Compounds used as apelin receptor antagonists

Abstract

The present invention relates to synthetic polypeptide compounds that bind to apelin receptors, which are class A G protein-coupled receptors. These compounds can act as apelin receptor antagonists. These compounds and compositions containing them can be used to treat diseases, such as cancer.

Description

Technical Field

[0001] The present invention relates to compounds and compositions having apelin receptor antagonist activity, which can be used to treat diseases such as cancer. Background Art

[0002] Apelin

[0003] The apelin receptor, a class A GPCR first identified in 1993[1], maintained orphan status until apelin was identified as a cognate ligand in 1998[2]. Endogenous apelin is derived from the C-terminus of the 77 amino acid precursor pre-pro-apelin. Proteolytic cleavage has revealed apelin-17, apelin-13, and [pyr 1 ] Apelin-13 is the most biologically relevant. In human heart[3] and plasma[4], [pyr 1 ]Apelin-13 (Pyr1-RPRLSHKGPMPF) is the major isoform.

[0004] The apelin response is consistent with coupling via GaI and via a G protein-dependent manner through recruitment of β-arrestin, a protein that initiates receptor internalization and downstream signaling [5].

[0005] Apelin is critical in many homeostatic and signaling processes, such as controlling blood pressure and angiogenesis in the cardiovascular system, acting as a co-receptor for HIV and regulating systemic metabolic and homeostatic processes [6, 7].

[0006] It is noteworthy that another recently discovered apelin agonist, Elabela / Toddler[8,9] (ELA), also acts through the apelin receptor and is critical in cardiac development[8], despite having little sequence homology to the established ligand apelin. The APELA gene expresses a 54 amino acid protein containing a 32 amino acid mature peptide (ELA-32). Degradation products produce the active peptides ELA-21 (LRKHNCLQRRCMPLHSRVPFP) and ELA-11.

[0007] Apelin has been reported to be a multifactorial causal factor in many disease processes, including, for example, diabetes, cardiovascular disease, HIV infection, kidney disease, and angiogenesis.[10-22]

[0008] Apelin has been implicated in the etiology of many different subtypes of cancer [refs. Cancer 23-53, US 20140005181A1]. Recent work has identified apelin as a persistent endocrine factor in glioblastoma

[60] .

[0009] Apelin receptor antagonists

[0010] A number of patents have been filed recently for apelin receptor antagonists. Apelin receptor antagonists are claimed for their putative mechanism as cancer targets (US2017146518(A1)). Combinations of apelin receptor antagonists and angiogenesis inhibitors have been claimed (WO2017 / 174758) to reduce or overcome resistance to anti-angiogenic therapy. Functional antagonists (apelin-13 (F13A)) and apelin receptor antagonists have been reported. [54-60]

[0011] For human apelin receptors in vitro, apelin-13 (F13A) exhibited similar binding, calcium mobilization, and internalization responses as (Pyr1) apelin-13, and in human cardiac tissue, F13A competed with [125I]-(Pyr1) apelin-13 for binding in the left ventricle and effectively constricted the endothelial-denuded saphenous vein. Thus, although apelin-13 (F13A) has been reported to act as a functional antagonist, it actually acts as an apelin receptor agonist in vitro.

[15]

[0012] MM54 [cyclic (1-6) CRPRLC-KH-cyclic (9-14) CRPRLC] is a competitive macrocyclic apelin receptor antagonist

[57] . MM54 exhibits antitumor properties in glioblastoma. In addition, the combination of MM54 and the anticancer compound temozolomide exhibits synergistic properties in a glioblastoma model

[60] . The pharmacology of MM54 showed a binding affinity of 82 nM in hCHO cells expressing apelin, a binding to human left ventricle (Kd) of 358 nM, and was an antagonist in the DRx β-arrestin assay with pA2 = 6.63. However, in the DRx cAMP assay, MM54 showed weak agonist activity (pD2 = 5.86, EC50 = 1.40 μM). In a human forearm study, MM54 unexpectedly showed functional agonist activity indicated by vasodilation. For this reason, there may be additional effects associated with this pharmacological property, including blood pressure reduction mediated by apelin signaling via cAMP. In addition, there is the added complexity and cost associated with the synthesis of macrocyclic analogs.

[0013] Unexpectedly, linear peptide analogs of MM54 were observed to exhibit apelin receptor antagonism. MM107, the linear sequence of MM54, CRPRLCKHCRPRLC, showed a binding affinity of 180 nM in hCHO cells expressing the apelin receptor and was an antagonist in the DRx β-arrestin assay (pA2 = 7.03), but surprisingly, and unlike MM54, showed no agonist effect in the DRx cAMP assay at 100 μM. Further modification of the linear structure led to the identification of antagonists that showed higher affinity at the apelin receptor, enhanced antagonism of the apelin receptor in the DRx β-arrestin and DRx cAMP assays, and no evidence of an apelin receptor agonist effect. The linear apelin antagonist MM 193 also showed significant anticancer effects in a glioblastoma model

[60] . Summary of the invention

[0014] The present inventors have discovered a number of linear peptides that are capable of acting as competitive apelin receptor antagonists. These include compounds that are more potent antagonists and have improved pharmacological properties compared to the known macrocyclic apelin receptor antagonist MM54.

[0015] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0016] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -[ 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0017] (Formula I)

[0018] in

[0019] X 1It can be any amino acid;

[0020] X 2 may be selected from the group consisting of R, H and K;

[0021] X 3 It is P;

[0022] X 4 It is R;

[0023] X 5 Can be selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0024] X 6 Can be selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0025] X 7 may be selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0026] X 8 may be selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0027] X 9 Can be selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0028] X 10 may be selected from the group consisting of R, H and K;

[0029] X 11 The group consisting of Aib and P can be selected;

[0030] X 12 may be selected from the group consisting of R, H and K;

[0031] X 13 Can be selected from the group consisting of Nle, Aib, L, V, I and A;

[0032] X 14 Can be selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14It may be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid;

[0033] in:

[0034] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0035] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0036] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl (Ac), formyl, propynyl, biotin, a myristoyl or palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0037] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0038] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0039] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0040] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0041] (Formula I)

[0042] in

[0043] X 1 It can be any amino acid;

[0044] X 2 may be selected from the group consisting of R, H and K;

[0045] X 3 It is P;

[0046] X 4 It is R;

[0047] X 5 Can be selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0048] X 6 Can be selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0049] X 7 may be selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0050] X 8 may be selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0051] X 9 Can be selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0052] X 10 may be selected from the group consisting of R, H and K;

[0053] X 11 The group consisting of Aib and P can be selected;

[0054] X 12 may be selected from the group consisting of R, H and K;

[0055] X 13 Can be selected from the group consisting of Nle, Aib, L, V, I and A;

[0056] X 14 Can be selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Na1), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0057] in:

[0058] 1) For X1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0059] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0060] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl (Ac), formyl, propynyl, biotin, a myristoyl or palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0061] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0062] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0063] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0064] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0065] (Formula I)

[0066] in

[0067] X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A;

[0068] X 2 It is R;

[0069] X 3 It is P;

[0070] X 4 It is R;

[0071] X 5 Selected from the group consisting of A, V, I, Nle and L;

[0072] X 6 Selected from the group consisting of Abu, M, P and C;

[0073] X 7 Selected from the group consisting of H, R and K;

[0074] X 8 Selected from the group consisting of R, K and H;

[0075] X 9 Selected from the group consisting of Abu, M, P and C;

[0076] X 10 is R or K;

[0077] X 11 Selected from the group consisting of Aib and P;

[0078] X 12 is R, H or K;

[0079] X 13 Selected from the group consisting of A, V, I, Nle and L;

[0080] X 14 is selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid;

[0081] in:

[0082] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0083] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0084] R1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0085] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0086] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0087] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0088] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L14 -X 14 (-L c -R 2 )

[0089] (Formula I)

[0090] in

[0091] X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A;

[0092] X 2 It is R;

[0093] X 3 It is P;

[0094] X 4 It is R;

[0095] X 5 Selected from the group consisting of A, V, I, Nle and L;

[0096] X 6 Selected from the group consisting of Abu, M, P and C;

[0097] X 7 Selected from the group consisting of H, R and K;

[0098] X 8 Selected from the group consisting of R, K and H;

[0099] X 9 Selected from the group consisting of Abu, M, P and C;

[0100] X 10 is R or K;

[0101] X 11 Selected from the group consisting of Aib and P;

[0102] X 12 is R, K or H;

[0103] X 13 Selected from the group consisting of A, V, I, Nle and L;

[0104] X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0105] in:

[0106] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0107] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0108] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0109] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0110] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0111] In one aspect, the invention provides compounds that are apelin receptor antagonists.

[0112] In one aspect, the present invention provides compounds that are ligands for the apelin receptor.

[0113] In one aspect, the present invention provides a pharmaceutical composition comprising a compound and a pharmaceutically acceptable diluent, excipient or carrier.

[0114] In one aspect, the invention provides a compound or composition for use in medicine.

[0115] In one aspect, the invention provides a method of treating a disease or condition in a patient, the method comprising administering to the patient a compound or composition of the invention.

[0116] In one aspect, the invention provides compounds or compositions for use in treating a condition or disease selected from the group consisting of: tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, preeclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (e.g., arthritis and inflammatory bowel disease), avascular or ischemic lesions, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis, and HIV infection,

[0117] In one aspect, the present invention provides a method for treating the following diseases: tumors, cancers, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reducing dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, preeclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (such as arthritis and inflammatory bowel disease), avascular or ischemic injuries, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric kidney disease, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection, the method comprising administering to the patient a compound or composition of the present invention.

[0118] In one aspect, the invention provides a substance or composition for use in the preparation of a medicament for treating a disease or condition selected from the group consisting of: tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, preeclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (e.g., arthritis and inflammatory bowel disease), avascular or ischemic lesions, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis, and HIV infection.

[0119] In one aspect, the invention provides a method of treating a disease or condition in a patient comprising administering a compound or composition of the invention.

[0120] In one aspect, the present invention provides a compound comprising 6 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0121] In one aspect, the present invention provides a compound comprising 6 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0122] In one aspect, the present invention provides a compound comprising 7 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0123] In one aspect, the present invention provides a compound comprising 7 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0124] In one aspect, the present invention provides a compound comprising 8 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0125] In one aspect, the present invention provides a compound comprising 8 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0126] In one aspect, the present invention provides a compound comprising 9 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0127] In one aspect, the present invention provides a compound comprising 9 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0128] In one aspect, the present invention provides a compound comprising 10 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0129] In one aspect, the present invention provides a compound comprising 10 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0130] In one aspect, the present invention provides a compound comprising 11 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0131] In one aspect, the present invention provides a compound comprising 11 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0132] In one aspect, the present invention provides a compound comprising 12 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0133] In one aspect, the present invention provides a compound comprising 12 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0134] In one aspect, the present invention provides a compound comprising 13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0135] In one aspect, the present invention provides a compound comprising 13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0136] In one aspect, the present invention provides a compound comprising 6-13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32, which is used in medicine.

[0137] In one aspect, the present invention provides a compound comprising 6-13 consecutively linked (L 1-14 )Amino Acid(X 1-14), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17, which is used in medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0138] Figure 1a Antagonism of [pyr1] apelin-13-mediated β-arrestin recruitment by 1 μM MM193 is described. The effect of apelin-13 was antagonized in a competitive manner by the addition of MM 193.

[0139] Figure 1b Depicted is the antagonistic effect of 1 μM MM193 on [pyr1] apelin-13 inhibition of forskolin-stimulated cAMP accumulation. The effect of apelin-13 was antagonized in a competitive manner by the addition of MM 193.

[0140] Figure 2a Describe the effects of MM54 on forskolin-stimulated cAMP responses.

[0141] Figure 2b The effects of MM54 on inhibition of β-arrestin recruitment are described.

[0142] Figure 3a Antagonism of [Pyr1]apelin-13-mediated β-arrestin recruitment by 1 μM MM299 is described.

[0143] Figure 3b Antagonism of [Pyr1] inhibition of forskolin-stimulated cAMP accumulation by 10 μM MM299 is described.

[0144] Figure 4a Antagonism of [Pyr1]apelin-13-mediated β-arrestin recruitment by 1 μM MM300 is described.

[0145] Figure 4b Antagonism of [Pyrl] inhibition of forskolin-stimulated cAMP accumulation by 10 μM MM300 is described.

[0146] These figures demonstrate antagonism of apelin-13 and show a pharmacological profile consistent with antagonism of apelin receptor signaling. Since apelin receptor signaling appears to alter the disease course of glioblastoma (60), these compounds are claimed to alter the disease course of glioblastoma via this mechanism of apelin receptor antagonism. DETAILED DESCRIPTION

[0147] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0148] (R 1 -L c )-X1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0149] (Formula I)

[0150] in

[0151] X 1 is any amino acid;

[0152] X 2 Selected from the group consisting of R, H and K;

[0153] X 3 It is P;

[0154] X 4 It is R;

[0155] X 5 Selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0156] X 6 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0157] X 7 Selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0158] X 8 Selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0159] X 9 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0160] X 10 Selected from the group consisting of R, H and K;

[0161] X 11 Selected from the group consisting of Aib and P;

[0162] X 12 Selected from the group consisting of R, H and K;

[0163] X 13 Selected from the group consisting of Nle, Aib, L, V, I and A;

[0164] X 14 is selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid;

[0165] in:

[0166] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0167] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0168] R 1 , R2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0169] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0170] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0171] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0172] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14-X 14 (-L c -R 2 )

[0173] (Formula I)

[0174] in

[0175] X 1 is any amino acid;

[0176] X 2 Selected from the group consisting of R, H and K;

[0177] X 3 It is P;

[0178] X 4 It is R;

[0179] X 5 Selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0180] X 6 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0181] X 7 Selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0182] X 8 Selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0183] X 9 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0184] X 10 Selected from the group consisting of R, H and K;

[0185] X 11 Selected from the group consisting of Aib and P;

[0186] X 12 Selected from the group consisting of R, H and K;

[0187] X 13 Selected from the group consisting of Nle, Aib, L, V, I and A;

[0188] X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0189] in:

[0190] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0191] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0192] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl (Ac), formyl, propynyl, biotin, a myristoyl or palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0193] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0194] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0195] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0196] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0197] (Formula I)

[0198] in

[0199] X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A;

[0200] X 2 It is R;

[0201] X 3 It is P;

[0202] X 4 It is R;

[0203] X5 Selected from the group consisting of A, V, I, Nle and L;

[0204] X 6 Selected from the group consisting of Abu, M, P and C;

[0205] X 7 Selected from the group consisting of H, R and K;

[0206] X 8 Selected from the group consisting of R, K and H;

[0207] X 9 Selected from the group consisting of Abu, M, P and C;

[0208] X 10 is R or K;

[0209] X 11 Selected from the group consisting of Aib and P;

[0210] X 12 is R, K or H;

[0211] X 13 Selected from the group consisting of A, V, I, Nle and L;

[0212] X 14 is selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid;

[0213] in:

[0214] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0215] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0216] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0217] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0218] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0219] In one aspect, the invention provides a compound comprising the sequence of Formula I:

[0220] (R 1 -L c )-X1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0221] (Formula I)

[0222] in

[0223] X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A;

[0224] X 2 It is R;

[0225] X 3 It is P;

[0226] X 4 It is R;

[0227] X 5 Selected from the group consisting of A, V, I, Nle and L;

[0228] X 6 Selected from the group consisting of Abu, M, P and C;

[0229] X 7 Selected from the group consisting of H, R and K;

[0230] X 8 Selected from the group consisting of R, K and H;

[0231] X 9 Selected from the group consisting of Abu, M, P and C;

[0232] X 10 is R or K;

[0233] X 11 Selected from the group consisting of Aib and P;

[0234] X 12 is R, K or H;

[0235] X 13 Selected from the group consisting of A, V, I, Nle and L;

[0236] X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0237] in:

[0238] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0239] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0240] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0241] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0242] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0243] In some embodiments, X 1 may be selected from the group consisting of V, I, L, M, P, Y, W, C, Q, G1p and A;

[0244] In some embodiments, X 2 It can be R;

[0245] In some embodiments, X 3 It can be P;

[0246] In some embodiments, X 4 It can be R;

[0247] In some embodiments, X 5 Can be selected from the group consisting of A, V, I, Nle and L;

[0248] In some embodiments, X 6 may be selected from the group consisting of Abu, M, P and C;

[0249] In some embodiments, X 7 may be selected from the group consisting of H, R and K;

[0250] In some embodiments, X 8 may be selected from the group consisting of R, K and H;

[0251] In some embodiments, X 9 may be selected from the group consisting of Abu, M, P and C;

[0252] In some embodiments, X 10 Can be selected from the group consisting of R or K;

[0253] In some embodiments, X 11 The group consisting of Aib and P can be selected;

[0254] In some embodiments, X 12 may be selected from the group consisting of R, K or H;

[0255] In some embodiments, X 13 Can be selected from the group consisting of A, V, I, Nle and L;

[0256] In some embodiments, X 14 can be selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), phenylalanine (F), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may specifically be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-phenylstyrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid.

