 142, wherein the weight loss is a loss of muscle mass, a loss of fat mass, or both.

144. The method according to any one of claims 116 to 143, wherein the method (i) stimulates the appetite of the subject; (ii) increases the food consumption of the subject; (iii) prevents or alleviates nausea, vomiting and / or anorexia of the subject; (iv) increases or maintains the weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains the muscle mass of the subject; (vii) prevents or reduces muscle mass loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

145. A method for treating cancer in a subject of need, the method comprising: The composition according to any one of claims 77 to 96 is administered to the subject.

146. The method of claim 145, wherein, compared with a control, the subject experienced a tumor size reduction of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

147. The method of claim 145, wherein, compared with a control, the subject experienced a reduction in cancer metastasis, as measured by a reduction in cancer cell proliferation of approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

148. A method for treating a subject suffering from cancer, the method comprising: The subject is given the composition according to any one of claims 77 to 96. in: The method reduces or prevents side effects associated with the anticancer agent in combination therapy, wherein the side effects are at least one of the following selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass, and loss of muscle mass.

149. A method for improving the survival of a subject suffering from cancer, the method comprising: The subject is given the composition according to any one of claims 77 to 96. in: The method reduces or prevents side effects associated with the anticancer agent in combination therapy, thereby improving the survival of the subject, wherein the side effects are at least one of the following selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass, and loss of muscle mass.

150. A method for increasing the weight of a subject compared with a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

151. The method of claim 150, wherein, compared with the control, the subject experienced a weight gain of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500%.

152. A method for increasing muscle mass in a subject compared to a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

153. The method of claim 152, wherein, compared with the control, the subject experienced an increase in muscle mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

154. A method for increasing the fat mass of a subject compared with a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

155. The method of claim 154, wherein, compared with the control, the subject experienced an increase in fat mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

156. A method for increasing the heart mass of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

157. The method of claim 156, wherein, compared with the control, the subject experienced an increase in heart mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

158. A method for increasing bone mineral density in a subject compared to a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

159. The method of claim 158, wherein, compared with the control, the subject experienced an increase in bone mineral density of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

160. A method for reducing fatigue in a subject compared to a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

161. A method for reducing vomiting in a subject compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

162. A method for reducing diarrhea in a subject compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

163. A method for increasing the cumulative mass of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

164. The method of claim 163, wherein, compared with the control, the subject experiences a cumulative mass increase of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

165. A method for increasing the net weight gain of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

166. The method of claim 165, wherein, compared with the control, the subject experienced an increase in net weight gain of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

167. A method for reducing the rate of cumulative mass loss in a subject compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

168. The method of claim 167, wherein, compared with the control, the subject experiences a reduction in the rate of cumulative mass loss of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

169. A method for increasing the cumulative food intake of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

170. The method of claim 169, wherein, compared with the control, the subject experienced a cumulative increase in food intake of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

171. A method for increasing the body mass index (BMI) of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

172. The method of claim 171, wherein, compared with the control, the subject experienced a BMI increase of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.

173. A method for reducing the level of pro-inflammatory transcripts or proteins in a subject compared with a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

174. The method of claim 173, wherein, compared with the control, the subject experiences a reduction of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% in inflammatory transcript or protein levels.

175. The method of claim 173 or 174, wherein the pro-inflammatory transcript is selected from the group consisting of: IL1b transcript, IL1R1 transcript, IL6 transcript, CCL2 transcript, and GDF-15 transcript.

176. The method of claim 173 or 174, wherein the pro-inflammatory protein is selected from the group consisting of: IL1b protein, IL1R1 protein, IL6 protein, CCL2 protein, and GDF-15 protein.

177. A method for increasing the treatment function assessment of anorexia / cachexia (FAACT) score of a subject compared with a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

178. The method of claim 177, wherein the subject experiences an increase of at least 1, 2, 3, 4, or 5 points in FAACT score compared to the control.

179. A method for increasing the persistence of BMI in a subject compared with a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

180. The method of claim 179, wherein, compared with the control, the subject experienced a sustained increase in BMI of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

181. The method according to any one of claims 150 to 180, wherein the subject has cancer.

182. A method for reducing or maintaining the Eastern Cooperative Oncology Group (ECOG) performance status score of a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

183. The method of claim 182, wherein the subject experienced a reduction of approximately 1, 2, or 3 in ECOG score compared to the control.

