Apelinergic macrocycle and uses thereof

Abstract

Apelinergic macrocycle compounds are provided, in particular compounds of formula (II): JPEG2025504750000051.jpg2287, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester, or solvate thereof. Also provided is a method of using an apelinergic macrocycle compound of the present disclosure for treating cardiovascular disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application was filed on December 15, 2022, PCT Application No. PCT / CA2022 / 05 * , which has been published in English under PCT Article 21(2), and which itself claims the benefit of U.S. Provisional Application No. 63 / 290,394, filed December 16, 2021. All of the above documents are incorporated herein by reference in their entireties.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT N / A The present disclosure relates to an apelinergic macrocycle and uses thereof. More specifically, the present disclosure relates to an apelinergic macrocycle derived from apelin-13, apelin-17, and Elabella.

[0003] Sequence Listing Reference In accordance with 37 CFR 1.821(c), the Sequence Listing is submitted as an ASCII compliant text file named G14692-0087.xml, created on December 15, 2022, and having a size of 80 kilobytes. The contents of the aforementioned file named G14692-0087.xml are incorporated herein by reference in their entirety. [Background technology]

[0004] The APJ receptor is a regulator of cardiovascular and metabolic activity. Two endogenous ligands, apelin and elabella, bind to the APJ receptor with nanomolar affinity, stimulating cardiac contraction, reducing resistance to peripheral vascular disease, endothelial cell proliferation and new blood vessel formation. Their protective effects have been demonstrated in pathological models of myocardial ischemia, cerebral ischemia, diabetes, pulmonary arterial hypertension, sepsis, and neuropathic pain. However, these endogenous peptides have poor plasma stability, which limits their use. The majority of studies indicate that apelin and elabella must be administered by continuous infusion to maintain therapeutic efficacy.

[0005] Adrenergic analogs are used as standard treatment for cardiac dysfunction associated with sepsis. However, they are not always effective and cause multiple side effects such as myocardial or peripheral ischemia. Resistance to treatment is a problem with recurrence of pulmonary arterial hypertension. Available drugs show variable efficacy, and the prognosis of this disease remains poor. Non-opioid pain relievers are also needed to avoid dose escalation and side effects.

[0006] There is a need for improved apelin agonist analogs.

[0007] This description references a number of documents, the contents of which are incorporated herein by reference in their entireties. Summary of the Invention

[0008] This disclosure provides novel macrocycle analogs of apelin-13, apelin-17, and ellabella (apelinergic macrocycles). Macrocyclization was applied to apelin isoforms and ellabella, yielding molecules with significantly improved stability (plasma half-life of 5-24 hours compared to plasma half-life of 24-30 minutes for apelin-13 and ellabella). Affinity was measured by displacement of radiolabeled ligand (Nle75, Tyr77) [125I]-Pyr-apelin-13, which indicates that some macrocycle peptides exhibit affinity for APJ similar to that of apelin (Ki 0.2-5.7 nM).

[0009] In certain embodiments, the macrocycle analogs of the present disclosure are reduced in size (33% reduction in molecular weight relative to apelin-13) while maintaining good affinity with the receptor (Ki 0.8-5 nM vs. apelin-13, Ki 0.8 nM).

[0010] In certain embodiments, macrocyclic apelin agonist analogs produce cardiovascular effects that are comparable to the endogenous ligand.

[0011] More specifically, the present disclosure provides the following items and items':

[0012] Item 1. A compound of any one of formulas (I) to (VIII), or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0013] Item 2. The compound of item 1, which is any one of compounds 3-4, 9-29, 35-46, 62-70, 72-79, 84, and 89-94 in Tables I-III.

[0014] Item 3. A pharmaceutical composition comprising a compound, stereoisomer, mixture, pharma- ceutically acceptable salt, ester or solvate of item 1 or 2, and at least one pharma- ceutically acceptable carrier or excipient.

[0015] Item 4. A method of using a compound of any one of Formulas (I)-(IV) for treating cardiovascular disease in a subject in need thereof comprising administering to the subject an effective amount of the compound.

[0016] Item 5. The method according to item 4, wherein the compound is any one of compounds 3 to 4, 9 to 29, and 35 to 46.

[0017] Item 6. The method of item 5, wherein the compound is compound 42 or 43.

[0018] Item '1. A compound of formula (II), (II) During the ceremony, X1 is absent or is X7-X8; X7 is -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11; natural amino acids, synthetic amino acids, the side chain of which is H; -(C1-C12)alkyl, -(CF2)q-CF3, where q is 0 to 11; -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0 to 5; and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl. optionally fused to an aryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, wherein the alkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is N, O, or S; X8 is absent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is not limited to cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. aryl is optionally substituted with at least one amino or guanidino group; cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused to one or two (C-C)aryl, (C-C)heteroaryl, (C-C)cycloalkyl or -(C-C)heterocycloalkyl; heteroatoms in heteroalkyl, heteroaryl or heterocycloalkyl are 1, 2 or 3 N, O or S; Y is absent, NH2-, Ac-NH-, guanidine, or H; A is -(CH)-, -(CH)NH=C(NH)N-CH-CH=CH- (preferably allyl-glycine or N-allyl-arginine) where n is 2, 3 or 4, or -CH=CH-(CH)-, where m is 0, 1 or 2; B is not present or R is O, P, m-alkyl, halogen or nitro and n is 1, 2 or 3; R is H, C3-C7 alkyl, benzyl or arylalkyl and n is 1, 2 or 3; n is 1, 2, 3 or 4 and m is 0 or 1; or X9 is CH or N; X2 and X3 are each independently nonexistent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and are not limited to cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group; cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C-C)aryl, (C-C)heteroaryl, (C-C)cycloalkyl, or -(C-C)heterocycloalkyl; and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S; X4 is a natural or unnatural amino acid having a positively charged or uncharged side chain; X5 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp, or Hyp(OBn); X6 is X10-X11-X12, X10 is any naturally occurring or synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, a halogen, an amino group, a guanidino group, a cycloalkyl group, a heterocycloalkyl ... The groups are -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S). In certain embodiments, X10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0 to 5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each of which is independently O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p is 0 to 5. In certain embodiments, it is not Ala.In more specific embodiments, X10 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr. X11 is absent or is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, it is absent or is Pro, The compound, wherein X12 is absent or is Phe, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0019] Item '2. - X2 and X3 are each independently an amino acid whose side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0 to 4; and / or - the compound of item '1, wherein X10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0 to 5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each substituent being independently -OH, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0020] Item '3. - X2 and X3 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine; - X4 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), - X5 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), and / or - the compound of item '1, wherein X10 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g. (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0021] Item '4. - X2 and X3 are each independently Lys, Arg, hArg, Nle, Leu, Phe, or Cha; - X4 is Gly, and / or - the compound of item '3, wherein X5 is Pro, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0022] Item '5. - X1 is not present, - Y is NH2, Ac-NH-, guanidine or H, A is -CH=CH-(CH)-, where m is 0, 1 or 2; - B is absent, R is O, P, m-alkyl, halogen or nitro, n is 1, 2 or 3 and X9 is CH or N, and / or - the compound of any one of items '1-4, wherein X10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0-5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each substituent being independently -OH, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0-5, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0023] Item '6. The compound of item '5, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof, wherein X10 is Nle or D-1Nal.