[0257] In some embodiments, X 14 Can be selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), phenylalanine (F), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14In particular, it may be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan.

[0258] In some embodiments, the compound may be a compound of formula (I) or a pharmaceutically acceptable salt, solvate or deuterated analog thereof.

[0259] In some embodiments, the compound may be a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0260] In some embodiments, X 1 To X 14 One or more of the can be independently conjugated via a linker L c Connect to R 3 part.

[0261] In some embodiments, X 1 , X 6 , X 9 and X 14 One or more of the can be independently conjugated via a linker L c With R 3 moiety, optionally wherein the conjugation linker is maleimide or PEGylated maleimide, optionally wherein R 3 It is a fatty acid, a pegylated molecule, a peptide, a polypeptide or an antibody molecule.

[0262] In some embodiments, X 1 To X 14 None of them can be conjugated to the linker L c With R 3 connect.

[0263] In some embodiments, (R 1 -L c ) and (-L c -R 2 ) may not exist.

[0264] In some embodiments, (R 1 -L c ) and (-L c -R 2) can be absent, so that the sequence ends at X 1 and X 14 .

[0265] In some embodiments, for X 1 To X 14 In each of the above, the listed natural amino acids are not modified, and the listed modified amino acids are not further modified.

[0266] In some embodiments, X 1 To X 14 Each may be an amide bond or an N-methylated amide bond, or may be an amide bond.

[0267] In some embodiments, X 1 Can be C, Q, Glp or A.

[0268] In some embodiments, X 1 It can be C.

[0269] In some embodiments, X 1 It can be Q.

[0270] In some embodiments, X 1 It can be Glp.

[0271] In some embodiments, X 1 It can be A.

[0272] In some embodiments, X 2 It can be R.

[0273] In some embodiments, X 3 It can be P.

[0274] In some embodiments, X 4 It can be R.

[0275] In some embodiments, X 2 It may be R, which may be modified by methylation.

[0276] In some embodiments, X 4 It may be R, which may be modified by methylation.

[0277] In some embodiments, X 5 It can be selected from the group consisting of Nle and L.

[0278] In some embodiments, X 13 It can be selected from the group consisting of Nle and L.

[0279] In some embodiments, X 6It may be selected from the group consisting of C and Abu.

[0280] In some embodiments, X 9 Can be independently selected from the group consisting of C and Abu.

[0281] In some embodiments, X 7 Can be K and X 8 Can be H, or X 7 Can be H and X 8 Can be K, or X 7 Can be A and X 8 Can be K, or X 7 Can be K and X 8 It can be A.

[0282] In some embodiments, X 7 and X 8 One can be H and the other can be K.

[0283] In some embodiments, X 10 It can be R.

[0284] In some embodiments, X 10 and X 12 It can be R.

[0285] In some embodiments, X 11 It may be selected from the group consisting of P and Aib.

[0286] In some embodiments, X 14 It can be selected from C and (3,4,5-trifluoro-)F, preferably (3,4,5-trifluoro-)F.

[0287] In some embodiments, X 1 Can be C, optionally wherein R 1 It may be myristoyl.

[0288] In some embodiments, X 5 It can be Nle.

[0289] In some embodiments, X 6 It could be Abu.

[0290] In some embodiments, X 7 Can be K and X 8 It can be H.

[0291] In some embodiments, X 9 It could be Abu.

[0292] In some embodiments, X 10It can be R.

[0293] In some embodiments, X 11 It can be Aib.

[0294] In some embodiments, X 12 It can be R.

[0295] In some embodiments, X 13 It can be Nle.

[0296] In some embodiments, X 14 It may be (3,4,5-trifluoro)F.

[0297] In some embodiments, X 1 Can be modified.

[0298] In some embodiments, X 1 Can be left unmodified.

[0299] In some embodiments, X 2 Can be modified.

[0300] In some embodiments, X 2 Can be left unmodified.

[0301] In some embodiments, X 3 Can be modified.

[0302] In some embodiments, X 3 Can be left unmodified.

[0303] In some embodiments, X 4 Can be modified.

[0304] In some embodiments, X 4 Can be left unmodified.

[0305] In some embodiments, X 5 Can be modified.

[0306] In some embodiments, X 5 Can be left unmodified.

[0307] In some embodiments, X 6 Can be modified.

[0308] In some embodiments, X 6 Cannot be modified.

[0309] In some embodiments, X 7 Can be modified.

[0310] In some embodiments, X7 Can be left unmodified.

[0311] In some embodiments, X 8 Can be modified.

[0312] In some embodiments, X 8 Can be left unmodified.

[0313] In some embodiments, X 9 Can be modified.

[0314] In some embodiments, X 9 Can be left unmodified.

[0315] In some embodiments, X 10 Can be modified.

[0316] In some embodiments, X 10 Can be left unmodified.

[0317] In some embodiments, X 11 Can be modified.

[0318] In some embodiments, X 11 Can be left unmodified.

[0319] In some embodiments, X 12 Can be modified.

[0320] In some embodiments, X 12 Can be left unmodified.

[0321] In some embodiments, X 13 Can be modified.

[0322] In some embodiments, X 13 Can be left unmodified.

[0323] In some embodiments, X 14 Can be modified.

[0324] In some embodiments, X 14 Can be left unmodified.

[0325] In some embodiments, X 1 To X 14 One or more of the may be C, R or K and may be modified, wherein the modification comprises directly or indirectly linking the C, R or K to a protein or a fatty acid.

[0326] In some embodiments, R 1 It can be a C1-C25 saturated or unsaturated fatty acyl moiety, which is optionally conjugated via a linker Lc With X 1 Combine.

[0327] In some embodiments, the fatty acyl moiety can include a fatty acyl group selected from the group consisting of butyryl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, octadecandioyl, octadecanoyl, sebacoyl, dodecanedioyl, adipoyl, succinoyl, tetradecanedioyl, and hexadecandioyl.

[0328] In some embodiments, R 1 It may be optionally conjugated via a linker L c With X 1 Conjugated polyethylene glycol polymer moiety.

[0329] In some embodiments, the polyethylene glycol polymer moiety can comprise a 5 kDa, 10 kDa, or 20 kDa polyethylene glycol polymer.

[0330] In some embodiments, there may be at least one conjugation linker L c , and it contains 3-mercaptopropionic acid.

[0331] In some embodiments, R 1 is an immunoglobulin portion or an immunoglobulin Fc domain portion, which is optionally conjugated via a linker L c With X 1 Combine.

[0332] In some embodiments, there may be at least one conjugation linker L c , and it may be a peptidyl linker.

[0333] In some embodiments, there may be at least one conjugation linker L c , and it may be a non-peptidyl linker.

[0334] In some embodiments, the non-peptidyl conjugation linker L c Polyethylene glycol polymers may be included.

[0335] In some embodiments, there may be at least one conjugation linker L c , and it may contain a maleimide moiety, a pegylated maleimide moiety or a thioether.

[0336] In some embodiments, X 1 Can be C, R 1It may be a protein, for example a protein selected from albumin and albudAb. AlbudAb is defined in the reference: O'Connor-Semmes, Lin J, Hodge RJ, Andrews S1, Chism J, Choudhury A, Nunez DJ. GSK2374697, a novel albumin-binding domain antibody (AlbudAb), extends systemic exposure of exendin-4: first study in humans--PK / PD and safety. Clin Pharmacol Ther. 2014 Dec; 96(6): 704-12.

[0337] In some embodiments, the compound can be selected from the following table:

[0338]

[0339] In some embodiments, the compound can be selected from the following table:

[0340]

[0341]

[0342] In some embodiments, the compound is an apelin receptor antagonist.

[0343] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable diluent, excipient or carrier.

[0344] In one aspect, the present invention provides a composition formulated for:

[0345] (a) systemic delivery, such as intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, intravaginal, intrarectal, intrapulmonary, intracranial or oral delivery;

[0346] (b) local delivery, such as topical or iontophoretic delivery; or

[0347] (c) Transdermal delivery, for example via a patch.

[0348] (d) Inhalation through the lungs

[0349] (e) Intraocular delivery, including topical, injectable, contact lens-releasing drugs, biodegradable micro- and nanoparticles, and surgical implant systems.

[0350] In one aspect, the present invention provides a compound comprising 6 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0351] In one aspect, the present invention provides a compound comprising 6 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0352] In one aspect, the present invention provides a compound comprising 7 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0353] In one aspect, the present invention provides a compound comprising 7 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0354] In one aspect, the present invention provides a compound comprising 8 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0355] In one aspect, the present invention provides a compound comprising 8 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0356] In one aspect, the present invention provides a compound comprising 9 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0357] In one aspect, the present invention provides a compound comprising 9 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0358] In one aspect, the present invention provides a compound comprising 10 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0359] In one aspect, the present invention provides a compound comprising 10 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0360] In one aspect, the present invention provides a compound comprising 11 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0361] In one aspect, the present invention provides a compound comprising 11 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0362] In one aspect, the present invention provides a compound comprising 12 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0363] In one aspect, the present invention provides a compound comprising 12 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0364] In one aspect, the present invention provides a compound comprising 13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32.

[0365] In one aspect, the present invention provides a compound comprising 13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0366] In one aspect, the present invention provides a compound comprising 6-13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-32, which is used in medicine.

[0367] In one aspect, the present invention provides a compound comprising 6-13 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17, which is used in medicine.

[0368] definition

[0369] The compounds of the present invention may comprise two or more amino acids linked together and may be referred to as peptides or polypeptides. The terms "polypeptide" and "peptide" may also be used interchangeably to refer to two or more amino acids linked together. The peptide is represented by the N-terminus on the left, and the sequence is written from the N-terminus to the C-terminus.

[0370] Natural amino acids refer to those found in nature. Generally, most naturally occurring peptides contain L-amino acids. However, it is not beyond the scope of the present invention to envision an apelin receptor antagonist containing D-amino acids. The L- and D- prefixes refer to the chirality of the amino acid. Unless specified as a D-amino acid, the amino acids used in the compounds of the present invention are L-amino acids. The peptides of the present invention may contain modified amino acids (i.e., amino acids not found in nature or natural amino acids that have been synthesized or biosynthetically transformed) having the following general structure:

[0371]

[0372] How to choose the right R 1 and R 2 Substituents are obvious to those skilled in the art. For example, R 1 and R 2 It may contain the same substituent or may contain different substituents. 1 and R 2 Substituents may create stereogenic centers that may affect the 3-dimensional shape and / or properties of the peptide of which the amino acid is a part. 1 and R 2 may independently be hydrogen and may not be explicitly represented in the formula. An amino acid may have more than one stereogenic center.

[0373] In addition to alpha (α) amino acids (eg, a carbon bonded to an amine, a carboxylic acid, and one or two R groups), modified amino acids may also refer to beta (β) and gamma (γ) amino acids.

[0374] When the single-letter codes are used to represent naturally occurring amino acids, the following codes are used:

[0375]

[0376]

[0377] When the following compound names (or abbreviated codes) are used herein, these refer to the corresponding compounds as shown below:

[0378]

[0379]

[0380] A more comprehensive list is shown below:

[0381]

[0382]

[0383]

[0384] As used herein, unless otherwise defined, K(GluPAL) refers to lysine substituted with a glutamate spacer by palmitic acid. As used herein, unless otherwise defined, K(PAL) refers to lysine substituted with palmitic acid. As used herein, and unless otherwise defined, PAL refers to palmitic acid.

[0385] For any natural or modified amino acid described herein, for example corresponding to X 1 -X 14 It should be understood that the -NH2 and -CO2H moieties may not be present as a whole in the compounds of the present invention, as they may contribute to the formation of one or more bonds L1-L1 described herein. 14 and / or conjugated linker L c For example, the -NH2 moiety of one natural or modified amino acid can combine with the -CO2H moiety of an adjacent natural or modified amino acid to form an amide bond.

[0386] For any natural or modified amino acid described herein, for example, corresponding to X in the compound of formula (I) 1 -X 14 It should be understood that one or more of the atoms depicted may not be present because they may contribute to the formation of one or more conjugated linkers L described herein.c .

[0387] For example, cysteine ​​can be conjugated to:

[0388] a) maleimide, heterobifunctional maleimide cross-linker, maleimide conjugated with fatty acid, PEGylated maleimide linker; and / or

[0389] b) connecting to another moiety by replacing the hydrogen atom of the thiol moiety with iodoacetamide, 2-thiopyridine, 3-arylmalononitrile, 3-mercaptopropionic acid moiety or thioether moiety.

[0390] In another example, a suitably functionalized amino acid side chain (e.g., arginine or lysine) can be conjugated via, for example, a peptidyl linker or a non-peptidyl linker (e.g., using click chemistry), an amide linker, or a linker comprising a polyethylene glycol polymer or a fatty acid. For other suitable amino acid side chains such as arginine or lysine, suitable modifications are optionally alkylation (mono- or di- or C2-C6 chains), esterification, N-alkyl amidation, or substitution of hydrogen with any alkane, halogen group, or hydroxyl group.

[0391] In another example, the aspartic acid side chain can be conjugated via an amide linker, carbamate, thioamide, ester or other suitable linker.

[0392] Examples of modified amino acids include, but are not limited to, hydroxyproline, carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid (Abu), 4-aminobutyric acid, 6-aminobutyric acid, 2-aminoglutamate, 2-aminoheptanoic acid, 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2′-diaminopimelic acid, 2,3-diaminopropionic acid, N-ethylglycine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalene, norvaline, norleucine (Nle), ornithine, pentylglycine, pipecolic acid, 5-oxopyrrolidine-2-carboxylic acid (Glp or Pyr or pE), and thioproline. Amino acids also include amino acids that occur naturally in certain organisms, such as ornithine, D-ornithine, and D-arginine.

[0393]

[0394] It will be apparent to those skilled in the art that any amino acid shown or listed in any of the above tables or lists may also be selected as the opposite enantiomer, or any diastereomer if applicable, or as a racemate and used in the compounds of the present invention.

[0395] As used herein, "modification" refers to replacing at least a portion of a compound, such as an amino acid, with an alternative moiety. Examples of modifications include alkylation, esterification, N-alkylamidation, or replacement of hydrogen with any halogen group or hydroxyl group. The term "modification" also includes X in the compound of formula I. 1 -X 14 Any one of the conjugated linkers L c With compounds such as R 3 For example, in Formula I, X 1 , X 6 , X 9 or X 14 The cysteine ​​at c With compound R 3 Conjugated to modify, optionally wherein the conjugated linker L c It is maleimide, pegylated maleimide or fatty acid.