184. A method for increasing or maintaining the Karnofsky Performance Status (KPS) score of a subject with cancer compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

185. The method of claim 184, wherein the subject experiences an increase in KPS score of about 100, 90, 80, 70, 60, 50, 40 or 30 compared to the control.

186. A method for increasing the overall survival (OS) of a subject with cancer compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

187. The method of claim 186, wherein the subject experiences an increase in OS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

188. A method for increasing progression-free survival (PFS) in a subject with cancer compared to a control, the method comprising administering to the subject the composition according to any one of claims 1 to 115.

189. The method of claim 188, wherein the subject experiences an increase in PFS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

190. A method for reducing the time to cancer treatment failure in a subject with cancer compared to a control, the method comprising administering to the subject a composition according to any one of claims 1 to 115.

191. The method of claim 190, wherein, compared with a control, the subject experiences a reduction in cancer treatment failure time of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

192. The method according to any one of claims 116 to 191, wherein the control comprises a subject at baseline or a second subject who has not received the composition according to any one of claims 1 to 115.

193. The method of claim 148 or 149, wherein the subject does not follow a high-carbohydrate, high-calorie (HCHC) diet.

194. The method of claim 193, wherein the HCHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from carbohydrates.

195. The method according to any one of claims 148 to 194, wherein the subject does not follow a high-fat, high-calorie (HFHC) diet.

196. The method of claim 195, wherein the HFHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from fat.

197. The method according to any one of claims 148 to 196, wherein the first compound, the second compound, the third compound, and the anticancer agent are administered simultaneously as a single composition.

198. The method according to any one of claims 148 to 197, wherein: The first compound is present in the first pharmaceutical composition; If present, the second compound is present in the second pharmaceutical composition; If present, the third compound is present in the third pharmaceutical composition; and The anticancer agent is present in the fourth pharmaceutical composition.

199. The method of claim 198, wherein the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition are different and are administered simultaneously but separately.

200. The method of claim 198, wherein the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition are different and administered sequentially.

201. The method of claim 198, wherein the first pharmaceutical composition is administered prior to the initial administration of the second pharmaceutical composition.

202. The method of claim 198, wherein the first pharmaceutical composition is administered prior to the initial administration of the third pharmaceutical composition.

203. The method of claim 198, wherein the first pharmaceutical composition is administered prior to the initial administration of the fourth pharmaceutical composition.

204. The method of claim 200, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially over about 24 hours.

205. The method of claim 204, wherein the first pharmaceutical composition is administered in the morning and the second pharmaceutical composition is administered at night.

206. The method of claim 200, wherein the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially over about 24 hours.

207. The method of claim 206, wherein the first pharmaceutical composition is administered in the morning and the third pharmaceutical composition is administered at night.

208. The method according to any one of claims 148 to 207, wherein the first compound comprises the sequence of SEQ ID NO:

306.

209. The method according to any one of claims 148 to 208, wherein the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

210. The method according to any one of claims 148 to 209, wherein the first compound is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the weight of the subject.

211. The method according to any one of claims 148 to 210, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10% to 75% lower than the therapeutically effective amount of the second compound when administered alone.

212. The method according to any one of claims 148 to 211, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25% to 50% lower than the therapeutically effective amount of the second compound when administered alone.

213. The method according to any one of claims 148 to 212, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10% to 75% lower than the therapeutically effective amount of the third compound when administered alone.

214. The method according to any one of claims 148 to 213, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25% to 50% lower than the therapeutically effective amount of the third compound when administered alone.

215. The method according to any one of claims 148 to 214, wherein the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

216. The method according to any one of claims 148 to 214, wherein the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

217. The method according to any one of claims 148 to 216, wherein the subject is a human being.

218. The method according to any one of claims 148 to 216, wherein the subject is an animal.

219. The method according to any one of claims 148 to 218, which does not reduce the efficacy of the anticancer agent.

220. The method according to any one of claims 148 to 219 or 181 to 191, wherein the cancer is at least one selected from the group consisting of: bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary gland cancer, liver cancer, gastric cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

221. The method according to any one of claims 148 to 220, wherein the cancer is at least one selected from the group consisting of: bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

222. The method according to any one of claims 148 to 221, wherein the subject suffering from cancer has previously undergone treatment with the anticancer agent.