[0024] 2. - X1 is X7-X8, and / or - any one of the compounds of items 1 to 4, wherein Y is absent; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0025] Item '7. - the compound of item '7, in which X1 is X7-X8, and X8 is an amino acid whose side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0 to 4, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0026] Item '8. - the compound of item '7 or 8, wherein A is -(CH2)n- or -CH=CH-(CH2)m-, where m is 0, 1 or 2, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0027] Item '9. A compound of any one of formulas (I) to (VIII), or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0028] Item '10. Any one of compounds 3 to 4, 9 to 29, 35 to 46, 62 to 70, 72 to 79, 84, and 89 to 94, preferably any one of compounds 11, 13, 15 to 16, 18 to 20, and 42 to 44: Compound number Name Structure 3 KT01-16Pyr-c[XPRX]cSHKGP-Nle-PF 4 KT01-17 Pyr-c[XPRLSX]cKGP-Nle-PF 9 KT02-98 Pyr-RPRLSHK-[dX-P-Nle-PX] 10 KT03-32 Pyr-RPRLSHK-[XP-Nle-P-dX] 11 KT02-136 Pyr-R-P-R-L-S-H-K-G-P-[X-P-X] 12 KT02-137 Pyr-R-P-R-L-S-H-K-G-P-[dX-P-X] 13 KT01-125 Pyr-R-c * [X-R-L-S-X]c-K-G-P-Nle-P-F 14 KT01-105 Pyr-R-c[Dap-R-L-S-Asp]c-K-G-P-Nle-P-F 15 KT01-98 Pyr-R-c[X-R-L-S-Alh]c-K-G-P-Nle-P-F 16 KT01-123 Pyr-R-c[X-R-L-S-Alnb]c-K-G-P-Nle-P-F 17 KT01-106 Pyr-R-c[Lys-R-L-S-Asp]c-K-G-P-Nle-P-F 18 KT01-126 Pyr-R-c[X-R-L-S-Alb]c-K-G-P-Nle-P-F 19 KT01-122 Pyr-R-c[X-R-L-S-Almb]c-K-G-P-Nle-P-F 20 KT01-100 NH2-c[X-R-L-S-X]c-K-G-P-Nle-P-F 21 KT01-118 Ac-NH-c[X-R-L-S-X]c-K-G-P-Nle-P-F 22 KT01-110 φ-c[X-R-L-S-X]c-K-G-P-Nle-P-F 23 KT01-121 グアニジン-c[X-R-L-S-X]c-K-G-P-Nle-P-F 24 KT01-133 NH2-c[X-Nle-L-S-X]c-K-G-P-Nle-P-F 25 KT01-127 NH2-c[X-R-L-S-Alh]c-K-G-P-Nle-P-F 26 KT01-120 NH-c[Rx-R-L-S-AlH]-K-G-P-Nle-P-F 27 KT01-111 φ-c[X-R-L-S-AlH]-K-G-P-Nle-P-F 28 KT01-135 NH2-c[X-R-L-S-Alnb]c-K-G-P-Nle-P-F 29 KT01-116 NH2-c[X-R-L-S-X]c-K-G-P-Nle 35 KT03-57 NH2-c[X-R-L-S-X]c-K-G-P-1Nal 36 KT03-58 NH2-c[X-R-L-S-X]c-K-G-P-2Nal 37 KT03-51 NH2-c[X-R-L-S-X]c-K-G-P-TyrOBn 38 KT03-67 NH2-c[X-R-L-S-X]c-K-G-P-cypTyr(OBn) 39 KT03-68 NH2-c[X-R-L-S-X]c-K-G-P-dcypTyr(OBn) 40 KT03-69 NH2-c[X-R-L-S-X]c-K-G-P-cypTyr(OCyp) 41 KT03-70 NH2-c[X-R-L-S-X]c-K-G-P-cypTyr(OPr) 42 KT04-43 NH2-c[X-R-L-S-X]c-K-G-P-(D-1Nal) 43 KT04-44 NH2-c[X-R-L-S-X]c-K-G-P-(D-2Nal) 44 KT04-42F1 NH2-c[X-R-L-S-X]c-K-G-P-(D-TyrOBn) 45 KT04-42b NH2-c[X-R-L-S-X]c-K-G-P-(D-Tyr) 46 KT01-145 Ac-c[E-N-T-N-(8-aminooctanoic acid)-R-P-R-L-K]-H-K-G-P-Nle-P-F 62 KT02-62 Ac-K-F-R-R-Q-R-P-R-L-[E-H-A-K]-P-A-P-F 63 KT02-76 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-cypTyrOBn 64 KT02-78 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-cypY 65 KT02-99 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-dcypTyrOBn 66 KT03-02 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-TyrOBn 67 KT02-18 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-B1 68 KT02-19 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-B2 69 KT02-20 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-B3 70 KT02-21 Ac-K-F-R-R-Q-R-P-R-L-[E-H-K-K]-P-Nle-P-B4 72 AM03-37 c[K-R-R-E]-Nle-P-L-H-S-R-V-P-F-P 73 AM03-66 c[K-R-R-E]-Nle-P-L-H-S-R-V-Oic-F-P 74 AM03-38 Pyr-R-R-c[K-Nle-P-E]-H-S-R-V-P-F-P 75 ABB01-105 Pyr-R-R-c[E-Nle-P-K]-H-S-R-V-P-F-P 76 AM03-40 Pyr-R-R-S-c[K-P-L-H-E]-R-V-P-F-P 77 ABB01-106 Pyr-R-R-S-c[E-P-L-H-K]-R-V-P-F-P 78 AM03-67 Pyr-R-R-S-c[E-P-L-H-K]-R-V-Oic-F-P 79 AM03-68 c[K-R-R-E]-Nle-c[C-L-H-C]-R-V-P-F-P 84 ABB01-109 Nle-P-c[E-H-S-R-K]-P-F-P 89 KT03-14 4BrBz-R-R-S-[E-P-L-H-K]-R-V-P-F-P 90 KT03-16 Pyr-hR-RS-[EPLHK]-RVPFP 91 KT03-17 Pyr-R-hR-S-[EPLHK]-RVPFP 92 KT03-15 Pyr-RRS-[EPLHK]-RVP-4BrF-P 93 KT03-19 Pyr-RRS-[EPLHK]-RVPF-Hyp(OBn) 94 KT04-16 The compound of item '9, which is 4BrBz-RRS-[EPLHK]-RVP-4BrF-P, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0029] Item '11. A compound of item 10, which is any one of compounds 13 to 25, 27 to 29, 35 to 37 and 42 to 45, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0030] Item '12. A pharmaceutical composition comprising a compound, stereoisomer, mixture, pharma- ceutically acceptable salt, ester or solvate of any one of items 1 to 11, and at least one pharma- ceutically acceptable carrier or excipient.