[0396] Any amino acid that forms part of the compounds of the invention through one or more bonds can be modified. For example, natural amino acids can be modified, and modified amino acids can be modified.

[0397] In some embodiments, each R 3 R is independently a fatty acid, such as myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or a conjugated or saturated or branched derivative thereof. 3 is a pegylated moiety, such as PEG 1-20, but preferably PEG 1-10, PEG-NHS ester, PEG-PFP ester, PEG-tert-butyl ester, PEG-alcohol, PEG-amine, PEG-amine, amido-PEG-acid. In some embodiments, R 3 is a PEGylated moiety, such as a 5 kDa, 10 kDa, or 20 kDa PEGylated polymer. For example, the term "20 kDa" PEGylated polymer is an average M n 20,000 polymers.

[0398] PEG refers to polyethylene glycol. For example, PEG1-20 may contain 1-20 polymerized ethylene glycol units. For example, PEG1-10 may contain 1-10 polymerized ethylene glycol units. PEG-NHS esters may contain N-hydroxysuccinimide ester groups, PEG-PFP esters may contain pentafluorophenyl ester groups, and PEG-tert-butyl esters may contain tert-butyl ester groups. Alcohol, amine, amido, and acid refer to those functional groups at one or both ends of the PEG molecule. In some embodiments, PEG may also be a 5kDa, 10kDa, or 20kDa polyethylene glycol polymer. For example, the term "20kDa" polyethylene glycol polymer is an average M n 20,000 polymers.

[0399] The term "modification" also includes conservative substitutions, for example according to the following table. Amino acids in the same segment in the second column and preferably in the same row in the third column can be substituted for each other:

[0400]

[0401] In some embodiments of the present invention, the natural amino acid may be modified, wherein the modification comprises substituting the amino acid for a different amino acid in the same segment in the second column of the above table, preferably substituting for a different amino acid in the same row in the third column of the above table.

[0402] As used herein, "linked" refers to any moiety suitable for linking two amino acids together. Examples of suitable links include amide bonds, N-methylated amides, ureas, esters, carbamates, peptoids, sulfonamides, alkylenes, thioamides, thioethers, fluoroalkylenes, azapeptides, difluoroketones, or epoxides.

[0403] As used herein, a "conjugation linker" refers to a 1 The amino acid is attached to R 1 represents any part of the rest of the compound, or is suitable for X 14 The amino acid is attached to R 2 Any moiety on the rest of the compound, or suitable for X in the compound of formula I 1 -X 14 Connect any one of them to R 3 Any moiety on the rest of the compound represented. Examples of suitable conjugation linkers include linkers comprising a 3-mercaptopropionic acid moiety, a maleimide moiety, a PEGylated maleimide moiety, or a thioether moiety, or a peptidyl linker, a non-peptidyl linker (e.g., using click chemistry), an amide linker, or a linker comprising a polyethylene glycol polymer linker.

[0404] As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without serious toxicity, irritation, allergic response or other complications, commensurate with a reasonable benefit-risk ratio for the medical condition being treated.

[0405] As used herein, "pharmaceutically acceptable salts" refer to derivatives of compounds in which the parent compound is modified by preparing acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids, such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, etc. These physiologically acceptable salts are prepared by methods known in the art, such as by dissolving the free amine base with excess acid in aqueous alcohol, or neutralizing the free carboxylic acid with an alkali metal base such as a hydroxide or with an amine. Therefore, pharmaceutically acceptable salts can be formed from compounds of the present invention having acidic, basic or two functional groups. For example, a peptide with a carboxylic acid group can form a carboxylate anion paired with a cation such as sodium or potassium cation in the presence of a pharmaceutically suitable base. Similarly, a peptide with an amine functional group can form a salt in the presence of a pharmaceutically suitable acid such as HCl. An example of a pharmaceutically acceptable solvate of a compound is a combination of a compound with a solvent molecule that produces a complex of such solvent molecules bound to the compound. Hydrates of particularly suitable compounds are hydrates with considerable activity or hydrates that are converted back to active compounds after administration. Pharmaceutically acceptable N-oxides of compounds containing amines are compounds in which the nitrogen atom of the amine is bonded to an oxygen atom.

[0406] Compounds of the present invention

[0407] The compounds of the present invention may be prodrugs. Prodrugs of the compounds of the present invention include pharmaceutically acceptable derivatives that can be converted into the biologically active form of the compound by metabolism or other processes after administration. It is particularly desirable when the prodrug has more favorable properties than the active compound in terms of bioavailability, stability or suitability for a particular formulation.

[0408] The pharmaceutically acceptable crystalline, isomorphous crystalline or amorphous form of the compound of the invention may be any crystalline or non-crystalline form of a pharmaceutically acceptable acidic, basic, zwitterionic, salt, hydrate or any other suitable stable, physiologically compatible form of the compound of the invention.

[0409] Mode of administration

[0410] The pharmaceutical compositions of the invention can be delivered or administered intravenously, transdermally, transmucosally, intranasally, subcutaneously, intramuscularly, orally, or topically (e.g., to the eye). The compositions can be administered for the prophylactic treatment of individuals suffering from a disease or condition or at risk of a disease or condition. For therapeutic applications, the pharmaceutical composition is typically administered to a subject suffering from a disease or condition in an amount sufficient to inhibit, prevent, or ameliorate the disease or condition. An amount sufficient to achieve this is defined as a "therapeutically effective dose."

[0411] As used herein, topical application or administration refers to applying a pharmaceutical composition according to the invention to the site of a cancer or tumor, or alternatively, for example, to a site where a tumor has been removed. Application may be by injection, catheter, or delivery as part of a biocompatible device or material. Thus, topical application refers to application to discrete internal areas of the body, such as soft tissue areas (e.g., muscle, intraocular, brain, kidney, lung, etc., or other fleshy internal areas), or other internal areas of the body where the compound may have a local or systemic beneficial effect.

[0412] The compounds of the present invention may be administered all at once, or may be divided into a number of smaller doses to be administered at regular intervals, or may be administered as a controlled release formulation.

[0413] Composition

[0414] According to another aspect of the present invention, there is provided a composition comprising the compound of the present invention itself or a combination thereof with a pharmaceutically acceptable diluent, excipient or carrier.

[0415] The compounds of the present invention can be incorporated into pharmaceutical compositions. The compositions can include an effective amount of the compound in a pharmaceutically acceptable diluent, excipient or carrier. Conventional excipients, carriers and / or diluents used in pharmaceutical compositions are generally inert and constitute the bulk of the formulation. In one embodiment, the compound is an apelin antagonist.

[0416] Pharmaceutical excipient or carrier can be any compatible, nontoxic material suitable as the carrier for delivering the compounds of this invention. Suitable excipient or carrier include but are not limited to sterile water (preferably pyrogen-free), saline, phosphate buffered saline (PBS), water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone (PVP), citric acid, tartaric acid, oil, fatty substances, wax or a suitable mixture of any of the foregoing substances.

[0417] The pharmaceutical composition of the present invention can be formulated into liquid, semisolid or solid dosage forms. For example, the pharmaceutical composition can be in the form of injection solution, drops, syrups, sprays, suspensions, tablets, patches, capsules, dressings, suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or granular forms, such as pills or granules, which are optionally pressed into tablets or lozenges, packaged in capsules or suspended in liquids. Tablets can contain adhesives, lubricants, diluents, colorants, flavorings, wetting agents, and can be enteric-coated, so as to survive in the acidic environment of the stomach, and dissolve under the more alkaline conditions of the intestinal cavity. As an alternative, tablets can be sugar-coated or with a film of water-soluble film coating. Pharmaceutically acceptable adjuvants, buffers, dispersants, etc. can also be introduced into the pharmaceutical composition.

[0418] Binders include, for example, starch, mucus, gelatin and sucrose. Lubricants include talc, lycopodium, magnesium stearate and calcium stearate / stearic acid. Diluents include lactose, sucrose, mannitol, salt, starch and kaolin. Wetting agents include propylene glycol and sorbitan monostearate.

[0419] For oral administration, active ingredients can be formulated into solid dosage forms, such as capsules, tablets and powders, or formulated into liquid dosage forms, such as elixirs, syrups and suspensions. Active ingredients can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate, etc. The examples of other inactive ingredients that can be added to provide required color, taste, stability, buffering capacity, dispersion or other known required characteristics are iron oxide red, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink, etc. Similar diluents can be used to prepare compressed tablets. Tablets and capsules can all be made into sustained-release products to provide continuous release of medicine within a few hours or days. Compressed tablets can be coated with sugar or film to cover any unpleasant taste and protect tablets from atmospheric influences, or enteric coatings to selectively disintegrate in the gastrointestinal tract. Liquid dosage forms for oral administration may contain colorants and flavoring agents to increase patient acceptance. In order to promote drug stability and absorption, the peptides of the present invention may be released from the capsule after passing through the harsh proteolytic environment of the stomach. Methods for enhancing peptide stability and absorption after oral administration are well known in the art (e.g., Mahato RI. Emerging trends in oral delivery of peptide and protein drugs. Critical Reviews in Therapeutic Drug Carrier Systems. 20: 153-214, 2003).

[0420] Compared to oral dosage forms of the compounds of the invention with significant oral absorption, dosage forms such as lozenges, chewable tablets and chewing gum allow for more rapid therapeutic action. Chewing gum formulations are solid single-dose formulations having a matrix consisting primarily of chewing gum that is intended to be chewed rather than swallowed and contains one or more compounds of the invention that are released by chewing and are intended for local treatment of oral pain and inflammation or for systemic delivery after absorption through the buccal mucosa. See, for example, U.S. Pat. No. 6,322,828 to Athanickar and Gubler, entitled Process for manufacturing a pharmaceutical chewing gum.

[0421] For nasal administration, the compounds of the present invention can be formulated as an aerosol. The term "aerosol" includes any airborne suspension of the compounds of the present invention that can be inhaled into the bronchioles or nasal passages. Specifically, aerosols include airborne suspensions of droplets of the compounds of the present invention, which can be produced in a metered dose inhaler or nebulizer, or in a spray machine. Aerosols also include dry powder compositions of the compounds of the present invention suspended in air or other carrier gases, which can be delivered, for example, by blowing from an inhaler device. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6: 273-313; and Raebum et al. (1992) J. Pharmacol. Toxicol. Methods 27: 143-159.

[0422] The pharmaceutical compositions of the present invention can be prepared in a formulation suitable for systemic delivery, such as by intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, transdermal, intravaginal, rectal, intrapulmonary or oral delivery. Alternatively, the pharmaceutical compositions of the present invention can be appropriately formulated for local delivery, such as for topical or iontophoretic delivery, or for transdermal delivery by coating, diffusion or impregnation with a patch of the formulation, and topically applied to a joint, such as by intraarticular injection.

[0423] Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products (including subcutaneous tablets) ready for combination with solvents immediately before use, sterile suspensions ready for injection, sterile dry insoluble products ready for combination with a carrier immediately before use, and sterile emulsions. The solution may be aqueous or non-aqueous, and is therefore formulated for delivery by injection, infusion, or using an implantable pump. For intravenous, subcutaneous, and intramuscular administration, useful preparations of the present invention include microcapsule preparations having controlled release properties (R. Pwar et al. Protein and peptide parenteral controlled delivery. Expert Opin Biol Ther. 4 (8): 1203-12, 2004) or encapsulated in liposomes, an exemplary form being polyethylene-coated liposomes, which are known in the art to have extended circulation time in the vascular system (e.g., Koppal, T. "Drug delivery technologies are right on target", Drug Discov. Dev. 6, 49-50, 2003).

[0424] The formulation for transdermal delivery is introduced into a device suitable for such delivery, the device utilizing, for example, iontophoresis (Kalia YN et al. Iontophoretic Drug Delivery. Adv Drug Deliv Rev. 56: 619-58, 2004) or a dermal transdermal surface (Prausnitz MR. Microneedles for Transdermal Drug Delivery. Adv Drug Deliv Rev. 56: 581-7, 2004), such as those known in the art for improving transdermal delivery of drugs. An electrotransport device and method of operating the same are disclosed in U.S. Pat. No. 6,718,201. Methods for promoting transdermal delivery of peptides using iontophoresis are disclosed in U.S. Pat. No. 6,313,092 and U.S. Pat. No. 6,743,432.

[0425] Other useful transdermal application devices employ high-speed delivery under pressure to achieve skin penetration without the use of needles. As is known in the art, transdermal delivery can be improved by the use of chemical enhancers, sometimes referred to in the art as "penetration enhancers," compounds that are applied with the drug (or in some cases used to pretreat the skin prior to application) to increase the permeability of the stratum corneum and thereby provide enhanced penetration of the drug through the skin. Chemical penetration enhancers are harmless compounds that serve only to promote diffusion of the drug through the stratum corneum, whether by passive diffusion or energy-driven processes such as electromigration. See, e.g., Meidan VM et al. Enhanced iontophoretic delivery of buspironehydrochloride across human skin using chemical enhancers. Int. J. Pharm. 264: 73-83, 2003.

[0426] Pharmaceutical dosage forms for rectal administration include rectal suppositories, capsules and tablets for systemic action. Rectal suppositories used herein refer to solids for insertion into the rectum, which melt or soften at body temperature, releasing one or more substances pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances for rectal suppositories include bases or carriers and agents that improve the melting point of suppositories. Examples of bases include cocoa butter (cocoa butter), glycerol-gelatin, carbowax, (polyoxyethylene glycol) and suitable mixtures of monoglycerides, diglycerides and triglycerides of fatty acids. Combinations of various bases can also be used. Agents that improve the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared by compression methods or by molding. Rectal suppositories usually weigh about 2 gm to about 3 gm. Tablets and capsules for rectal administration are prepared using the same pharmaceutically acceptable substances and the same methods as the preparations for oral administration.

[0427] Pharmaceutically acceptable carriers for parenteral formulations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, sequestering or chelating agents and other pharmaceutically acceptable substances.

[0428] Examples of aqueous vehicles include sodium chloride for injection, Ringer's solution for injection, isotonic dextrose for injection, sterile water for injection, dextrose for injection, and lactated Ringer's solution. Non-aqueous parenteral vehicles include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers, including phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl or propyl parabens, thimerosal, benzalkonium chloride, and benzethonium chloride.

[0429] Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfite. Local anesthetics include procaine hydrochloride.

[0430] Suspending agents and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone. Emulsifiers include polysorbate 80 (Tween 80). Metal ion sequestering agents or chelating agents such as EDTA may also be introduced.

[0431] Pharmaceutical carriers also include ethanol, polyethylene glycol and propylene glycol for water miscible vehicles, and the pH can be adjusted to a physiologically compatible pH by the addition of sodium hydroxide, hydrochloric acid, citric acid or lactic acid.

[0432] The term "controlled release formulation" includes formulations that allow the compounds of the present invention to be continuously delivered to a subject over a period of time, such as several days to several weeks. These formulations can be administered subcutaneously or intramuscularly, and can allow a predetermined amount of the compound to be continuously released in a steady state over time in a subject. The controlled release formulation of the compound of the present invention can be, for example, a pharmaceutical formulation containing polymer microcapsules, such as those described in U.S. Patent Nos. 4,677,191 and 4,728,721, which are incorporated herein by reference. The concentration of the pharmaceutically active compound is adjusted so that an effective amount is provided to produce the desired effect. As is known in the art, the exact dosage depends on the age, weight and condition of the patient or animal. For any particular subject, the specific dosage regimen can be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the formulation. Therefore, the concentration ranges described herein are exemplary only and are not intended to limit the scope or practice of the claimed invention. Unit dose parenteral formulations include packaging in ampoules or pre-packaged in syringes with or without needles for delivery. All preparations for parenteral administration are generally sterile, as practiced in the art. For example, intravenous infusion of a sterile buffered aqueous solution containing the active compound is an effective mode of administration. In another embodiment, a sterile aqueous or oily solution or suspension containing the active substance can be injected as needed to produce the desired pharmacological effect.