223. The method of claim 222, wherein the subject has previously experienced one or more adverse side effects while being treated with the anticancer agent, wherein the adverse side effects are selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass, and loss of muscle mass.

224. The method according to any one of claims 148 to 223, wherein the one or more anticancer agents are administered at a higher amount when present in a composition comprising the first compound and the third compound compared to a composition comprising the one or more anticancer agents and the first compound or the one or more anticancer agents and the third compound.

225. The method of claim 224, wherein administering the one or more anticancer agents at a higher dose comprises increasing the dose amount, administering the dose more frequently, prolonging the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

226. The method according to any one of claims 148 to 225, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at at least about 6 mg / mL, 7 mg / mL or 8 mg / mL, compared to about 2 mg / mL or about 3 mg / mL of the first compound or the third compound.

227. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

228. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

229. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

230. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

231. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

232. The method of claim 226, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

233. The method according to any one of claims 226 to 232, wherein the one or more anticancer agents comprise cisplatin.

234. The method according to any one of claims 148 to 233, wherein the method reduces or prevents one or more side effects of the subject, and further comprises administering the one or more anticancer agents at a higher amount, thereby increasing the efficacy of the one or more anticancer agents in the subject.

235. The method according to any one of claims 148 to 234, wherein the method increases the efficacy of the anticancer agent.

236. Use of the composition according to any one of claims 1 to 115 for increasing the appetite of a subject in need.

237. The use according to claim 236, wherein the increase in appetite comprises an increase in food intake of about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000 or more calories compared to a control.

238. Use of the composition according to any one of claims 1 to 115 for treating a subject with cancer in comparison with a control.

239. The use according to claim 238, wherein, compared with the control, the subject experienced a tumor size reduction of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

240. The use according to claim 238, wherein, compared with a control, the subject experienced a reduction in cancer metastasis, as measured by a reduction in cancer cell proliferation of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.

241. Use of the composition according to any one of claims 1 to 115 for increasing the survival of subjects with cancer compared with a control.

242. Use of the composition according to any one of claims 1 to 115 for increasing the weight of a subject compared with a control.

243. The use according to claim 242, wherein, compared with the control, the subject experienced a weight gain of approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500%.

244. Use of the composition according to any one of claims 1 to 115 for increasing muscle mass in a subject compared with a control.

245. The use according to claim 244, wherein, compared with the control, the subject experienced an increase in muscle mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

246. Use of the composition according to any one of claims 1 to 115 for increasing the fat mass of a subject compared with a control.

247. The use according to claim 246, wherein, compared with the control, the subject experienced an increase in fat mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

248. Use of the composition according to any one of claims 1 to 115 for increasing the heart mass of a subject compared with a control.

249. The use according to claim 248, wherein, compared with the control, the subject experienced an increase in heart mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

250. Use of the composition according to any one of claims 1 to 115 for increasing bone mineral density in a subject compared with a control.

251. The use according to claim 250, wherein, compared with the control, the subject experienced an increase in bone mineral density of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

252. Use of the composition according to any one of claims 1 to 115 for reducing fatigue in subjects compared with a control.

253. Use of the composition according to any one of claims 1 to 115 for reducing vomiting in subjects compared with a control.

254. Use of the composition according to any one of claims 1 to 115 for reducing diarrhea in a subject compared with a control.

255. Use of the composition according to any one of claims 1 to 115 for increasing the cumulative mass of a subject compared with a control.

256. The use according to claim 255, wherein, compared with the control, the subject experiences a cumulative mass increase of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

257. The use of the composition according to any one of claims 1 to 115 for increasing the net weight gain of a subject compared with a control.

258. The use according to claim 257, wherein the subject experiences an increase in net weight gain of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

259. Use of the composition according to any one of claims 1 to 115 for reducing the rate of cumulative mass loss in a subject compared with a control.

260. The use according to claim 259, wherein, compared with the control, the subject experiences a reduction in the rate of loss of the cumulative mass of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

261. Use of the composition according to any one of claims 1 to 115 for increasing the cumulative food intake of a subject compared with a control.

262. The use according to claim 261, wherein, compared with the control, the subject experienced a cumulative increase in food intake of at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

263. Use of the composition according to any one of claims 1 to 115 for increasing the BMI of a subject compared with a control.

264. The use according to claim 263, wherein, compared with the control, the subject experienced a BMI increase of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.