[0031] Item '13. A method of using a compound of any one of formulas (I)-(IV), or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester, or solvate thereof, for treating cardiovascular disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound.

[0032] Item '14. The method of item '13, wherein the compound is any one of compounds 3 to 4, 9 to 29, and 35 to 46 defined in item '10, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0033] Item '15. The process of item '13, wherein the compound is a compound of formula (II) as defined in any one of items '1 to 8.

[0034] Item '16. The method of item '15, wherein the compound is any one of compounds 13 to 25, 27 to 29, 35, 36 to 37 and 42 to 45 defined in item '10, preferably any one of compounds 13, 15 to 16, 18 to 20, 23 and 42 to 44, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0035] Item '17. The method of item '16, wherein the compound is compound 42 or 43, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

[0036] Other objects, advantages and features of the present disclosure will become more apparent upon reading the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings. [Brief description of the drawings]

[0037] [Figure 1] Figure 1 shows the structures of Ape13 and compound 97. The cyclization positions, Pro3 and His7, are indicated and circled. [Figure 2A] 2A-B show macrocyclic Ape13 analogs with various linkers (Figure 2A) and macrocyclic Ape13 analogs with various non-natural residues (Figure 2B). [Figure 2B] Same as above. [Figure 3A]3A-B show macrocyclization by ring-closing metathesis to produce the precursors of 97, 16, 18, and 19. The linear and cyclic precursors of 97 (SEQ ID NOs: 87-89) (Figure 3A), and 16, 18, and 19 (SEQ ID NOs: 90-92) (Figure 3B). [Figure 3B] Same as above. [Figure 4] Figure 4 shows the synthesis of Nα-Fmoc-(Nπ-allyl)-L-histidine-OH: (a) MeOH, HOBt, EDC, DCM, rt, ovn73%, (b) i. Tf2O (1.1 eq), DIPEA (1.2 eq), allyl alcohol (1.1 eq), -78 °C for 10 min and rt overnight, ii. TFA, TIPS, DCM, rt, 2 h, 70% in two steps, (c) HCl 2M, dioxane-water, reflux, ovn, 77%. [Diagram 5] Figure 5. Synthesis of Fmoc-Alnb-containing peptides. Linear precursors of compounds 15, 18 and 19 are shown. [Figure 6] FIG. 6 shows the synthesis of the Nα-Fmoc-cypTyr(OR)-OH analog. (a) Phosphoric acid 85%, cyclopentanol, 100 °C, overnight; (b) SOCl2, MeOH, room temperature, overnight, 26% for two steps a and b; (c) Boc2O, NaHCO3, THF-water (1:1), room temperature, 1 h, 84%; (d) RBr, K2CO3, ACN, reflux, overnight, yields 17a (57%), 17b (54%), 17c (52%); (e) LiOH, THF-water (1:1), room temperature, 3 h, yields 113 (96%), 114 (100%), 115 (93%); (f) i. TFA-DCM (1:1), room temperature, 2 h; ii. Fmoc-Cl, NaHCO3, THF-water (2:1), room temperature, 2 h, yields 116 (68%), 117 (41%), 118 (71%). [Figure 7] FIG. 7 shows N-terminal truncated analogs of 97, 15, and 16, i.e., compounds 20-23, and 24-28. [Figure 8] FIG. 8 shows the substitution of Nle11 (compound 29) with natural and unnatural amino acids to generate compounds 34-45. [Figure 9A]9A-B show a synthetic scheme for an exemplary compound of formula VI (eg, compound 79, AM03-68 in Table III). [Figure 9B] Same as above. [Figure 10] FIG. 10 shows a synthetic scheme for exemplary compounds of Formula VII (eg, compounds 75, 77-78, and 89-93 of Table III). [Figure 11A] 11A-B show synthetic schemes for exemplary compounds of Formula VIII (eg, compounds 72-73 in Table III). [Figure 11B] Same as above. [Figure 12] Figure 12 shows concentration response curves of Gai1, Ga12 and Ape13 macrocycle analogs of the b-arrestin2 pathway. Ligand-induced binding of the G protein Gαi1 (A) monitored using a BRET-based G protein dissociation assay (Gales et al., 2006). Ligand-induced recruitment of β-arrestin2 (B) using a BRET-based β-arrestin2 recruitment assay (Gales et al., 2006). Each set represents the average of at least three independent experiments and is expressed as the mean ± SEM. [Figure 13] Figure 13 shows the in vivo pharmacokinetic profile of macrocycles 42 and 43 in male Sprague-Dawley rats (n=3). The compounds were administered intravenously at 3 mg / kg, and their concentrations in blood samples were quantified by LC / MS-MS. [Figure 14] Figure 14 shows the attenuating effect of compounds 15, 20, 29, 42 and 43 in anesthetized male Sprague-Dawley rats. The tracings show the change in blood pressure upon receiving two doses (65 nmol / kg and 19.6 nmol / kg) or a bolus (iv) of Ape13 compounds 15, 20, 29, 39, 42 and 43 via the jugular vein (n=4-6 per group). [Figure 15A]Figures 15A-B show the effect of macrocycles 42 and 43 (n=5 for all groups) on left ventricular fractional shortening (Figure 15A) and cardiac output (Figure 15B). *p<0.05, **p<0.01 versus time-matched NS (no stimulation) using one-way ANOVA test. [Figure 15B] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] Compounds of the Disclosure The present disclosure provides novel apelinergic compounds, including apelin 13 analogs, apelin 17 analogs and Elabella analogs.