[0433] Therapeutic applications

[0434] The present invention also provides a method of treating a disease or condition comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds or pharmaceutical compositions of the present invention.

[0435] In one embodiment, the mammal is a human patient / subject.

[0436] Examples of diseases and conditions that can be treated using the compounds of the invention are described below.

[0437] The compounds of the present invention are antagonists of apelin receptors and may have therapeutic application in any disease that has apelin receptor activity as a component.

[0438] For example, the compounds of the invention may have therapeutic applications in conditions or diseases selected from the group consisting of tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular disease, septic shock, hypotension, pre-eclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (e.g., arthritis and inflammatory bowel disease), avascular or ischemic injury, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis, and HIV infection.

[0439] The terms "breast cancer" and "breast cancer" are used interchangeably. A patient with a malignant "breast tumor" is equivalent to a patient with breast cancer.

[0440] In one embodiment, the compounds of the present invention are useful for treating glioblastoma, preferably glioblastoma multiforme.

[0441] In one embodiment, the compounds of the invention are useful for treating gliomas, preferably astrocytomas, oligodendrogliomas or ependymomas.

[0442] In one embodiment, the compounds of the invention are useful for treating colorectal cancer.

[0443] In one embodiment, the compounds of the invention are useful for treating renal cancer.

[0444] In one embodiment, the compounds of the invention are useful for treating ocular degenerations.

[0445] In one embodiment, the compounds of the invention are useful for treating diabetic retinopathy.

[0446] In another embodiment, provided is a method of treating a tumor or disease caused by abnormal angiogenesis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein.

[0447] In another embodiment, administration of the compound alters tumor cell growth or endothelial cell growth in a patient by inhibiting the action of apelin as a sustaining endocrine factor.

[0448] In one embodiment, administration of the compound alters tumor cell growth or endothelial cell growth in a patient, thereby treating the tumor.

[0449] In certain embodiments, the tumor or disease caused by abnormal angiogenesis is cancer.

[0450] However, abnormal angiogenesis is not limited to cancer. Other diseases, including macular degeneration, are associated with abnormal development of blood vessels.

[0451] Treatment

[0452] In another aspect, the present invention provides a compound or composition of the invention for use in medicine.

[0453] In another aspect, the present invention provides a compound or composition of the present invention for use in treating a condition or disease selected from the group consisting of tumors, cancers, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, pre-eclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (e.g., arthritis and inflammatory bowel disease), avascular or ischemic lesions, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection.

[0454] In some embodiments, the compounds or compositions of the present invention can be used to treat a condition or disease selected from the group consisting of cancer, colorectal cancer, lung cancer, breast cancer / breast cancer, glioma, glioblastoma, glioblastoma multiforme, renal cancer, ocular degeneration and / or diabetic retinopathy.

[0455] In some embodiments, the compounds or compositions of the invention may be used to treat cancer in a patient.

[0456] In some embodiments, the compounds or compositions of the present invention can be used to treat glioblastoma, preferably glioblastoma multiforme, in a patient.

[0457] In some embodiments, the compounds or compositions of the invention may be used to treat glioblastoma in a patient.

[0458] In some embodiments, the compounds or compositions of the invention may be used to treat lung cancer in a patient.

[0459] In some embodiments, the compounds or compositions of the present invention may be used to treat breast cancer / breast cancer in a patient.

[0460] In some embodiments, the compounds or compositions of the invention can be used to treat endometriosis in a patient.

[0461] In some embodiments, the compounds or compositions of the invention may be used to treat colorectal cancer in a patient.

[0462] In some embodiments, the compounds or compositions of the invention may be used to treat renal cancer in a patient.

[0463] In some embodiments, the compounds or compositions of the invention may be used to treat ocular degeneration in a patient.

[0464] In some embodiments, the compounds or compositions of the invention may be used to treat diabetic retinopathy in a patient.

[0465] In some embodiments, the compounds or compositions of the invention may be used to treat a tumor or disease caused by abnormal angiogenesis in a patient in need thereof, optionally wherein administration of the compound modulates tumor cell growth or endothelial growth in the patient.

[0466] In another aspect, the invention provides a method of treating a disease or condition in a patient, the method comprising administering to the patient a compound or composition of the invention.

[0467] In some embodiments, the present invention provides a method for treating the following diseases: tumors, cancers, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reducing dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, preeclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (such as arthritis and inflammatory bowel disease), avascular or ischemic injuries, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric kidney disease, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection, the method comprising administering to the subject a compound or composition of the present invention.

[0468] In some embodiments, the present invention provides a method of treating cancer, colorectal cancer, lung cancer, breast cancer / breast cancer, glioma, glioblastoma, glioblastoma multiforme, renal cancer, ocular degeneration and / or diabetic retinopathy in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0469] In some embodiments, the present invention provides a method of treating glioblastoma, preferably glioblastoma multiforme, in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0470] In some embodiments, the present invention provides a method of treating glioblastoma, preferably lung cancer, in a patient, comprising administering to the subject a compound or composition of the present invention.

[0471] In some embodiments, the present invention provides a method of treating glioblastoma, preferably breast cancer / breast cancer, in a patient, comprising administering to the subject a compound or composition of the present invention.

[0472] In some embodiments, the present invention provides a method of treating endometriosis in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0473] In some embodiments, the present invention provides a method of treating colorectal cancer in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0474] In some embodiments, the present invention provides a method of treating renal cancer in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0475] In some embodiments, the present invention provides a method of treating ocular degeneration in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0476] In some embodiments, the present invention provides a method of treating diabetic retinopathy in a patient, the method comprising administering to the subject a compound or composition of the present invention.

[0477] In some embodiments, the present invention provides a method of treating a tumor or disease caused by abnormal angiogenesis in a patient in need thereof, optionally wherein administration of the compound alters tumor cell growth or endothelial growth in the patient, the method comprising administering to the patient a compound or composition of the present invention.

[0478] In another aspect, the present invention provides the use of a substance or composition of the present invention in the preparation of a medicament for treating a disease or condition selected from the group consisting of: tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, preeclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (e.g., arthritis and inflammatory bowel disease), avascular or ischemic injury, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection.

[0479] In another aspect, the invention includes a method for treating a tumor in a human or animal subject, the method comprising the steps of:

[0480] a) Identifying a human or animal subject in need of tumor treatment

[0481] b) Determining the sensitivity of a mammal to treatment with an apelin receptor antagonist according to the invention

[0482] c) administering a therapeutically effective amount of the apelin receptor antagonist to the subject.

[0483] In one embodiment of the invention, the tumor is a glioblastoma.

[0484] In one embodiment, the present invention provides a method of inhibiting tumor cell growth, invasion and / or proliferation in a subject, wherein the method comprises administering an apelin receptor antagonist of the present invention to a subject in need thereof.

[0485] Joint treatment

[0486] Apelin receptor antagonists may be beneficial when administered in combination with one or more anti-cancer or therapeutic agents. Examples include chemotherapeutic agents selected from the group consisting of temozolomide, etoposide, doxorubicin, cisplatin, paclitaxel, carmustine, lomustine, ceramide and phosphorylcholine.

[0487] Apelin receptor antagonists may be beneficial when administered in combination with anti-angiogenesis inhibitors. [WO2017174758A1]

[0488] In another aspect, the present invention provides a compound or composition of the present invention, which can be used to treat a tumor in a subject, the method comprising the steps of:

[0489] a) Identifying a human or animal subject in need of tumor treatment

[0490] b) Determining the sensitivity of a mammal to treatment with an apelin receptor antagonist according to the invention

[0491] c) administering a therapeutically effective amount of the apelin receptor antagonist to the subject.

[0492] In some embodiments, the tumor is a glioblastoma.

[0493] In another aspect, the present invention provides a compound or composition of the present invention for use in a treatment for inhibiting the growth, invasion and / or proliferation of tumor cells in a subject, wherein the method comprises administering the compound to a subject in need thereof.

[0494] In some embodiments, the treating comprises administering the compound intravenously to the patient.

[0495] In some embodiments, the treatment comprises administering the compound or composition to a patient who has undergone tumor resection surgery, and wherein the compound or composition is administered at the tumor resection site.

[0496] In some embodiments, the treatment comprises administering to the patient a combination of the compound or composition and one or more additional anti-cancer agents.

[0497] In some embodiments, the compound or composition and the one or more anti-cancer agents are each administered to the patient simultaneously, separately, or sequentially.

[0498] In some embodiments, the one or more anticancer agents are selected from the group consisting of bevacizumab, temozolomide, vincristine, irinotecan, procarbazine, BiCNU and carmustine.

[0499] In some embodiments, the anticancer agent is temozolomide.

[0500] In some embodiments, the anti-cancer agent is a chemotherapeutic agent.

[0501] In some embodiments, the chemotherapeutic agent is selected from the group consisting of temozolomide, etoposide, doxorubicin, cisplatin, paclitaxel, carmustine, lomustine, ceramide, and phosphorylcholine, and other suitable anti-cancer agents including kinase inhibitors.

[0502] In some embodiments, the treatment further comprises subjecting the patient to radiation therapy.

[0503] In another aspect, the present invention provides a method of treating a tumor in a subject, the method comprising the steps of:

[0504] a) Identifying a human or animal subject in need of tumor treatment

[0505] b) Determining the sensitivity of a mammal to treatment with an apelin receptor antagonist according to the invention

[0506] c) administering a therapeutically effective amount of the apelin receptor antagonist to the subject.

[0507] In some embodiments, the tumor is a glioblastoma.

[0508] In another aspect, the present invention provides a method of inhibiting the growth, invasion and / or proliferation of tumor cells in a subject, wherein the method comprises administering to a subject in need thereof a compound or composition of the present invention.

[0509] In some embodiments, the method comprises administering the compound or composition intravenously to the patient.

[0510] In some embodiments, the method comprises administering the compound or composition to a patient who has undergone tumor resection surgery, and wherein the compound or composition is administered at the tumor resection site.

[0511] In some embodiments, the method comprises administering to the patient a combination of the compound or composition and one or more additional anti-cancer agents.

[0512] In some embodiments, the compound or composition and the one or more anti-cancer agents are each administered to the patient simultaneously, separately, or sequentially.

[0513] In some embodiments, the one or more anticancer agents are selected from the group consisting of bevacizumab, temozolomide, vincristine, irinotecan, procarbazine, BiCNU and carmustine.

[0514] In some embodiments, the anticancer agent is temozolomide.

[0515] In some embodiments, the anti-cancer agent is a chemotherapeutic agent.

[0516] In some embodiments, the anticancer agent is a kinase inhibitor.

[0517] In some embodiments, the anticancer agent is selected from the group consisting of temozolomide, etoposide, doxorubicin, cisplatin, paclitaxel, carmustine, lomustine, ceramide and phosphorylcholine and other suitable anticancer agents including kinase inhibitors.

[0518] In some embodiments, the method further comprises subjecting the patient to radiation therapy.

[0519] Apelin Receptor Antagonist Activity The present inventors have discovered that the compounds of the present invention have the ability to act as apelin receptor antagonists.

[0520] A therapeutically effective amount of an apelin receptor antagonist can be administered to humans or mammals other than humans. The therapeutically effective amount varies according to each patient, disease, symptom, dosage form and administration route. For example, in the case of an adult patient with cancer (body weight of about 60 kg), using an apelin receptor antagonist according to the present invention or a pharmaceutically active salt thereof as an active ingredient, the dosage can be 0.05 mg to 10 g per day. Such an amount can be administered to the patient once or several times a day.

[0521] A receptor antagonist (in this case an apelin receptor antagonist) refers to a substance that antagonizes or blocks the action of another ligand at a receptor, rather than activating it like an agonist would. A competitive antagonist is a substance that competes with the available agonist for receptor binding sites on the same receptor. The presence of a competitive antagonist will shift the agonist dose-response curve to the right. The slope of the Schild plot for a competitive antagonist will be close to 1, with the X-intercept and Y-intercept each equal to the dissociation constant of the antagonist. [Pharmacology in Drug Discovery and Development: Understanding Drug Response, Edition 2, Terry Kenakin, October 21, 2016, Academic Press]

[0522] Antagonist activity at apelin receptors was measured in two assays. The cAMP assay (Example 4A) measures canonical signaling pathways through G-proteins. pA2 is the negative logarithm to base 10 of the molar concentration of the antagonist, which necessitates doubling the concentration of agonist required to elicit the original submaximal response obtained in the absence of the antagonist.

[61]

[0523] The β-arrestin assay (Example 4B) measures alternative signaling pathways and receptor internalization. pA2 is the negative logarithm to base 10 of the molar concentration of the antagonist, which requires doubling the concentration of agonist required to elicit the original submaximal response obtained in the absence of the antagonist.

[0524] Examples of antagonist activity are taken from Table 3.

[0525] Example 1

[0526] MM193, CRPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluoro-)F, has a binding affinity of Ki = 19 nM at the apelin receptor (Cerep) and pA2 = 7.68 in the DRx β-arrestin assay and pA2 = 7.37 in the DRx cAMP assay.

[0527] Example 2.

[0528] MM300, myristoyl-CRPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluoro-)F, has a binding affinity of Ki = 13 nM at the apelin receptor (Cerep), pA2 = 8.96 in the DRx β-arrestin assay, and pA2 = 9.66 in the DRxcAMP assay.

[0529] Example 3

[0530] MM301, Pyr-RPR-Nle-Abu-KH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F, has a binding affinity of Ki = 28 nM at the apelin receptor (Cerep), pA2 = 7.28 in the DRx β-arrestin assay, and pA2 = 6.29 in the DRxcAMP assay.

[0531] The therapeutic effects of apelin receptor antagonists are due to effects on beta-arrestin or cAMP signaling or a combination of both. The compounds may exhibit pA2 values ​​consistent with inhibition of beta-arrestin and / or cAMP signaling, with pA2 values ​​of 0-10, preferably pA2 values ​​of 4-10.

[0532] Example

[0533] Example 1: Synthesis of compounds

[0534] Peptides MM54, MM107, MM108, MM193, MM262. Synthesis was performed using PT Symphony and using standard Fmoc chemistry using Cambridge Peptides (Cambridge Peptides Limited, 1 PhilipVictor Road, Birmingham, West Midland, B202 QB, UK) and purified by RP-HPLC on a C18 column. If applicable, peptides were cyclized using iodine oxidation and purified by RP-HPLC. Peptides were analyzed by LCMS and mass spectrometry.

[0535] Peptides MM297, MM298, MM299, MM300, MM301, MM302, MM312, MM313, MM314, MM315, MM316, MM412, MM413, MM414, MM415, MM416, MM417, MM418, MM419, MM420, MM421, MM422, MM423, MM424, MM426, MM428.

[0536] The synthesis was performed by Pepmic Co., Ltd. NO. 35 XingXian Road, High-tech Development Zone, Suzhou, China 215151, using standard fMOC synthesis. The peptides were analyzed by LCMS and mass spectrometry.

[0537] The final peptide was purified using COSMOSIL C18 (30*250mm, 15μm, ), purified by preparative HPLC, eluting with a linear gradient of CH3CN (11-20% (00520-5, -6), 8-18% (00520-7), 10-20% (00520-8)) in 0.1% TFA / H2O at a flow rate of 20 ml / min in 30 min, and detecting the peptide by UV at 230 nm.

[0538] The purity of the collected major peak was confirmed by analytical HPLC using an injection volume of 20 μL, injected into a Kinetix 100A 4, 6×50 mm column at 60° C. at a flow rate of 1.5 ml / min over 8 minutes with a gradient of 2% to 80% acetonitrile. The peptide sequence and cyclization were confirmed by electrospray ionization mass spectrometry in either positive or negative scan mode.