265. The use of the composition according to any one of claims 1 to 115 for reducing the level of pro-inflammatory transcripts or proteins in a subject compared with a control.

266. The use according to claim 265, wherein, compared with the control, the subject experiences a reduction of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% in inflammatory transcript or protein levels.

267. The use according to claim 265 or 266, wherein the pro-inflammatory transcript is selected from the group consisting of: IL1b transcript, IL1R1 transcript, IL6 transcript, CCL2 transcript and GDF-15 transcript.

268. The use according to claim 265 or 266, wherein the pro-inflammatory protein is selected from the group consisting of: IL1b protein, IL1R1 protein, IL6 protein, CCL2 protein and GDF-15 protein.

269. Use of the composition according to any one of claims 1 to 115 for increasing the FAACT score of a subject compared with a control.

270. The use according to claim 269, wherein the subject experiences an increase of at least 1, 2, 3, 4 or 5 points in FAACT score compared to the control.

271. The use of the composition according to any one of claims 1 to 115 for increasing the persistence of BMI in a subject compared with a control.

272. The use according to claim 271, wherein, compared with the control, the subject experienced a sustained increase in BMI of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

273. The use according to any one of claims 242 to 272, wherein the subject has cancer.

274. Use of the composition according to any one of claims 1 to 115 for reducing or maintaining the ECOG performance status score of a subject with cancer compared with a control.

275. The use according to claim 274, wherein the subject experienced a reduction of approximately 1, 2, or 3 in ECOG score compared to the control.

276. Use of the composition according to any one of claims 1 to 115 for increasing or maintaining the KPS score of a subject with cancer compared with a control.

277. The use according to claim 276, wherein the subject experienced an increase in KPS score of about 100, 90, 80, 70, 60, 50, 40 or 30 compared to the control.

278. Use of the composition according to any one of claims 1 to 115 for increasing the overall survival (OS) of subjects with cancer compared to a control.

279. The use according to claim 278, wherein the subject experiences an increase in OS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

280. Use of the composition according to any one of claims 1 to 115 for increasing PFS in subjects with cancer compared to a control.

281. The use according to claim 280, wherein the subject experiences an increase in PFS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

282. Use of the composition according to any one of claims 1 to 115 for reducing the time of cancer treatment failure in subjects with cancer compared with a control.

283. The use according to claim 282, wherein, compared with a control, the subject experiences a reduction in cancer treatment failure time of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

284. The use according to any one of claims 236 to 283, wherein the control comprises a subject at baseline or a second subject who has not received the composition according to any one of claims 1 to 115.

285. The use according to any one of claims 236 to 241, wherein the subject does not follow a high-carbohydrate, high-calorie (HCHC) diet.

286. The use according to any one of claims 236 to 285, wherein the HCHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from carbohydrates.

287. The use according to any one of claims 236 to 286, wherein the subject does not follow a high-fat, high-calorie (HFHC) diet.

288. The use according to claim 287, wherein the HFHC diet comprises a daily food intake providing at least 2000 kcal of energy, and at least 50% of the energy is derived from fat.

289. The use according to any one of claims 236 to 288, wherein the first compound, the second compound, and the third compound are applied simultaneously as a single composition.

290. The use according to any one of claims 236 to 289, wherein: The first compound is present in the first pharmaceutical composition; If present, the second compound is present in the second pharmaceutical composition; and If present, the third compound is present in the third pharmaceutical composition.

291. The use according to claim 290, wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and are administered simultaneously but separately.

292. The use according to claim 290, wherein the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition are different and are administered sequentially.

293. The use according to claim 292, wherein the first pharmaceutical composition is administered prior to the initial administration of the second pharmaceutical composition.

294. The use according to claim 292, wherein the first pharmaceutical composition is administered prior to the initial administration of the third pharmaceutical composition.

295. The use according to claim 292, wherein the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially over about 24 hours.

296. The use according to claim 295, wherein the first pharmaceutical composition is administered in the morning and the second pharmaceutical composition is administered at night.

297. The use according to claim 292, wherein the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially over about 24 hours.

298. The use according to claim 297, wherein the first pharmaceutical composition is administered in the morning and the third pharmaceutical composition is administered in the evening.

299. The use according to any one of claims 236 to 298, wherein the first compound comprises the sequence of SEQ ID NO:

306.