[0039] Apelin is a peptide hormone that acts as an endogenous ligand for the class A G protein-coupled APJ receptor (Tatemoto et al., 1998; O'Dowd et al., 1993; Read et al., 2019). As a GPCR target, the APJ receptor inhibits the cAMP-dependent pathway primarily by inhibiting adenylate cyclase activity, a Gα i It is known that the APJ receptor couples to distinct G proteins such as β-arretin, which is associated with receptor desensitization (Masri et al. 2006, and Habata et al., 1999). The APJ receptor also signals through the recruitment of β-arretin, which is associated with receptor desensitization (Besserer-Offroy et al., 2018, et Gurevich et al., 2019). The β-arretin pathway is also known to couple to various effectors and initiate downstream signaling by itself (Gurevich et al., 2019; and Reiter et al., 2012).

[0040] Apelin and ellabella are two endogenous peptide ligands of APJ that, despite their very different primary sequences, have similar binding potency and signaling properties (Chng et al., 2013; Pauli et al., 2014; and Murza et al., 2016). Apelin exists in several isoforms: apelin-36, apelin-17, apelin-13, [Pyr 1 ]-Apelin-13 and [Pyr 1 ]-Apelin-13 (1-12) Among them, [Pyr 1 ]-Apelin-13 (Ape13) is the predominant isoform circulating in human plasma and cardiac tissue ( Tatemoto et al., 1998 , Maguire et al., 2009 , Yang et al., 2017 , Nyimanu et al., 2019 , Zhen et al., 2013 ).

[0041] Compounds of the Disclosure In certain embodiments, macrocyclic compounds of the present disclosure are developed from cyclization of synthetic peptides (generally made from natural and / or unnatural amino acids) derived from apelin-13 (PyrRPRLSHKGPMPF (SEQ ID NO: 47)), apelin-17 (KFRRQRPRLSHKGPMPF (SEQ ID NO: 86)), or a fragment of E. vera (PyrRRCMPLHSRVPFP (SEQ ID NO: 85)).

[0042] In certain embodiments, the cyclization of the peptide is side-chain to side-chain cyclization. In certain embodiments, the cyclization of the synthetic peptide is achieved via a ring-closing metathesis reaction of an alkene (-C=C-) (or alkyne (-C≡C-)) group at the end of each of the N-moieties and the side chain of the central amino acid (or acid) moiety, resulting in a single carbon-carbon double bond (or a single carbon-carbon triple bond if an alkyne group is used). The macrocycle may then be further modified to replace the double bond with a single bond via palladium-catalyzed hydrogenation (see, for example, compound 13).

[0043] In other particular embodiments, cyclization of the peptide is accomplished via a macrolactamization reaction between the terminal amine of the side chain of one of the N-terminal amino acids and the terminal carboxylic acid of the side chain of the amino acid residue used to close the ring or ring back.

[0044] In certain embodiments, the compound of the present disclosure is any one of the compounds of formula I-VIII, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester, or solvate thereof.If there is a discrepancy herein between the name (list of residues) and the structure (formula) of the compound of the present disclosure or a part thereof mentioned herein, the structure (formula) shall prevail.If there is a discrepancy herein between the compound described in the sequence listing and the name (list of residues) and / or the structure (formula) of the compound of the present disclosure or a part thereof mentioned herein, the name (list of residues) and / or the structure (formula) shall prevail.

[0045] Reference herein to an amino acid or acid that is part of a molecule of the present disclosure should be understood to designate an amino acid or acid residue that is linked at least one of its termini to another amino acid or acid, for example, by forming a peptide bond, thereby losing a hydroxy group and / or one hydrogen of the amine group. Thus, for example, an amino acid or acid listed in any one of the definitions of X1, X2, X3, X4, X5 and X6 should be understood to be the corresponding amino acid or acid residue.

[0046] Compounds of the present disclosure have a binding affinity (Ki binding (nM)) for APJ of less than 1000 nM, in certain embodiments less than 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 35, 30, 35, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or 2 nM, or less than 1 nM. In certain embodiments, the compounds of the present disclosure are any one of Formulas I-VIII or Tables I-III having a binding affinity (Ki binding (nM)) for APJ of less than 1000 nM, in certain embodiments, less than 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 35, 30, 35, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or 2 nM or less than 1 nM.