[0539] Characterization of compounds of the invention

[0540] Table 1a

[0541] Compound structure MM54 Ring (1-6) CRPRLC-KH-Ring (9-14) CRPRLC MM107 CRPRLCHKCRPRLC MM108 CRPRLCKHCRPRLC MM193 CRPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluoro-)F MM262 QRPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluorophenylalanine) MM297 pyr-RPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluoro-)F MM298 CRPR-Nle-Abu-KHCR-Aib-R-Nle-(3,4,5-trifluoro-)F MM299 CRPR-Nle-CKH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM300 Myristoyl-CRPR-Nle-CKHCR-Aib-R-Nle-(3,4,5-trifluoro-)F MM301 Pyr-RPR-Nle-Abu-KH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM302 CRPR-Nle-CHKCR-Aib-R-Nle-(3,4,5-trifluoro-)F MM312 ARPR-Nle-CKH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM313 Ac-ARPR-Nle-CKH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM314 ARPR-Nle-Abu-KH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM315 Myristoyl-ARPR-Nle-Abu-KH-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F MM316 Myristoyl-ARPR-Nle-Abu-HK-Abu-R-Aib-R-Nle-(3,4,5-trifluoro-)F

[0542]

[0543]

[0544]

[0545]

[0546]

[0547] Example 2: Binding and functional assays

[0548] Binding assays were performed by Cerep (Celle L'Evescault, France) on Chinese hamster ovary (CHO-K1) cells expressing the human apelin receptor. Initial experiments were performed to determine whether a single concentration of the test peptide (1 or 10 μmol / L) inhibited [Glp 65 , Nle 75 , Tyr 77 ][ 125 I] Specific binding of apelin-13 [0.03nmol / L]. The results are expressed as the percentage of control specific binding obtained in the presence of the test compound ((measured specific binding / control specific binding)×100) and the percentage inhibition of control specific binding (100-((measured specific binding / control specific binding)×100)). Results showing inhibition greater than 50% are considered to indicate a significant effect of the test compound. Results showing inhibition of 20% to 50% indicate a weak to moderate effect. Results showing inhibition less than 20% are not considered significant and are primarily attributed to the variability of the signal around the control level. For those compounds that showed greater than 50% inhibition of specific binding, competition curves were generated and analyzed using nonlinear regression analysis of the average replicates to obtain the IC 50 The concentration that causes half-maximal inhibition of control specific binding was calculated and the curve fit using the Hill equation (Y = D + [(A-D) / (1 + (C / C 50 ) nH )], where Y = specific binding, D = minimum specific binding, A = maximum specific binding, C = compound concentration, C 50 =IC s0 , nH = slope factor). Using the ChengPrusoff equation (Ki = IC 50 / (1+(L / K D )) Calculate the inhibition constant (Ki), where L = the concentration of radioligand in the assay, K D = equilibrium dissociation constant of the radioligand for the receptor). In each experiment, the corresponding reference compound [Pyr 1 ]Apelin-13, tested simultaneously with the test compound.

[0549] Example 3: Determination of affinity (pK) for human apelin receptor i )

[0550] For competition binding experiments, human left ventricular homogenate was mixed with 0.1 nmol / L [Glp 65 , Nle 75 , Tyr77 ][ 125 I] Apelin-13 was incubated in the presence of increasing concentrations of the test peptide (0.5 pmol / L-10 pmol / L) for 90 min. 1 ] Apelin-13 defines nonspecific binding. Equilibrium was disrupted by centrifugation (20,000 g for 10 min, 4°C). The precipitate was washed with Tris-HCl buffer (50 mmol / L, pH 7.4, 4°C), centrifuged again and the bound radioactivity in the final precipitate was counted. Data from triplicate experiments were analyzed using iterative nonlinear curve fitting programs EBDA and LIGAND (KELL software package, BioSoft, UK) or GraphPad Prism 6 to derive affinities (expressed as equilibrium dissociation constants K D or the negative logarithm of the dissociation constant 10 , pK i ±sem) and receptor density (B MAx ± sem, values ​​are expressed in fmoles bound per mg protein).

[0551] Example 4: cAMP and β-arrestin assays

[0552] cAMP (cAMP Hunter TM Express AGTRL1 CHO-K1 GPCR assay, DiscoverX Corporation, Ltd. Birmingham, UK) and β-arrestin ( eXpress AGTRL1 CHO-K1 β-arrestin GPCRArray, DiscoverX Corporation, Ltd. Birmingham, UK) assays were performed according to the manufacturer's instructions. The cAMP assay measures the canonical signaling pathway through G-proteins. The β-arrestin assay measures the alternative signaling pathway and receptor internalization.

[0553] Example 4A: cAMP assay

[0554] To inhibit forskolin-induced cAMP accumulation, CHO-K1 cells artificially expressing human apelin receptor were seeded in cell plate medium in 96-well plates and incubated at 37°C in 5% CO2 for 24 hours, followed by replacement of the medium with cAMP antibody reagent in cell assay buffer. The basal level of cAMP was increased by incubating cells with 15 μmol / L forskolin for 30 minutes at 37°C in the absence or presence of test peptide (1 pmol / L-0.3 μmol / L) diluted in cell assay buffer. The cells were then incubated with a mixture of lysis buffer, cAMP buffer D and detection reagent for 1 hour at room temperature, followed by incubation with cAMP reagent A for 3 hours at room temperature. Using LumiLITE TM Chemiluminescence was read by a microplate reader (DiscoverX).

[0555] Agonist concentration-response data measured in relative light units (RLU) were analyzed using a 4-parameter logistic equation in GraphPad Prism 6 (La Jolla, CA, USA) to determine the pD2 value (negative log of ECSO). 10 (EC 50 is the concentration that produces a half-maximal response) and a maximum response (E MAX ). Average data from replicate experiments were normalized to percent inhibition of forskolin-stimulated cAMP production. Peptides that did not produce an agonist response but showed receptor affinity in the human heart binding assay were subsequently tested as receptor antagonists. For these experiments, a series of antagonists against [pyr 1 ]Concentration response curve of apelin-13. Gaddum / Schild EC was used in GraphPad Prism 6 50 Functional analysis of data to determine antagonist affinity expressed as pA2 (shifting concentration response curves by a factor of 2 to [pyr 1 ] is the negative logarithm of the antagonist concentration required for apelin-13). If not different from 1, the Schild slope is constrained to 1 so that pA2 is equal to the antagonist dissociation constant K B The negative logarithm of .

[0556] Example 4B: β-Arrestin Assay

[0557] To recruit β-arrestin, CHO-K1 cells artificially expressing the human apelin receptor were seeded in cell plating medium in 96-well plates and cultured for 48 h at 37°C in 5% CO2. Concentration response curves were constructed to test peptides (1 pmol / L-30 μmol / L) diluted in cell plating medium and added to cells for 90 min at 37°C. If no response was obtained, the test peptide was investigated as an antagonist. For antagonist experiments, an additional 30 min incubation was performed in the absence or presence of a single concentration (1-30 μmol / L) of the test peptide [pyr 1 ], and then add the apelin-13 concentration response curve. Then add the detection reagent and incubate for 2 hours at room temperature. The agonist response measured in RLU was fitted to a 4-parameter logistic equation in GraphPadPrism 6 (La Jolla, CA, USA) to determine the potency pD2 and E as described in the cAMP assay. MAX The data were then normalized to [pyr 1 ] maximal response of apelin-13, which was used as the reference agonist in each experiment. If no agonist response was obtained, the agonist was tested by repeating [pyr 1 ] Apelin-13 concentration response curves were used to investigate the antagonist activity of the test compounds. The Gaddum / Schild EC was analyzed in GraphPad Prism 6 as described for the cAMP assay. 50 Functional analysis data were used to determine pA2 values.

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564] As demonstrated by the data in Table 3, there exists a class of linear apelin receptor antagonists that exhibit a range of pharmacological properties including apelin receptor affinity, c-AMP inhibition, and β-arrestin inhibition.

[0565] The affinity of the disclosed compounds (Cerep K i) ranged from 80 nM to 3 nM, indicating high binding affinity for apelin receptors. High binding affinity generally confers high receptor selectivity at the concentration required for receptor inhibition. High binding affinity generally translates into lower effective therapeutic doses. The disclosed compounds have higher binding affinity than the previously disclosed antagonist MM54 [Brain, Vol. 140, No. 11, November 1, 2017, pp. 2939-2954] and show antagonism to cAMP and β-arrestin.

[0566] The disclosed activity in the human left ventricle assay (HLV pKi) indicates that the compound can bind to the human apelin receptor in excised human tissue.

[0567] The activity disclosed in the β-arrestin assay (DRx β-arrestin, pA2 range 5.87-8.96) indicates the ability of the antagonist compound to inhibit apelin-13 to activate this pathway, which is generally considered to be after receptor internalization, signaling, and receptor deactivation (desensitization). Greater antagonist activity corresponds to less activation of β-arrestin by apelin-13.

[0568] The activity disclosed in the c-AMP assay (DRx cAMP, pA2 range 5.86-9.7) indicates inhibition of the receptor signaling cascade regulated by the release of c-AMP. Greater antagonistic activity corresponds to less c-AMP activity of apelin-13.

[0569] Within this class of compounds, there is evidence of a bias towards either c-AMP (MM300) or β-arrestin (MM302) inhibition. This is an unexpected and novel finding. For example, MM193 is similar in its inhibitory effects between β-arrestin and cAMP pathways, while MM302 shows an inhibition bias of almost one log unit towards inhibition of the β-arrestin pathway.

[0570] The inhibition of the cAMP pathway or the shift in inhibition of the beta-arrestin pathway to the apelin receptor is novel and identifies selective apelin receptor inhibitors that may confer more specific therapeutic effects.

[0571] Embodiments of the invention are set out in the following numbered clauses.

[0572] 1. A compound comprising the sequence of formula I:

[0573] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5-L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0574] (Formula I)

[0575] in

[0576] X 1 is any amino acid;

[0577] X 2 Selected from the group consisting of R, H and K;

[0578] X 3 It is P;

[0579] X 4 It is R;

[0580] X 5 Selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0581] X 6 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0582] X 7 Selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0583] X 8 Selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0584] X 9 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0585] X 10 Selected from the group consisting of R, H and K;

[0586] X 11 Selected from the group consisting of Aib and P;

[0587] X12 Selected from the group consisting of R, H and K;

[0588] X 13 Selected from the group consisting of Nle, Aib, L, V, I and A;

[0589] X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0590] in:

[0591] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0592] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0593] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0594] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0595] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0596] 2. The compound according to clause 1, comprising the sequence of formula I:

[0597] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L s -X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0598] (Formula I)

[0599] in

[0600] X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A;

[0601] X 2 It is R;

[0602] X 3 It is P;

[0603] X 4 It is R;

[0604] X 5 Selected from the group consisting of A, V, I, Nle and L;

[0605] X 6 Selected from the group consisting of Abu, M, P and C;

[0606] X 7 Selected from the group consisting of H, R and K;

[0607] X 8 Selected from the group consisting of R, K and H;

[0608] X 9 Selected from the group consisting of Abu, M, P and C;

[0609] X 10 is R or K;

[0610] X 11 Selected from the group consisting of Aib and P;

[0611] X 12 is R, K or H;

[0612] X 13 Selected from the group consisting of A, V, I, Nle and L;

[0613] X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14It may be particularly one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan;

[0614] in:

[0615] 1) For X 1 To X 14 , any of the listed natural amino acids may be optionally modified independently, and wherein 2) for X 1 To X 14 Any of the modified amino acids listed can be optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) can be optionally alkylated, esterified, N-alkylamidated, hydrogen replaced by any halogen group or hydroxyl group, or conjugated to a linker L c With R 3 Partial conjugation;

[0616] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0617] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 can independently be a peptide, an acetyl, a formyl, a propynyl, a biotin, a myristoyl or a palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, an albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0618] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0619] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0620] 2a. A compound according to any one of the preceding clauses, wherein X 1 Selected from the group consisting of V, I, L, M, P, Y, W, C, Q, Glp and A.

[0621] 2b. A compound according to any one of the preceding clauses, wherein X 2 It's R.

[0622] 2c. A compound according to any one of the preceding clauses, wherein X 3 It's P.

[0623] 2d. A compound according to any one of the preceding clauses, wherein X 4 It's R.

[0624] 2e. A compound according to any one of the preceding clauses, wherein X 5 Selected from the group consisting of A, V, I, Nle and L.

[0625] 2f. A compound according to any one of the preceding clauses, wherein X 6 Selected from the group consisting of Abu, M, P and C.

[0626] 2g. A compound according to any one of the preceding clauses, wherein X 7 Selected from the group consisting of H, R and K.

[0627] 2h. A compound according to any one of the preceding clauses, wherein X 8 Selected from the group consisting of R, K and H.

[0628] 2i. A compound according to any one of the preceding clauses, wherein X 9 Selected from the group consisting of Abu, M, P and C.

[0629] 2j. A compound according to any one of the preceding clauses, wherein X 10 Selected from the group consisting of R or K.

[0630] 2k. A compound according to any one of the preceding clauses, wherein X 11 Selected from the group consisting of Aib and P.

[0631] 21. A compound according to any one of the preceding clauses, wherein X 12 Selected from the group consisting of R, K or H.

[0632] 2m. A compound according to any one of the preceding clauses, wherein X 13 Selected from the group consisting of A, V, I, Nle and L.

[0633] 2n. A compound according to any one of the preceding clauses, wherein X 14 is selected from the group consisting of C, F, other hydrophobic amino acids (alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 It may specifically be one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-phenylvinylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine or aminoindan.

[0634] 3. A compound according to any one of the preceding clauses, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or deuterated analogue thereof.

[0635] 4. A compound according to any one of the preceding clauses, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0636] 5. A compound according to any one of the preceding clauses, wherein X 1 To X 14 One or more of each independently conjugated linker L c Connect to R 3 part.

[0637] 6. A compound according to any one of the preceding clauses, wherein X 1 , X 6 , X 9 and X 14One or more of each independently conjugated linker L c With R 3 moiety, optionally wherein the conjugation linker is maleimide or PEGylated maleimide, optionally wherein R 3 It is a fatty acid, a pegylated molecule, a peptide, a polypeptide or an antibody molecule.

[0638] 7. A compound according to any one of the preceding clauses, wherein X 1 To X 14 None of them is conjugated by linker L c With R 3 connect.

[0639] 8. A compound according to any one of the preceding clauses, wherein (R 1 -L c ) and (-L c -R 2 ) does not exist.

[0640] 9. A compound according to any one of the preceding clauses, wherein (R 1 -L c ) and (-L c -R 2 ) do not exist, so that the sequence ends at X 1 and X 14 .

[0641] 10. A compound according to any one of the preceding clauses, wherein for X 1 To X 14 In each of the above, the listed natural amino acids are not modified, and the listed modified amino acids are not further modified.

[0642] 11. A compound according to any one of the preceding clauses, wherein X 1 To X 14 Each is an amide bond or an N-methylated amide bond, or is an amide bond.

[0643] 12. A compound according to any one of the preceding clauses, wherein X 1 It is C, Q, Glp or A.

[0644] 12a. A compound according to any one of the preceding clauses, wherein X 1 It is C.

[0645] 12b. A compound according to any one of the preceding clauses, wherein X 1 It's Q.

[0646] 12c. A compound according to any one of the preceding clauses, wherein X 1It's Glp.

[0647] 12d. A compound according to any one of the preceding clauses, wherein X 1 It is A.

[0648] 13. A compound according to any one of the preceding clauses, wherein X 2 It's R.

[0649] 14. A compound according to any one of the preceding clauses, wherein X 3 It's P.