300. The use according to any one of claims 236 to 299, wherein the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg, depending on the weight of the subject.

301. The use according to any one of claims 236 to 300, wherein the first compound is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg, depending on the weight of the subject.

302. The use according to any one of claims 236 to 301, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10% to 75% lower than the therapeutically effective amount of the second compound when administered alone.

303. The use according to any one of claims 236 to 302, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25% to 50% lower than the therapeutically effective amount of the second compound when administered alone.

304. The use according to any one of claims 236 to 303, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10% to 75% lower than the therapeutically effective amount of the third compound when administered alone.

305. The use according to any one of claims 236 to 304, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25% to 50% lower than the therapeutically effective amount of the third compound when administered alone.

306. The use according to any one of claims 236 to 305, wherein the composition is applied to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year or 5 years.

307. The use according to any one of claims 236 to 306, wherein the composition is applied to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days or 120 days.

308. The use according to any one of claims 236 to 307, wherein the subject experienced loss of appetite, reduced food consumption, and / or weight loss prior to the administration.

309. The use according to claim 308, wherein the loss of appetite, reduced food consumption, and / or weight loss are caused by cachexia.

310. The use according to claim 308 or 309, wherein the weight loss is a loss of muscle mass, a loss of fat mass, or both.

311. The use according to any one of claims 236 to 310, wherein the use (i) stimulates the appetite of the subject; (ii) increases the food consumption of the subject; (iii) prevents or alleviates nausea, vomiting and / or anorexia of the subject; (iv) increases or maintains the weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains the muscle mass of the subject; (vii) prevents or reduces muscle mass loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

312. The use according to any one of claims 236 to 311, wherein the use reduces or prevents side effects associated with the anticancer agent in combination therapy, wherein the side effects are at least one of the group consisting of cachexia, anorexia, weight loss, loss of fat mass and loss of muscle mass.

313. The use according to any one of claims 236 to 312, wherein the use reduces or prevents side effects associated with the anticancer agent in combination therapy, thereby improving the survival of the subject, wherein the side effects are at least one selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass and loss of muscle mass.

314. The use according to any one of claims 236 to 313, wherein the subject is a human being.

315. The use according to any one of claims 236 to 314, wherein the subject is an animal.

316. The use according to any one of claims 236 to 315, without reducing the efficacy of the anticancer agent.

317. The use according to any one of claims 236 to 316, wherein the cancer is at least one selected from the group consisting of: bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary gland cancer, liver cancer, gastric cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

318. The use according to any one of claims 236 to 317, wherein the cancer is at least one selected from the group consisting of: bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

319. The use according to any one of claims 236 to 318, wherein the subject suffering from cancer has previously undergone treatment with the anticancer agent.

320. The use according to claim 319, wherein the subject has previously experienced one or more adverse side effects while being treated with the anticancer agent, wherein the adverse side effects are selected from the group consisting of cachexia, anorexia, weight loss, loss of fat mass and loss of muscle mass.

321. The use according to any one of claims 236 to 320, wherein the one or more anticancer agents are administered in a higher amount when present in a composition comprising the first compound and the third compound compared to a composition comprising the one or more anticancer agents and the first compound or the one or more anticancer agents and the third compound.

322. The use according to claim 321, wherein administering the one or more anticancer agents at a higher dose comprises increasing the dose amount, administering the dose more frequently, prolonging the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

323. The use according to any one of claims 236 to 322, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at at least about 6 mg / mL, 7 mg / mL or 8 mg / mL, compared to about 2 mg / mL or about 3 mg / mL of the first compound or the third compound.

324. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

325. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

326. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 2 mg / mL of the first compound or the third compound.

327. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 6 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

328. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 7 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

329. The use according to claim 323, wherein the combination of the one or more anticancer agents with the first compound and the third compound is administered at a rate of at least about 8 mg / mL, compared to about 3 mg / mL of the first compound or the third compound.

330. The use according to any one of claims 236 to 329, wherein the one or more anticancer agents comprise cisplatin.

331. The use according to any one of claims 236 to 330, wherein the use reduces or prevents one or more side effects of the subject, and further comprises administering the one or more anticancer agents at a higher amount, thereby increasing the efficacy of the one or more anticancer agents in the subject.

332. The use according to any one of claims 236 to 331, wherein the use increases the efficacy of the anticancer agent.

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