[0047] Unless otherwise indicated, the definitions for residues provided herein include both the L and D configurations.

[0048] Apelin 13 analogues The present disclosure encompasses apelin 13 cyclic analogs such as those set forth in formulas (I)-(IV).

[0049] In certain embodiments, the apelin 13 cyclic analog comprises or has the following formula (I): X1-X2-Y-[X3-X4-X5-X6-X7-X8-X9-X10-X11-X12]-X13-X14-X15-X16-X17-X18 During the ceremony, X1 is absent, -(CH2)q-CH3 or -(CF2)q-CF3, where q is 0-11, or any natural amino acid or any synthetic amino acid whose side chain is H, --(C1-C12)alkyl, -(CF2)q-CF3, where q is 0-11, -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0-5, and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, Optionally fused with (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S. In certain embodiments, it is Pyr or absent, X2 and X7 are each independently absent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and are selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Heteroaryl is optionally substituted with at least one amino or guanidino group, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in heteroalkyl, heteroaryl or heterocycloalkyl are 1, 2 or 3 N, O or S, preferably N. In certain embodiments, X2 and X7 are each independently absent or an amino acid whose side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, where p is 0-4. In certain embodiments, X2 and X7 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, or absent. In more specific embodiments, X2 and X7 are each independently absent, -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4, or each independently Arg or Lys; Y is H, Ac, Ac-NH, -NH2, guanidine or absent; X3 and X12 close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, at least one or both of X3 and X12 are allylglycine. In certain embodiments, when X3 is allylglycine, X12 is not allylglycine.

[0050] X4, X5 and X6 are each independently Ser, Thr, Asn, Gln, Asn-(8-aminooctanoic acid), Trp-(8-aminooctanoic acid), or absent. In certain embodiments, X4, X5 and X6 are each independently Thr, Asn, Asn-(8-aminooctanoic acid), Trp-(8-aminooctanoic acid), or absent. In another specific embodiment, they are all absent.

[0051] X8 is absent or is Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, it is absent or is Pro.

[0052] X9 is any naturally occurring or synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, halogen, amino, and the heteroaryl, heteroaryl, heterocycloalkyl, heteroaryl group, -C-C-aryl, -C-C-cycloalkyl ...In a more specific embodiment, X9 is absent or any natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0-5, and The alkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is 1, 2, or 3 N, O, or S, preferably N. In a more specific embodiment, X9 is an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4. In more specific embodiments, X9 is Nle, Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, or hArg. In more specific embodiments, X9 is Arg. X10 is any natural or synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The aryl is substituted with one or more substituents, each of which is independently, for example, a halogen, an amino group, a guanidino group, -OH, S, or (C1-C6) alkyl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8) aryl, (C3-C8) heteroaryl, (C3-C8) cycloalkyl, or -(C3-C8) heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In more specific embodiments, X10 is Leu, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine, alpha-methylphenylalanine, Ala, Val, Ile. In more specific embodiments, it is Leu, X11 is absent or any naturally occurring amino acid, or any synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, halo. halogen, an amino group, a guanidino group, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In a more specific embodiment, X11 is Ser or absent; X13 is a natural or synthetic amino acid whose side chain is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. is optionally substituted with at least one amino or guanidino group, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are one, two or three N, O or S. In certain embodiments, X13 is Lys, Orn, Dab, Dap, Arg, -CH2-(CH2)p-guanidine, where p is 0-4, or His. In certain embodiments, X13 is Lys.

[0053] X14 is Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In a particular embodiment, it is Gly, X15 and X17 are each independently Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X15 and X17 are each independently absent or Pro.

[0054] X16 is any naturally occurring or synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, halogen, amino, and n is 1, 2 or 3; and n is 1, 2 or 3; and m is 1, 2 or 3; and n is 1, 2 or 3; and n is 1, 2 or 3; and n is 1, 2 or 3; and n is 1, 2 or 3; In certain embodiments, it is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each of which is independently O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl.In more specific embodiments, it is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine, alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr. X18 is absent or any naturally occurring amino acid, or a synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, a halogen. , an amino group, a guanidino group, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In certain embodiments, it is absent or is an amino acid whose side chain is -(CH2)p-(C3-C8)aryl, where aryl is optionally substituted with one or more substituents, each of which is independently halogen, amine, -OH, S, or -(C1-C6)alkyl. In another particular embodiment, it is Phe or halogen-substituted Phe. In another particular embodiment, it is absent. In another embodiment, it is Phe.

[0055] In certain embodiments of a compound of formula (I), when X3 is allylglycine, X12 is not allylglycine. In certain embodiments of a compound of formula (I), when X17 and X18 are absent, X16 is not Ala. In certain embodiments, a compound of formula (I) is any one of compounds 13-29, and 35-46 of Table I. In other certain embodiments, a compound of formula (I) is any one of compounds 13, 15-16, 18-20, 28, and 42-44 of Table I.

[0056] The present disclosure includes compounds of formula (I), wherein each of X1-X18 is independently defined using either the more general or more specific definitions provided above for those residues in formula (I).

[0057] In another particular embodiment, the apelin 13 cyclic analog has the following formula (II): [ka] In the formula, X1 is absent or represents X7 to X8; X7 is -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11, a natural amino acid or a synthetic amino acid, the side chain of which is H, -(C1-C12)alkyl, -(CF2)q-CF3, q is 0 to 11, -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C 8) optionally fused to a cycloalkyl or -(C3-C8)heterocycloalkyl, where the alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which independently includes or has, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S. In certain embodiments, X7 is Pyr; X8 is absent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. X is optionally substituted with at least one amino or guanidino group, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C-C)aryl, (C-C)heteroaryl, (C-C)cycloalkyl or -(C-C)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is one, two or three N, O or S, preferably N. In certain embodiments, X is an amino acid and the side chain is -CH-(CH)-guanidine, -CH-(CH)-NH, or -(CH)-imidazole, preferably -CH-(CH)-guanidine or -CH-(CH)-NH, where p is 0-4. In certain embodiments, X8 is Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, or absent, preferably Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, or hArg. In more specific embodiments, X8 is Arg.