[0650] 15. A compound according to any one of the preceding clauses, wherein X 4 It's R.

[0651] 16. A compound according to any one of the preceding clauses, wherein X 2 is R, and said R is modified by methylation.

[0652] 17. A compound according to any one of the preceding clauses, wherein X 4 is R, and said R is modified by methylation.

[0653] 18. A compound according to any one of the preceding clauses, wherein X 5 Selected from the group consisting of Nle and L.

[0654] 19. A compound according to any one of the preceding clauses, wherein X 13 Selected from the group consisting of Nle and L.

[0655] 20. A compound according to any one of the preceding clauses, wherein X 6 Selected from the group consisting of C and Abu.

[0656] 21. A compound according to any one of the preceding clauses, wherein X 9 Independently selected from the group consisting of C and Abu.

[0657] 22 A compound according to any one of the preceding clauses, wherein X 7 is K and X 8 is H, or X 7 is H and X 8 is K, or where X 7 is A and X 8 is K, or where X7 is K and X 8 It is A.

[0658] 23. A compound according to any one of the preceding clauses, wherein X 7 and X 8 One is H and the other is K.

[0659] 24. A compound according to any one of the preceding clauses, wherein X 10 It's R.

[0660] 25. A compound according to any one of the preceding clauses, wherein X 10 and X 12 It's R.

[0661] 26. A compound according to any one of the preceding clauses, wherein X 11 Selected from the group consisting of P and Aib.

[0662] 27. A compound according to any one of the preceding clauses, wherein X 14 It is selected from C and (3,4,5-trifluoro-)F, preferably (3,4,5-trifluoro-)F.

[0663] 28. A compound according to any one of the preceding clauses, wherein X 1 is C, optionally wherein R 1 It is myristoyl.

[0664] 29. A compound according to any one of the preceding clauses, wherein X 5 It's Nle.

[0665] 30. A compound according to any one of the preceding clauses, wherein X 6 It's Abu.

[0666] 31. A compound according to any one of the preceding clauses, wherein X 7 is K and X 8 It's H.

[0667] 32. A compound according to any one of the preceding clauses, wherein X 9 It's Abu.

[0668] 33. A compound according to any one of the preceding clauses, wherein X 10 It's R.

[0669] 34. A compound according to any of the preceding clauses, wherein X 11 It's Aib.

[0670] 35. A compound according to any one of the preceding clauses, wherein X 12 It's R.

[0671] 36. A compound according to any one of the preceding clauses, wherein X 13 It's Nle.

[0672] 37. A compound according to any one of the preceding clauses, wherein X14 It is (3,4,5-trifluoro)F.

[0673] 37a. A compound according to any one of the preceding clauses, wherein X 1 Be modified.

[0674] 37b. A compound according to any one of the preceding clauses, wherein X 1 Not modified.

[0675] 37c. A compound according to any one of the preceding clauses, wherein X 2 Be modified.

[0676] 37d. A compound according to any one of the preceding clauses, wherein X 2 Not modified.

[0677] 37e. A compound according to any one of the preceding clauses, wherein X 3 Be modified.

[0678] 37f. A compound according to any one of the preceding clauses, wherein X 3 Not modified.

[0679] 37g. A compound according to any one of the preceding clauses, wherein X 4 Be modified.

[0680] 37h. A compound according to any one of the preceding clauses, wherein X 4 Be modified.

[0681] 37i. A compound according to any one of the preceding clauses, wherein X 5 Not modified.

[0682] 37j. A compound according to any one of the preceding clauses, wherein X 5 Be modified.

[0683] 37k. A compound according to any of the preceding clauses, wherein X 6 Not modified.

[0684] 371. A compound according to any of the preceding clauses, wherein X 6 Be modified.

[0685] 37m. A compound according to any one of the preceding clauses, wherein X 7 Not modified.

[0686] 37n. A compound according to any one of the preceding clauses, wherein X 7 Be modified.

[0687] 37o. A compound according to any one of the preceding clauses, wherein X 8 Be modified.

[0688] 37p. A compound according to any one of the preceding clauses, wherein X 8 Not modified.

[0689] 37q. A compound according to any one of the preceding clauses, wherein X 9 Be modified.

[0690] 37r. A compound according to any one of the preceding clauses, wherein X 9 Not modified.

[0691] 37s. A compound according to any one of the preceding clauses, wherein X 10 Be modified.

[0692] 37t. A compound according to any one of the preceding clauses, wherein X 10 Not modified.

[0693] 37u. A compound according to any one of the preceding clauses, wherein X 11 Be modified.

[0694] 37v. A compound according to any one of the preceding clauses, wherein X 11 Not modified.

[0695] 37w. A compound according to any one of the preceding clauses, wherein X 12 Be modified.

[0696] 37x. A compound according to any one of the preceding clauses, wherein X 12 Not modified.

[0697] 37y. A compound according to any one of the preceding clauses, wherein X 13 Be modified.

[0698] 37z. A compound according to any one of the preceding clauses, wherein X 13 Not modified.

[0699] 37aa. A compound according to any one of the preceding clauses, wherein X 14 Be modified.

[0700] 37ab. A compound according to any one of the preceding clauses, wherein X 14 Not modified.

[0701] 38. A compound according to any of the preceding clauses, wherein X 1 To X 14One or more of is C, R or K and is modified, wherein the modification comprises directly or indirectly linking the C, R or K to a protein or a fatty acid.

[0702] 39. A compound according to any one of the preceding clauses, wherein R 1 is a C1-C25 saturated or unsaturated fatty acyl moiety, which is optionally conjugated via a linker L c With X 1 Combine.

[0703] 40. A compound according to any of the preceding clauses, wherein the fatty acyl moiety comprises a fatty acyl group selected from the group consisting of butyryl, hexanoyl, octanoyl, decanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, octadecandioyl, suberate, sebacoyl, dodecanedioyl, adipoyl, succinoyl, tetradecanedioyl and hexadecandioyl.

[0704] 41. A compound according to any one of the preceding clauses, wherein R 1 is optionally conjugated via a linker L c With X 1 Conjugated polyethylene glycol polymer moiety.

[0705] 42. A compound according to any of the preceding clauses, wherein the polyethylene glycol polymer portion comprises a 5 kDa, 10 kDa or 20 kDa polyethylene glycol polymer.

[0706] 43. A compound according to any of the preceding clauses, wherein there is at least one conjugated linker L c , and it contains 3-mercaptopropionic acid.

[0707] 44. A compound according to any one of the preceding clauses, wherein R 1 is an immunoglobulin portion or an immunoglobulin Fc domain portion, which is optionally conjugated via a linker L c With X 1 Combine.

[0708] 45. A compound according to any of the preceding clauses, wherein there is at least one conjugated linker L c , and it is a peptidyl linker.

[0709] 46. ​​A compound according to any of the preceding clauses, wherein there is at least one conjugated linker L c , and it is a non-peptidyl linker.

[0710] 47. A compound according to any one of the preceding clauses, wherein the non-peptidyl conjugated linker L cContains polyethylene glycol polymer.

[0711] 48. A compound according to any of the preceding clauses, wherein there is at least one conjugated linker L c , and which contains a maleimide moiety, a pegylated maleimide moiety or a thioether.

[0712] 49. A compound according to any one of the preceding clauses, wherein X 1 It is C, R 1 is a protein, for example a protein selected from albumin and albudAb.

[0713] 50. A compound according to any of the preceding clauses, wherein the compound is selected from the following table:

[0714]

[0715] 51. A compound according to any of the preceding clauses, wherein the compound is an apelin receptor antagonist.

[0716] 52. A pharmaceutical composition comprising a compound as described in any one of the preceding clauses and a pharmaceutically acceptable diluent, excipient or carrier.

[0717] 53. A pharmaceutical composition according to clause 52, wherein the composition is formulated for:

[0718] (a) systemic delivery, such as intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, intravaginal, intrarectal, intrapulmonary, intracranial or oral delivery;

[0719] (b) local delivery, such as topical or iontophoretic delivery; or

[0720] (c) transdermal delivery, e.g., via a patch;

[0721] (d) Inhalation through the lungs;

[0722] (e) Intraocular delivery, including topical, injectable, contact lens-releasing drugs, biodegradable micro- and nanoparticles, and surgical implant systems.

[0723] 54. A compound or composition according to any preceding clause for use in medicine.

[0724] 55. A compound or composition according to any of the preceding clauses for use in treating a condition or disease selected from the group consisting of tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, pre-eclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (such as arthritis and inflammatory bowel disease), avascular or ischemic lesions, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection.

[0725] 56. A compound or composition according to any one of clauses 1 to 53 for use in treating a condition or disease selected from the group consisting of cancer, colorectal cancer, lung cancer, breast cancer / breast cancer, glioma, glioblastoma, glioblastoma multiforme, renal cancer, ocular degeneration and / or diabetic retinopathy.

[0726] 56a. A compound or composition according to any one of clauses 1 to 53 for use in treating a glioma, preferably an astrocytoma, an oligodendroglioma or an ependymoma, in a patient.

[0727] 57. A compound or composition according to any one of clauses 1 to 53 for use in treating cancer in a patient.

[0728] 58. A compound or composition according to any one of clauses 1 to 53 for use in treating glioblastoma, preferably glioblastoma multiforme, in a patient.

[0729] 59. A compound or composition according to any one of clauses 1 to 53 for use in treating glioblastoma in a patient.

[0730] 60. A compound or composition according to any one of clauses 1 to 53 for use in treating lung cancer in a patient.

[0731] 61. A compound or composition according to any one of clauses 1-53 for use in treating breast cancer / breast cancer in a patient.

[0732] 62. A compound or composition according to any one of clauses 1 to 53 for use in treating endometriosis in a patient.

[0733] 63. A compound or composition according to any one of clauses 1-53 for use in treating colorectal cancer in a patient.

[0734] 64. A compound or composition according to any one of clauses 1 to 53 for use in treating renal cancer in a patient.

[0735] 65. A compound or composition according to any one of clauses 1 to 53 for use in treating an ocular degeneration in a patient.

[0736] 66. A compound or composition according to any one of clauses 1 to 53 for use in treating diabetic retinopathy in a patient.

[0737] 67. A compound or composition according to any one of clauses 1-53 for use in treating a tumor or disease caused by abnormal angiogenesis in a patient in need thereof, optionally wherein administration of the compound modulates tumor cell growth or endothelial growth in the patient.

[0738] 68. A compound or composition according to any one of clauses 1 to 53 for use in treating a tumor in a patient, the method comprising the steps of:

[0739] a) identifying a human or animal subject in need of tumor treatment;

[0740] b) determining the sensitivity of a mammal to treatment with an apelin receptor antagonist compound as defined in any one of clauses 1 to 51 or a composition as defined in clause 52 or 53;

[0741] c) administering a therapeutically effective amount of the compound or composition to a subject.

[0742] 69. A compound or composition for use according to any one of clauses 67-68, wherein the tumour is a glioblastoma.

[0743] 70. A compound or composition according to any one of clauses 1 to 53 for use in treatment of inhibiting tumor cell growth, invasion and / or proliferation in a subject, wherein the method comprises administering the compound to a subject in need thereof.

[0744] 71. A compound or composition for use according to any one of clauses 67-70, wherein the treatment comprises administering the compound or composition intravenously to the patient.

[0745] 72. A compound or composition for use according to any one of clauses 67 to 71, wherein the treatment comprises administering the compound or composition to a patient who has undergone tumor resection surgery, and wherein the compound or composition is administered at the tumor resection site.

[0746] 73. A compound or composition for use according to any one of clauses 67 to 72, wherein the treatment comprises administering to the patient a combination of the compound or composition and one or more additional anti-cancer agents.

[0747] 74. The compound or composition for use according to clause 73, wherein the compound or composition and the one or more anti-cancer agents are each administered to the patient simultaneously, separately or sequentially.

[0748] 75. A compound or composition for use according to clause 74, wherein the one or more anticancer agents are selected from the group consisting of bevacizumab, temozolomide, vincristine, irinotecan, procarbazine, BiCNU and carmustine.

[0749] 76. A compound or composition for use according to clause 74, wherein the anticancer agent is temozolomide.

[0750] 77. A compound or composition for use according to clause 73, wherein the anticancer agent is a chemotherapeutic agent.

[0751] 78. A compound or composition for use according to clause 77, wherein the chemotherapeutic agent is selected from the group consisting of temozolomide, etoposide, doxorubicin, cisplatin, paclitaxel, carmustine, lomustine, ceramide and phosphorylcholine and other suitable anti-cancer agents (including kinase inhibitors).

[0752] 79. A compound or composition for use according to clauses 67-78, wherein the treatment further comprises subjecting the patient to radiation therapy.

[0753] 80. A method of treating a disease or condition in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0754] 81. A method of treating a disease or condition comprising: a tumor, a cancer, a metabolic disease, diabetes, a disease involving angiogenesis and lymphangiogenesis, an obesity disease including reduction of dietary sugar intake, a cardiovascular disease, a neoplasia, a peripheral vascular disease, a septic shock, a hypotension, a pre-eclampsia, an ocular degeneration, an idiopathic pulmonary fibrosis, an inflammatory disease (e.g., arthritis and inflammatory bowel disease), avascular or ischemic lesions, an eczema, an ulcer, a lymphedema, a bone disease, angiogenesis, a hemangioma, a proteinuric nephropathy, a diabetic retinopathy, a choroidal vascular disease (AMD), a macular degeneration disease, a psoriasis, an endometriosis, a glioma, a glioblastoma, a glioblastoma multiforme, a colorectal cancer, a renal cancer, a lung cancer, a breast cancer / breast cancer, an endometriosis, any disease involving angiogenesis and an HIV infection, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0755] 82. A method of treating the following diseases or conditions in a patient: cancer, colorectal cancer, lung cancer, breast cancer / breast cancer, glioma, glioblastoma, glioblastoma multiforme, renal cancer, ocular degeneration and / or diabetic retinopathy, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0756] 82a. A method of treating a glioma, preferably an astrocytoma, oligodendroglioma or ependymoma, in a patient, the method comprising administering to the patient a compound according to any one of clauses 1 to 51 or a composition according to any one of clauses 52 to 53.

[0757] 83. A method of treating glioblastoma, preferably glioblastoma multiforme, in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0758] 84. A method of treating cancer, preferably lung cancer, in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0759] 85. A method of treating cancer, preferably breast cancer / breast cancer, in a patient, the method comprising administering to the patient a compound as described in any one of clauses 1 to 51 or a composition as described in any one of clauses 52 to 53.

[0760] 86. A method of treating endometriosis in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0761] 87. A method of treating colorectal cancer in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0762] 88. A method of treating renal cancer in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0763] 89. A method of treating ocular degeneration in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0764] 90. A method of treating diabetic retinopathy in a patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0765] 91. A method of treating a tumor or disease caused by abnormal angiogenesis in a patient in need thereof, optionally wherein administration of the compound alters tumor cell growth or endothelial growth in the patient, the method comprising administering to the patient a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0766] 92. A method of treating a tumor in a subject, the method comprising the steps of:

[0767] a) identifying a human or animal subject in need of tumor treatment;

[0768] b) determining the sensitivity of a mammal to treatment with an apelin receptor antagonist compound according to any one of clauses 1 to 51 or a composition according to clause 52 or 53; and

[0769] c) administering a therapeutically effective amount of the apelin receptor antagonist or composition to the subject.

[0770] 93. The method of clause 91 or 92, wherein the tumor is a glioblastoma.

[0771] 94. A method of inhibiting tumor cell growth, invasion and / or proliferation in a subject, wherein the method comprises administering to a subject in need thereof a compound of any one of clauses 1 to 51 or a composition of any one of clauses 52 to 53.

[0772] 95. The method according to any one of clauses 91 to 94, comprising administering the compound or composition intravenously to the patient.