[0058] Y is absent, NH2-, Ac-NH-, guanidine, or H; A is -(CH)-, -(CH)NH=C(NH)N-CH-CH=CH- (preferably N-allyl-arginine), where n is 2, 3 or 4, or -CH=CH-(CH)m, where m is 0, 1 or 2 (preferably allyl-glycine); B is not present or [ka] wherein R is O, P, m-alkyl, halogen, or nitro, and n is 1, 2, or 3; [ka] wherein R is H, C3-C7 alkyl, benzyl or arylalkyl, and n is 1, 2 or 3; [ka] wherein n is 1, 2, 3 or 4 and m is 0 or 1; or [ka] In the formula, X9 is CH or N.

[0059] X2 and X3 are each independently absent or a natural or synthetic amino acid whose side chain is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and are not limited to cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. and heteroaryl is optionally substituted with at least one amino or guanidino group, and cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is one, two or three N, O or S, preferably N. In certain embodiments, X2 and X3 are each independently an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X2 and X3 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine. In certain embodiments, X2 and X3 are each independently Lys, Arg, hArg, Nle, Leu, Phe, or Cha. In more specific embodiments, X2 and X3 are each independently Arg or Lys.

[0060] X4 is a natural or unnatural amino acid with a positively charged or uncharged side chain. In certain embodiments, X4 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, it is Gly, X5 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn). In a particular embodiment, it is Pro, X6 is X 10 -X 11 -X 12 where: X 10 is any naturally occurring or synthetic amino acid whose side chain is H, -(CH)p-(C3-C8)alkyl, -(CH)p-(C3-C8)heteroalkyl, -(CH)p-(C3-C8)cycloalkyl, -(CH)p-(C3-C8)heterocycloalkyl, -(CH)p-(C3-C8)aryl, -(CH)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which may be independently selected from, for example, a halogen, an amino group, a guanidino group, -O H, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S. In certain embodiments, X 10is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0-5, the aryl is optionally fused to one or two (C3-C8)aryl, the aryl is optionally substituted with one or more substituents, each of which is independently -OH, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p is 0-5. In certain embodiments, it is not Ala. In more specific embodiments, X 10 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr; X 11 is absent or is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp, or Hyp(OBn). In certain embodiments, it is absent or is Pro, X 12 is absent or is Phe.

[0061] In certain embodiments, the compound of formula (II) is any one of compounds 13-25, 27-29, 35-37, and 42-45 of Table I. In other certain embodiments, the compound of formula (II) is any one of compounds 13, 15-16, 18-20, 28, and 42-44 of Table I.

[0062] In certain embodiments, X1 is Pyr-Arg, Y is -NH-, A is -CH2-CH2-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0063] In another particular embodiment, X1 is Pyr-Arg, Y is -NH-, A is -CH=CH- and B is [ka] wherein X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0064] In another particular embodiment, X1 is Pyr-Arg, Y is -NH-, A is -CH=CH- and B is [ka] wherein X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0065] In another particular embodiment, X1 is Pyr-Arg, Y is -NH-, A is -CH2-CH2- and B is [ka] wherein X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0066] In another particular embodiment, X1 is Pyr-Arg, Y is -NH-, A is -CH=CH- and B is [ka] wherein X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0067] In another specific embodiment, X1 is H, Y is -NH-, A is -CH=CH-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle-Pro-Phe.

[0068] In another specific embodiment, X1 is absent, Y is -H-, A is -CH=CH-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle.

[0069] In another specific embodiment, X1 is H, Y is -NH-, A is -CH=CH-, B is absent, X2 is Nle, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle.

[0070] In another specific embodiment, X1 is H, Y is -NH-, A is -CH=CH-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is Nle.

[0071] In another specific embodiment, X1 is H, Y is -NH-, A is -CH=CH-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is D-1Nal.

[0072] In another specific embodiment, X1 is H, Y is -NH-, A is -CH=CH-, B is absent, X2 is Arg, X3 is Lys, X4 is Gly, X5 is Pro, and X6 is D-2Nal.

[0073] In certain embodiments of compounds of formula (II), when A is allylglycine, then B is not allylglycine.

[0074] The present disclosure includes compounds of formula (II), wherein each of the variables X1, X2, X3, X4, X5, X6, Y, A and B is independently defined using any of the more general or more specific definitions provided above for those residues of formula (II).

[0075] In another embodiment, the apelin 13 cyclic analog has the following formula (III): X1-[X2-X3-X4-X5-X6-X7]-X8-X9-X10-X11-X12-X13-X14-X15 In the formula, X1 is absent, -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11, a natural amino acid, a synthetic amino acid, the side chain of which is H, -(C1-C12)alkyl, -(CF2)q-CF3, q is 0 to 11, -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, p is 0 to 5, and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl, and optionally fused to (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, where alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which independently includes or has, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S. In certain embodiments, X1 is Pyr, -(CH2)q-CH3 or -(CF2)q-CF3, where q is 0-11; X2 and X7 close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, at least one or both of X2 and X7 are allylglycine; X3 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, it is absent or is Pro, X4 is a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are at least The cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are one, two or three N, O or S, preferably N. In certain embodiments, X4 is an amino acid and the side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X4 is Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, or His. In more specific embodiments, X4 is Arg or Lys. In more specific embodiments, X4 is Arg.

[0076] X5 and X6 are each independently non-existent or any natural or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and are not limited to cycloalkyl, hetero ... X5 is Leu, and / or X6 is Ser; X8 is absent or any natural or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and is selected from cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently, for example, a halogen, an amino group, a guanidino group, -OH, S, or (C1-C6)alkyl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In certain embodiments, X8 is Ser; X9 is absent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The alkyl group is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are preferably one, two or three N, O or S. In certain embodiments, X9 is absent or an amino acid and its side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -(CH2)p-imidazole, where p is 0-4. In certain embodiments, X9 is absent, Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, or His. In more specific embodiments, X9 is absent or His; X10 is a natural or synthetic amino acid whose side chain is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. is optionally substituted with at least one amino or guanidino group, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are one, two or three N, O or S. In a more specific embodiment, X10 is an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X10 is Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, or His. In more specific embodiments, X10 is Lys; X11, X12 and X14 are each independently Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X11 is Gly. In certain embodiments, X12 and / or X14 are Pro, X13 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, preferably Nle; X15 is an amino acid whose side chain is -(CH2)p-(C3-C8)aryl, where aryl is optionally substituted with one or more substituents, each of which is independently halogen, amine, -OH, S, or (C1-C6)alkyl. In certain embodiments, X15 is Phe or halogen-substituted Phe. In certain embodiments, X15 is Phe.

[0077] In certain embodiments, the compound of formula (III) is any one of compounds 3 and 4 in Table I.

[0078] The present disclosure includes compounds of formula (III), wherein each of X1-X15 is independently defined using either the more general or more specific definitions provided above for those residues in formula (III).

[0079] In another embodiment, the apelin 13 cyclic analog has the following formula (IV): X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-[X11-X12-X13-X14-X15] In the formula, Xaa1 is -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11, a natural amino acid or a synthetic amino acid, the side chain of which is H, -(C1-C12)alkyl, -(CF2)q-CF3, q is 0 to 11, -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, p is 0 to 5, and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C 3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, where alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which independently includes or has, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S. In certain embodiments, X1 is Pyr, -(CH2)q-CH3 or -(CF2)q-CF3, where q is 0-11. In more specific embodiments, it is Pyr, X2, X4, X7 and X8 are each independently a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The aryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are one, two or three N, O or S, preferably N. In certain embodiments, X2, X4, X7 and X8 are each independently an amino acid whose side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, where p is 0-4. In certain embodiments, X2, X4, X7, and X8 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, or His. In more specific embodiments, X2, X4, X7, and X8 are each independently Arg, His, or Lys. In more specific embodiments, X2, X4, and X8 are each independently an amino acid whose side chain is -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4, or each independently Arg or Lys, and / or X7 is an amino acid whose side chain is -(CH2)p-imidazole, where p is 0-4, or His; X3 is Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X3 is Pro, X5 and X6 are each independently any natural or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and are not limited to cycloalkyl, heterocycloalkyl, aryl, and the like. In certain embodiments, X5 is Leu, and / or X6 is Ser; X9 is absent or a natural or unnatural amino acid with a positively charged or uncharged side chain. In certain embodiments, X4 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, it is Gly, X10 and X12 are each independently absent or Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp, or Hyp(OBn). In more specific embodiments, X10 is absent. In certain embodiments, X10 and X12 are each independently absent or Pro; X11 and X15 close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, X12 and X15 are independently allylglycine or D-allylglycine; X13 is absent or any natural or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently, for example, a halogen, an amino group, a guanidino group, -OH, S, or (C1-C6)alkyl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In certain embodiments, X13 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, preferably Nle.

[0080] X14 is Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X14 is Pro.

[0081] In certain embodiments of the compound of formula IV, X9 and X10 are not absent. In certain embodiments, when X11 is allylglycine, X15 is not allylglycine. In certain embodiments, X11 is not B1 or B2.

[0082] In certain embodiments, the compound of formula (IV) is any one of compounds 9-12 of Table I. In other certain embodiments, the compound of formula (I) is compound 12 of Table I.

[0083] The present disclosure includes compounds of formula (IV), wherein each of X1-X15 is independently defined using either the more general or more specific definitions provided above for those residues in formula (IV).

[0084] In certain embodiments of formulas (I)-(IV), at least 4 (or at least 5, 6, 7, 8, 9, or 10) of the residues (e.g., residues at positions Xn, defined above, where n is 1-18 for formula (I), 1-12 for formula (II), or 1-18 for formulas (III) and (IV)), excluding residues that close a ring that differ from the corresponding residues in AP-13 (SEQ ID NO:47), correspond to residues in AP-13 (SEQ ID NO:47). For example, compound 3 has at least 10 residues that correspond to residues in AP-13 (SEQ ID NO:47).

[0085] In other particular embodiments, the compounds of the present disclosure correspond to macrocyclic analogs of Ap13 PyrRPRLSHKGPMPF (SEQ ID NO: 47), where the compounds differ from Ap13 by at least two substitutions at the ring-closing positions and by at least one (or 2, 3, 4, 5, 6, 7, or 8) additional substitutions, deletions, and / or insertions. These substitutions, deletions, and / or insertions are defined in the various Xn of formulas (I)-(IV) above. The correspondence between these Xn and Ap13 is shown in Table A below, where the "["and"]" symbols are used to indicate the positions of the ring-closing residues of formulas (I)-(IV) and the compounds of the present disclosure that satisfy these formulas. [Table A] [Table B] [Table C]