[0773] 96. The method according to any one of clauses 91-95, wherein the method comprises administering the compound or composition to a patient who has undergone tumor resection surgery, and wherein the compound or composition is administered at the tumor resection site.

[0774] 97. The method according to any one of clauses 91 to 96, wherein the treatment comprises administering to the patient a combination of the compound or composition and one or more additional anti-cancer agents.

[0775] 98. The method according to clause 97, wherein the compound or composition and the one or more anti-cancer agents are each administered to the patient simultaneously, separately or sequentially.

[0776] 99. The method according to clause 98, wherein the one or more anticancer agents are selected from the group consisting of bevacizumab, temozolomide, vincristine, irinotecan, procarbazine, BiCNU and carmustine.

[0777] 100. The method according to clause 98, wherein the anticancer agent is temozolomide.

[0778] 101. A compound or composition for use according to clause 97, wherein the anticancer agent is a chemotherapeutic agent.

[0779] 102. The method according to clause 101, wherein the chemotherapeutic agent is selected from the group consisting of temozolomide, etoposide, doxorubicin, cisplatin, paclitaxel, carmustine, lomustine, ceramide and phosphorylcholine and other suitable anti-cancer agents (including kinase inhibitors).

[0780] 103. A method according to any of clauses 91-102, wherein the method further comprises subjecting the patient to radiation therapy.

[0781] 104. Use of a substance or composition as described in any one of clauses 1 to 53 in the preparation of a medicament for treating a disease or condition selected from the group consisting of: tumors, cancer, metabolic diseases, diabetes, diseases involving angiogenesis and lymphangiogenesis, obesity diseases including reduced dietary sugar intake, cardiovascular diseases, neoplasia, peripheral vascular diseases, septic shock, hypotension, pre-eclampsia, ocular degeneration, idiopathic pulmonary fibrosis, inflammatory diseases (such as arthritis and inflammatory bowel disease), avascular or ischemic lesions, eczema, ulcers, lymphedema, bone diseases, vascular proliferation, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, psoriasis, endometriosis, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer / breast cancer, endometriosis, any disease involving angiogenesis and HIV infection.

[0782] 105. A compound comprising 6 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0783] 106. A compound comprising 7 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0784] 107. A compound comprising 8 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0785] 108. A compound comprising 9 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0786] 109. A compound comprising 10 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0787] 110. A compound comprising 11 consecutively linked (L 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0788] 111. A compound comprising 12 consecutively linked (L) defined by formula I 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0789] 112. A compound comprising 13 consecutively linked (L) defined by formula I 1-14 )Amino Acid(X 1-14 ), wherein the sequence overlaps with a portion of one of SEQ.ID NOS 3-17.

[0790] 113. A compound according to clauses 105-112 for use in clauses 53-104.

[0791] 114. A compound comprising the sequence of Formula I:

[0792] (R 1 -L c )-X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 4 -L 11 -X 11 -L 12 -X 12 -L 13 -X 13 -L 14 -X 14 (-L c -R 2 )

[0793] (Formula I)

[0794] in

[0795] X 1 is any amino acid;

[0796] X 2 Selected from the group consisting of R, H and K;

[0797] X 3 It is P;

[0798] X 4 It is R;

[0799] X 5 Selected from the group consisting of Nle, L, A, V, I, M, F, Y and W;

[0800] X 6 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0801] X 7 Selected from the group consisting of H, K, A, V, I, L, M, F, Y, W and R;

[0802] X 8Selected from the group consisting of K, H, A, V, I, L, M, F, Y, W and R;

[0803] X 9 Selected from the group consisting of Abu, C, A, V, I, L, M, F, Y, W and P;

[0804] X 10 Selected from the group consisting of R, H and K;

[0805] X 11 Selected from the group consisting of Aib and P;

[0806] X 12 Selected from the group consisting of R, H and K;

[0807] X 13 Selected from the group consisting of Nle, Aib, L, V, I and A;

[0808] X 14 is selected from the group consisting of none, C, F, other hydrophobic amino acids (including alanine (A), isoleucine (I), leucine (L), methionine (M), tyrosine (Y), tryptophan (W), valine (V), proline (P), glycine (G)), and X 14 In particular, one of 3,4,5-trifluorophenylalanine (Tfpa or (3,4,5-trifluoro)F), β-cyclohexylalanine (Cha), naphthylalanine (Nal), 4-chlorophenylalanine (4cpa), 4-methoxyphenylalanine, 4-methylphenylalanine, 4-pyridylalanine, 3-pyridylalanine, 2-pyridylalanine, D-(-)-α-phenylglycine, homophenylalanine, 3-styrylalanine, O-benzyl-L-tyrosine, 4-benzoyl-L-phenylalanine, α-methyl-L-phenylalanine, α-methyl-D-phenylalanine, aminoindan, 2-aminoindan, O-benzyltyrosine or 4-aminopiperidine-4-carboxylic acid;

[0809] in:

[0810] 1) For X 1 To X 14 , any of the listed natural amino acids are independently optionally modified, and wherein 2) for X 1 To X 14 , any of the modified amino acids listed are optionally further modified independently, and in options 1) and 2), the modifications in option 1) and the further modifications in option 2) are optionally alkylated, esterified, N-alkylamidated, hydrogen is replaced by any halogen group or hydroxyl group, or by conjugation to a linker L c With R 3 Partial conjugation;

[0811] L1 to L 14 each of which is independently a bond suitable for linking two amino acids together, such as an amide bond, N-methylated amide, urea, ester, carbamate, peptoid, sulfonamide, alkylene, thioamide, thioether, fluoroalkylene, azapeptide difluoroketone or epoxide;

[0812] R 1 , R 2 and R 3 Independently absent or independently represents the rest of the compound, such as R 1 , R 2 and R 3 is independently a peptide, an acetyl, formyl, propynyl, biotin, a myristoyl or palmitoyl moiety, a methyl moiety, a saturated or unsaturated fatty acyl moiety, a polyethylene glycol polymer moiety, an immunoglobulin moiety, an immunoglobulin Fc domain moiety, albumin, a methylated moiety, an esterified moiety, or a portion of a natural apelin peptide compound;

[0813] Each L c is independently absent or is a conjugation linker, which converts R 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any one of the following, and is selected from the appropriate 1 Connect to X 1 , R 2 Connect to X 14 Or R 3 Partially connected to X 1 To X 14 Any key of any of

[0814] or a pharmaceutically acceptable salt, solvate, amide, ester, prodrug or deuterated analog of the compound.

[0815] 115. The compound according to clause 114, further as defined in any one of clauses 2 to 53.

[0816] 116. A compound according to clause 115 for use in any one of clauses 54-104.

[0817] 117. A compound according to any one of clauses 1 to 53, 105-112 or 114-115, or a compound for use according to any one of clauses 54-104, 113 or 116, wherein X 7 is K, and is modified, wherein the modification comprises linking K directly or indirectly to a fatty acid.

[0818] References

[0819] [1] B.F.O’dowd, M.Heiber, A.Chan, H.H.Q.Heng, L.C.Tsui, J.L.Kennedy, X.M.Shi, A.Petronis, S.R.George, T.Nguyen, Gene 1993, 136, 355 - 360.

[0820] [2] Tatemoto, K.et al.(1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor.Biochem.Biophys.Res.Commun.251, 471 - 476

[0821] [3] Maguire J.J.[Pyr 1 apelin - 13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease.Hypertension.2009;54:598 - 604.

[0822] [4] Zhen E.Y.Pyroglutamyl apelin - 13 identified as the major apelin isoform in human plasma.Anal.Biochem.2013, 442, 1 - 9.

[0823] [5] Yang P.R., Maguire J.J., Davenport A.P.Apelin, Elabela / Toddler, and biased agonists as novel therapeutic agents in the cardiovascular systemTrends Pharmacol Sci 2015, 36, 560 - 567.

[0824] [6]O′Carroll,A.M.;Lolait,S.J.;Harris,L.;E.;Pope,G.R.,The apelinreceptor APJ:journey from an orphan to a multifaceted regulator ofhomeostasis.J Endocrinol 2013,219(1),R13-R35.

[0825] [7]Pitkin,S.L.et ai.International Union of Basic and ClinicalPharmacology.LXXIV.Apelin receptor nomenclature,distribution,pharmacology,andfunction.Pharmacol.Rev.2010,62,331-342

[0826] [8]Chng SC,Ho L,Tian J,Reversade B.ELABELA:a hormone essential forheart development signals via the apelin receptor.Dev Cell.2013,27,672-680.

[0827] [9]Pauli A,Norris ML,Valen E,Chew GL,Gagnon JA,Zimmerman S,MitchellA,Ma J,Dubrulle J,Reyon D,Tsai SQ,Joung JK,Saghatelian A,SchierAF.Toddler:anembryonic signal that promotes cell movement via Apelinreceptors.Science.2014,343,1248636.

[0828]

[10] Kleinz,M.J.;Davenport,A.P.,Emerging roles of apelin in biologyand medicine.Pharmacol Therapeut 2005,107(2),198-211.

[0829]

[11] Sorli,S.C.;van den Berghe,L.;Masri,B.;Knibiehler,B.;Audigier,Y.,Therapeutic potential of interfering with apelin signalling.Drug Discov Today2006,11(23-24),1100-1106.

[0830]

[12] Charles,C.J.,The apelin peptides as putative targets incardiovascular drug discovery and development.Expert Opin Drug Dis 2008,3(1),51-64.

[0831]

[13] Barnes,G.;Japp,A.G.;Newby,D.E.,Translational promise of theapeline-APJ system.Heart2010,96(13),1011-1016.

[0832]

[14] Castan-Laurell,I.;Dray,C.;Attane,C.;Duparc,T.;KnaufC.;Valet,P.,Apelin,diabetes,and obesity.Endocrine 2011,40(1),1-9.

[0833]

[15] O′Carroll,A.M.;Lolait,S.J.;Harris,L.E.;Pope,G.R.,The apelinreceptor APJ:journey from an orphan to a multifaceted regulator ofhomeostasis.J Endocrinol2013,219(1),R13-R35.

[0834]

[16] Cao,J.G.;Li,H.N.;Chen,L.X.,Targeting Drugs to APJ Receptor:TheProspect of Treatment of Hypertension and Other CardiovascularDiseases.CurrDrug Targets 2015,16(2),148-155.

[0835]

[17] Cao,J.G.;Li,L.F.;Chen,L.X.,Apelin / APJ:Vascular FunctionRegulatory Factor and New Targets for Drug Treatment.Prog Biochem Biophys2015,42(8),721-732.

[0836]

[18] Chen,Z;Wu,D.;Li,L.F.;Chen,L.X.,Apelin / APJ System:A NovelTherapeutic Target for Myocardial Ischemia / Reperfusion Injury.DNA Cell Biol2016,35(12),766-775.

[0837]

[19] Hu,H.L;He,L;Li,L.F.;Chen,L.X.,Apelin / APJ system as a therapeutictarget in diabetes and its complications.Mol Genet Metab 2016,119(1-2),20-27.

[0838]

[20] Salska,A.;Chizynski,K.,Apelin-a potential target in the diagnosisand treatment of the diseases of civilization.Acta Cardiol2016,71(5),505-517.

[0839]

[21] Liu,JQ,Liu,MQ,Chen,LX,Novel pathogenesis:regulation ofapoptosis by Apelin / APJsystem.Acta Bioch Bioph Sin 2017,49(6),471-478.

[0840]

[22] Wu,LL,Chen,LX,Li,LF,Apelin / APJ system:A novel promisingtherapy target for pathological angiogenesis.Clin Chim Acta 2017,466,78-84.

[0841]

[23] Kalin,RE,Kretz,MP,Meyer,AMKispert,A.Heppner,FL,Brandli,AW,Paracrine and autocrine mechanisms of apelin signaling govern embryonicand tumor angiogenesis.Dev Biol 2007, 305(2), 599-614.

[0842]

[24] Sorli,SC,Le Gonidec,S.Knibiehler,B.Audigier,Y.,Apelin is an apotent activator of tumor neoangiogenesis.Oncogene 2007,26(55),7692-7699.

[0843]

[25] Wang,ZQ,Greeley,GH,Qiu,SM,Immunohistochemical localizationof apelin in human normal breast and breast carcinoma.J Mol Histol 2008,39(1),121-124.

[0844]

[26] Berta,J.;Kenessey,I.;Dobos,J.;Tovari,J.;Klepetko,W.;Ankersmit,H.J.;Hegedus,B.;Renyi-Vamos,F.;Varga,J.;Lorincz,Z;Paku,S.;Ostoros,G.;Rozsas,A.;Timar,J.;Dome,B.,Apelin Expression in Human Non-small Cell Lung CancerRole in Angiogenesis and Prognosis.J Thorac Oncol2010,5(8),1120-1129.

[0845]

[27] Rayalam,S.;Della-Fera,M.A.;Kasser,T;Warren,W.;Baile,C.A.,EmergingRole of Apelin as a Therapeutic Target in Cancer:A Patent Review.Recent PatAnti-Canc 2011,6(3),367-372.

[0846]

[28] Choi,Y.S.;Yang,H.I.;Cho,S.;Jung,J.A;Jeon,Y.E.;Kim,H.Y.;Seo,S.;Lee,B.S.,Serum asymmetric dimethylarginine,apelin,and tumor necrosis factor-alpha levels in non-obese women with polycystic ovary syndrome.Steroids 2012,77(13),1352-1358.

[0847]

[29] Heo,K;Kim,Y.H.;Sung,H.J.;Li,H.Y.;Yoo,C.W.;Kim,J.Y.;Park,J.Y.;Lee,U.L.;Nam,B.H.;Kim,E.O.;Kim,S.Y.;Lee,S.H.;Park,J.B.;Choi,S.W.,Hypoxia-inducedup-regulation of apelin is associated with a poor prognosis in oral squamouscell carcinoma patients.Oral Oncol 2012,48(6),500-506.

[0848]

[30] Kidoya,H.;Kunii,N.;Naito,H.;Muramatsu,F.;Okamoto,Y.;Nakayama,T.;Takakura,N.,The apelin / APJ system induces maturation of the tumor vasculatureand improves the efficiency of immune therapy.Oncogene 2012,31(27),3254-3264.

[0849]

[31] Farid,R.M.;Abu-Zeid,R.M.;El-Tawil,A.,Apelin Expression in theFibrosis-Cancer Axis in Hepatitis CVirus Patients.Hepatology 2013,58,1189a-1189a.

[0850]

[32] Kawahara,H.;Naito,H.;Takara,K.;Wakabayashi, T.;Kidoya,H.;Takakura,N.,Tumor Endothelial Cell-Specific Drug Delivery System UsingApelin-Conjugated Liposomes.Plos One 2013,8(6).

[0851]

[33] Kidova,H.Kunii,N.Naito,H.Takeshita,C.Takakura,N.EurJ Cancer 2013,49,S128-S128.

[0852]

[34] Diakowska,D.,Markocka-Maczka,K,Szelachowski,P,Grabowski,K,Serum Levels of Resistin,Adiponectin,and Apelin in Gastroesophageal CancerPatients 619649.

[0853]

[35] Muto, J. Shirabe, K. Yoshizumi, T. Ikegami, T. Aishima, S. Ishigami, K. Yonemitsu, Y. Ikeda, T. Soejima, Y. Maehara, Y., The Apelin-APJ System InducesTumor Arteriogenesis in Hepatocellular Carcinoma.Anticancer Res 2014,34(10),5313-5320.

[0854]

[36] Picault,FX,Chaves-Almagro,C.Projetti,F.Prats,H.Masri,B.Audigier,Y.,Tumor co-expression of apelin and its receptor is the basis ofan autocrine loop involved in the growth of colon adenocarcinomas.Eur JCancer 2014,50(3),663–674.

[0855]

[37] Altinkaya,S.O.;Nergiz,S.;Kucuk,M.;Yuksel,H.,Apelin levels arehigher in obese patients with endometrial cancer.J Obstet Gynaecol Re2015,41(2),294-300.

[0856]

[38] Lacquaniti,A.;Altavilla,G.;Picone,A.;Donato,V.;Chirico,V.;Mondello,P.;Aloisi,C.;Marabello,G.;Loddo,S.;Buemi,A.;Lorenzano,G.;Buemi,M.,Apelin beyond kidney failure and hyponatremia:a useful biomarker for cancerdisease progression evaluation.Clin Exp Med2015,15(1),97-105.

[0857]

[39] Wan,Y.P.;Zeng,Z.C.;Xi,M.;Wan,S.;Hua,W.;Liu,Y.L;Zhou,Y.L;Luo,H.W.;Jiang,F.N.;Zhong,W.D.,Dysregulated microRNA-224 / apeiin axis associated withaggressive progression and poorprognosis in patients with prostate cancer.HumPathol 2015,4(2),295-303.

[0858]

[40] Devapatla,B.K.;Jaiprasart,P.;Dogra,S.;Ha,J.H.;Woo,S.,Apelin / Apjpathway for targeting ovarian tumor microenvironment.Cancer Res 2016,76.

[0859]

[41] Ermin,S.;Cok,G.;Veral,A.;Kose,T,The role of apelin in theassessment of response to chemotherapy and prognosis in stage 4 nonsmall celllung cancer.Turk JMed Sci 2016,46(5),1353-1359.

[0860]

[42] Feng,M.Y.;Yao,G.D.;Yu,H.W.;Qing,Y.;Wang,K.A.,Tumor apelin,notserum apelin,is associated with the clinical features and prognosis ofgastric cancer.Bmc Cancer 2016,16(1),794.

[0861]

[43] Hall,C.;Ehrlich,L;White,T.;OBrien,A.;Lairmore,T.C.;Alpini,G.;Glaser,S.,Activation of the Apelin double right arrow Apelin Receptor Axis inCholangiocarcinoma Promotes Tumor Growth and Angiogenesis.Gastroenterology2016,150(4),S1124-Sl124.

[0862]

[44] Kim,H.S.;Kim,J.W.,Paradoxical expressions of hypoxia-induciblefactor-1 alpha and apelin affecting cervical carcinogenesis andprognosis.Journal of Clinical Oncology 2016 34:15_suppl,el7006-el7006.

[0863]

[45] Salman,T.Demir,L.Varol,U.Akyol,M.Oflazoglu,U.Yildiz,Y,Taskaynat an,H.Cengiz,H.Guvendi,G.Kucukzeybek,Y.Alacacioglu,ATarhan,O.,Serum Apelin levels and body composition changes in breast cancer patientstreated with an aromatase inhibitor J Buon 2016,21(6),1419-1424.

[0864]

[46] Yang,YJ.Lv,SY,Ye,WL,Zhang,L,Apelin / APJ system and cancer.ClinChim Acta 2016,457,112-1

[0865]

[47] Zhang,L,Takara,K.Yamakawa,D.Kidoya,H.Takakura,N.,Apelin as a marker for monitoring the tumor vessel normalization window duringantiangiogenic therapy.Cancer Sci 2016,107(1),36-44.

[0866]

[48] Hall,C.Ehrlich,LVenter,J.O′Brien,AWhite,T.Zhou,THDang,T.Meng ,FY,Invernizzi,P.Bernuzzi,F.Alpini,G.Lairmore,TCGlaser,S.,Inhibition of the apelin / apelin receptor axis decreases cholangiocarcinomagrowth.Cancer Lett,2017,386,179-188.

[0867]

[49] Hao,Y.Z;Li,M.L;Ning,F.L;Wang,X.W.,APJ Is Associated withTreatment Response in Gastric Cancer Patients Receiving ConcurrentChemoradiotherapy and Endostar Therapy.Cancer Biother Radio 2017,32(4),133-138.

[0868]

[50] Hoffmann,M.;Fiedor,E.;Ptak,A.,Bisphenol A and its derivativestetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression andsecretion in ovarian cancer cells through a peroxisome proliferator-activatedreceptor gamma-dependent mechanism.Toxicol Lett 2017,269,15-22.

[0869]

[51] Ni,Y.Y.;Liu,D.;Ge,G.;Zhu,Y.H.;Zhang,L,Apelin is a novelcirculating biomarker for the diagnosis of lung cancer.Int J Clin Exp Patho2017,10(5),5559-5565.

[0870]

[52] Zhang,H.P.;Zou,J.;Xu,Z.Q.;Ruan,J.;Yang,S.D.;Yin,Y.;Mu,H.J.,Association of leptin,visfatin,apelin,resistin and adiponectin with clearcell renal cell carcinoma.Oncol Lett2017,13(1),463-468.

[0871]

[53] Zuurbier,L.;Rahman,A.;Cordes,M.;Scheick,J.;Wong,TJ;Rustenburg,F.;Joseph,JC;Dynoodt,P.Casey;D. P.;Gerhards,M.;Barat,A.;Klinger;R.;Fender;B.;O′Connor,D P;Betge:J.;Ebert;MP;Gaiser;Gaiser;T.;Prehn;JHM;Griffioen;AW; van Grieken,NCT,Byrne,AT;van der Flier,LG,Gallagher,WM;Postel,R.,Apelin:A putative novel predictive biomarkerfor bevacizumab response in colorectal cancer. 2017,8(26),,42949-42961.

[0872]

[54] Lee,DK:Saldivia:VR;Nguyen;T.;Cheng;R.;George,SR;O′Dowd:BF,Modification of the terminal residue of apelin-13 antagonizes its hypothetical endocrine action. 2005,146(1),231-236.

[0873]

[55] Maloney,PRKhan,P.Hedrick,M.Gosalia,P.Milewski,M.Li, L,Roth,GP,Sergienko,E.Suyama,E.Sugarman,E.Nguyen,K,Mehta,A .Vasile,S.Su,Y.Stonich,D.Nguyen,H.Zeng,FYNovo,AMVicchi arelli,M.Diwan,J.Chung,TDY,Pinkerton,AB,Smith,LH,Functional antagonists of the Apelin(AP J)receptor.In Probe Reports from the NIH Molecular Libraries Program,Bethesda(MD),2010.

[0874]

[56] Masri,B.Barak,LS,Bai,Y.Knibiehler,B.Caron,MG,Audigier,Y,Identification and pharmacological properties of an antagonist of apelinreceptors.Regul Peptides 2010, 164(1), 26-26.

[0875]

[57] Macaluso,NJ,Pitkin,SL,Maguire,JJ,Davenport,AP,Glen,RC,Discovery of a competitive apelin receptor(APJ)antagonist.ChemMedChem 2011,6(6),1017-23.

[0876]

[58] Maloney,PRKhan,P.Hedrick,M.Gosalia,P.Milewski,M.Li,L.Roth,GP,Sergienko,E.Suyama,E.Sugarman,E.Ngu yen,K.Mehta,A.Vasile,S.Su,Y.Stonich,D.Nguyen,H.Ze ng,FY,Novo,AM,Vicchiarelli,M.Diwan,J.Chung,TDSmith,L H.,Pinkerton,AB,Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate(ML221)as a functional antagonist of theapelin(APJ) receptor.Biorganic&medicinal chemistry letters 2012,22(21),6656-60.

[0877]

[59] And Gonidec,S.Chaves-Almagro,C.Bai,Y.Kang,HJSmith,A.Wanecq,E.Huang,X..P.Prats, H.Knibiehler,B.Roth,BLBarak,LSCaron,MGValet,P.Audigier,Y.Masri,B.,Protamine is an apelin receptor antagonist, and its activity is reversed by heparin.Faseb J 2017,31(6),2507-2519.

[0878]

[60] Harford-Wright E., Andre-Gregoire G., Jacobs KA, Treps L., LeGonidec S., Leclair HM, Gonzalez-Diest S., Roux Q., Guillonneau F., Loussouarn D., Oliver L., Vallette FM, Foufelle F., Valet P., Davenport AP, Glen RC, Bidere N., Gavard J.Pharmacological targeting of apelin impairs glioblastomagrowth.Brain, 2017, 140(11), 2939-2954.

[0879]

[61] Neubig et al., International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Sequence Listing <110> Cambridge Enterprise Limited <120> Compounds used as apelin receptor antagonists <130> P032639CN <140> CN201980033458.8 <141> 2019-04-04 <150> GB1805675.4 <151> 2018-04-05 <160> 32 <170> PatentIn version 3.5 <210> 1 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> [Pyr1]apelin-13 - Table 3 <220> <221> MISC_FEATURE <222> (1) <223> 5-Oxopyrrolidine-2-carboxylic acid <400> 1 Xaa Arg Pro Arg Leu Ser His Lys Gly Pro Met Pro Phe 1 5 10 <210> 2 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM54 - Table 1a <220> <221> Disulfide <222> (1)..(6) <220> <221> Disulfide <222> (9)..(14) <400> 2 Cys Arg Pro Arg Leu Cys Lys His Cys Arg Pro Arg Leu Cys 1 5 10 <210> 3 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM107 - Table 1a <400> 3 Cys Arg Pro Arg Leu Cys His Lys Cys Arg Pro Arg Leu Cys 1 5 10 <210> 4 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM108 - Table 1a <400> 4 Cys Arg Pro Arg Leu Cys Lys His Cys Arg Pro Arg Leu Cys 1 5 10 <210> 5 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM193 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 5 Cys Arg Pro Arg Xaa Cys Lys His Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 6 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM262 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 6 Gln Arg Pro Arg Xaa Cys Lys His Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 7 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM297 - Table 1a <220> <221> MISC_FEATURE <222> (1) <223> 5-Oxopyrrolidine-2-carboxylic acid <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 7 Xaa Arg Pro Arg Xaa Cys Lys His Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 8 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM298 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 8 Cys Arg Pro Arg Xaa Xaa Lys His Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 9 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM299 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 9 Cys Arg Pro Arg Xaa Cys Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 10 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM300 - Table 1a <220> <221> LIPID <222> (1) <223> Myristate <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 10 Cys Arg Pro Arg Xaa Cys Lys His Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 11 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM301 - Table 1a <220> <221> MISC_FEATURE <222> (1) <223> 5-Oxopyrrolidine-2-carboxylic acid <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 11 Xaa Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 12 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM302 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 12 Cys Arg Pro Arg Xaa Cys His Lys Cys Arg Xaa Arg Xaa Xaa 1 5 10 <210> 13 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM312 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 13 Ala Arg Pro Arg Xaa Cys Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 14 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM313 - Table 1a <220> <221> MOD_RES <222> (1) <223> Acetylation <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 14 Ala Arg Pro Arg Xaa Cys Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 15 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM314 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 15 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 16 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM315 - Table 1a <220> <221> LIPID <222> (1) <223> Myristate <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 16 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 17 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM316 - Table 1a <220> <221> LIPID <222> (1) <223> Myristate <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 17 Ala Arg Pro Arg Xaa Xaa His Lys Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 18 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM412 - Table 1a <220> <221> MOD_RES <222> (1) <223> Acetylation <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MISC_FEATURE <222> (7) <223> Lysine with glutamic acid spacer replaced by palmitic acid <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenyl-L-alanine <400> 18 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 19 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> MM413 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <400> 19 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa 1 5 10 <210> 20 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM414 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <400> 20 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Ala 1 5 10 <210> 21 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM415 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> Phenylglycine <400> 21 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 22 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM416 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <400> twenty two Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Phe 1 5 10 <210> twenty three <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM417 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 4-Methoxyphenylalanine <400> twenty three Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> twenty four <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM418 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 4-Chlorophenylalanine <400> 24 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 25 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM419 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 4-Benzoylphenylalanine <400> 25 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 26 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM420 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> O-Benzyltyrosine <400> 26 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 27 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM421 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3-(1-Naphthyl)alanine <400> 27 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 28 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM422 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3-(2-Naphthyl)alanine <400> 28 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 29 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM423 - Table 1a <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 2-Aminoindan <400> 29 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 30 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM424 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 4-Aminopiperidine-4-carboxylic acid <400> 30 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 31 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM426 - Table 1a <220> <221> MOD_RES <222> (1) <223> Acetylation <220> <221> MOD_RES <222> (5) <223> Nle <220> <221> MOD_RES <222> (6) <223> Abu <220> <221> LIPID <222> (7) <223> Palmitate <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> 3,4,5-Trifluorophenylalanine <400> 31 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10 <210> 32 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> MM428 - Table 1a <220> <221> MOD_RES <222> (5)..(5) <223> Nle <220> <221> MOD_RES <222> (6)..(6) <223> Abu <220> <221> MOD_RES <222> (9)..(9) <223> Abu <220> <221> MOD_RES <222> (11)..(11) <223> Aib <220> <221> MOD_RES <222> (13)..(13) <223> Nle <220> <221> MISC_FEATURE <222> (14)..(14) <223> α-methyl-L-phenylalanine <400> 32 Ala Arg Pro Arg Xaa Xaa Lys His Xaa Arg Xaa Arg Xaa Xaa 1 5 10

Claims

1. A linear compound having the sequence of formula I: R 1 -X 1 -L1-X 2 -L2-X 3 -L3-X 4 -L4-X 5 -L5-X 6 -L6-X 7 -L7-X 8 -L8-X 9 -L9-X 10 -L 10 -X 11 -L 11 -X 12 -L 12 -X 13 -L 13 -X 14 (Formula I) in X 1 is C, Q, Glp or A; X 2 It is R; X 3 It is P; X 4 It is R; X 5 is Nle or L; X 6 It is C or Abu; X 7 is H or K; X 8 is H or K; X 9 It is C or Abu; X 10 It is R; X 11 is P or Aib; X 12 It is R; X 13 is Nle or L; X 14 is C or (3,4,5-trifluoro)F; in: L1 to L 14 each of is an amide bond; and R 1 is absent or is a methyl, acetyl, formyl, propynyl, biotinyl, myristoyl, palmitoyl, saturated or unsaturated fatty acid radical, polyethylene glycol, or ester radical; or a pharmaceutically acceptable salt, amide or ester of the compound.

2. The linear compound according to claim 1, wherein (i)X 1 is C; (ii)X 1 C and R 1 is myristoyl; (iii)X 5 for Nle; (iv)X 6 It is Abu; (v)X 7 is K and X 8 is H; (vi)X 9 It is Abu; (vii)X 11 It is Aib; (viii)X 13 is Nle; or (ix)X 14 It is (3,4,5-trifluoro)F.

3. The linear compound according to claim 1 or 2, wherein the compound is selected from the following table:

4. A pharmaceutical composition comprising the linear compound according to any one of claims 1 to 3 and a pharmaceutically acceptable diluent, excipient or carrier.

5. Use of the linear compound according to any one of claims 1 to 3 or the composition according to claim 4 in the preparation of a medicament for use in a method for treating a tumor, a metabolic disease, an inflammatory disease or an ocular degeneration.

6. Use of the linear compound according to any one of claims 1 to 3 or the composition according to claim 4 in the preparation of a medicament for use in a method for treating pathological angiogenesis and lymphangiogenesis, or vascular hyperplasia.

7. Use of a linear compound according to any one of claims 1 to 3 or a composition according to claim 4 in the preparation of a medicament for use in a method for treating diabetes, obesity including reduction of dietary sugar intake, cardiovascular disease, peripheral vascular disease, septic shock, hypotension, idiopathic pulmonary fibrosis, arthritis, inflammatory bowel disease, avascular or ischemic injury, eczema, bone disease, hemangioma, proteinuric nephropathy, diabetic retinopathy, choroidal vascular disease (AMD), macular degeneration, glioma, glioblastoma, glioblastoma multiforme, colorectal cancer, renal cancer, lung cancer, breast cancer, endometriosis or HIV infection.

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