[0086] Apelin 17 analogues In certain embodiments, the apelin 17 cyclic analog has the following formula (V): X1-X2-X3-X4-X5-X6-X7-X8-X9-[X10-X11-X12-X13]-X14-X15-X16-X17, In the formula, X1 is a natural or synthetic amino acid, the side chain of which is -R-CH2-(CH2)p-NH2, -R-CH2-(CH2)p-guanidine, -R-(CH2)p-(C3-C8)cycloalkyl, -R-(CH2)p-(C3-C8)heterocycloalkyl, -R-(CH2)p-(C3-C8)aryl, or -R-(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is selected from at least one amino or or guanidino groups, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl include or have one, two, or three N, O, or S, preferably N, and R is absent or acetyl. In certain embodiments, X1 is an amino acid and its side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X1 is R-His, R-Lys, R-Orn, R-Dab (2,4-diaminobutyric acid), R-Dap (2,3-diaminopropionic acid), R-Arg, R-hArg, and R is absent or acetyl. In certain embodiments, X1 is Ac-Lys; X2 is Phe; X3, X4, X6, X8, X11 and X12 are each independently a natural or synthetic amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and are not limited to cycloalkyl, heterocycloaryl, or heteroaryl. The alkyl, aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is one, two, or three N, O, or S, preferably N. In certain embodiments, X2, X4, X7, X8, X11, and X12 are each independently an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X3, X4, X6, X8, X11 and X12 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, or His. In certain embodiments, X3, X4, X6, X8, X11 and X12 are each independently an amino acid whose side chain is -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0-4, or each independently Arg, His or Lys.In certain embodiments, X3, X4, X6 and X8 are each, independently, an amino acid whose side chain is -CH2-(CH2)p-guanidine, where p is 0 to 4, or Arg, and / or X11 is an amino acid whose side chain is -(CH2)p-imidazole, where p is 0 to 4, or His, and / or X12 is an amino acid whose side chain is -CH2-(CH2)p-NH2, where p is 0 to 4, or X12 is Lys. X5 is Gln, X7, X14 and X16 are each independently Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, at least one, two or all three of X7, X14 and X16 are Pro; X9 and X15 are each independently any natural or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and are not limited to cycloalkyl, heterocycloalkyl, aryl, and the like. The aryl, heteroaryl, or heteroaryl are substituted with one or more substituents, each of which is independently, for example, a halogen, an amino group, a guanidino group, -OH, S, or (C1-C6)alkyl; the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl; and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In a more specific embodiment, X9 and X15 are each independently a natural or synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5. In a more specific embodiment, X9 and X15 are each independently a natural or synthetic amino acid whose side chain is -(C3-C6)alkyl. In another specific embodiment, X9 and X15 are each independently Nle, Leu, Ala, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, and in a more specific embodiment, X9 is Leu and / or X15 is Ala or Nle; X10 and X13 close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that give rise to terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, one of X10 and X13 is Glu and the other is Lys; X17 is any naturally occurring amino acid or any synthetic amino acid whose side chain is -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl or -(CH2)p-CONH-aryl, or -(CH2)p-CON(aryl)(alkylaryl), where p is 0 to 5, and the heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently selected from, for example, halogen, amine, -(C3-C8)aryl, -(C3-C8)cycloalkyl, -O-(C3-C8)aryl. , -O-(C3-C8)cycloalkyl, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, where cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S, and in certain embodiments, X17 is any naturally occurring amino acid or any synthetic amino acid, the side chain of which may or may not be substituted, -(CH2)p-(C3-C8)aryl, where p is 0 to 5. In certain embodiments, X17 is Phe, cypTyrOBn, cypTyr, dcypTyrOBn, TyrOBn, B1, B2, B3 or B4.

[0087] In certain embodiments, the compound of formula (V) is any one of compounds 62-70 in Table II.

[0088] The present disclosure includes compounds of formula (V), wherein each of X1-X17 is independently defined using either the more general or more specific definitions provided above for those residues in formula (V).

[0089] In certain embodiments of formula (V), at least four (or at least 5, 6, 7, 8, 9, 10, 11, or 12) of the residues at positions Xn, as defined above, where n is 1-12 and 14-17 (i.e., other than residues X10 and X13 that close a ring different from the corresponding residues in AP-17 (SEQ ID NO: 86)) correspond to residues in AP-17 (SEQ ID NO: 86). For example, compound 62 has 11 residues that correspond to residues in AP-17 (SEQ ID NO: 86). In other certain embodiments of formula (V), at least four (or at least 5, 6, 7, 8, or 9) of the residues correspond to residues in AP-13 (SEQ ID NO: 47), other than residues that close a ring different from the corresponding residues in AP-13 (SEQ ID NO: 47). For example, compound 62 has 8 residues that correspond to residues in AP-13 (SEQ ID NO: 47).

[0090] In other particular embodiments, the compounds of the present disclosure correspond to macrocyclic analogs of Ap17 KFRRQRPRLSHKGPMPF (SEQ ID NO: 86), where the compounds differ from Ap17 by at least two substitutions at the ring-closing positions and by at least one (or 2, 3, 4, 5, 6, 7, 8, 9, or 10) additional substitutions, deletions, and / or insertions. These substitutions, deletions, and / or insertions are defined in the various Xn of formula (V) above. The correspondence between these Xn and Ap13 and A17 is shown in Table B above, with the symbol "["and"]" being used to indicate the position of the ring-closing residue in formula (V) and the compounds of the present disclosure that satisfy this formula.

[0091] Elabella cyclic analogues The present disclosure also encompasses Ellabella cyclic analogs, such as those set forth in any one of formulas (VI)-(VIII).

[0092] In certain embodiments, the Ellabella cyclic analog comprises or has the following formula (VI): c[X1'-X2'-X3'-X4']c-X5'-X6'-c[C-X7'-X8'-X9'-C]c-X10'-X11'-X12'-X13'-X14', During the ceremony, X1' and X4' close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, one of X1' and X4' is Glu and the other is Lys. In certain embodiments, they are Lys and Glu or Glu and Lys; X2', X3', X9' and X10' are each independently a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is not limited to cycloalkyl, heterocycloalkyl, aryl, or aryl. The aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In certain embodiments, X2', X3', X9', and X10' are each independently absent or an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4. In certain embodiments, X2', X3', X9' and X10' are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, His, or absent. In more specific embodiments, X2' and X3' are each independently -CH2-(CH2)p-guanidine, where p is 0-4, or Arg, and / or X9' is -(CH2)p-imidazole, where p is 0-4, or His, and / or X10' is -(CH2)p-(C3-C8)aryl, -CH2-(CH2)p-guanidine, or -CH2-(CH2)p-NH2, where p is 0-4, or Arg, Orn, Lys, or 4-aminomethyl-phenylalanine; X12' and X14' are each independently Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X12' and / or X14' are Pro, X5', X7', and X11' are each independently any naturally occurring amino acid or any synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0 to 5, and is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Aryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, where alkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, or (C1-C6)alkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is N, O, or S. In other particular embodiments, X5', X7', and X11' are Nle, Leu, Ala, Val, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine, alpha-methylphenylalanine, Trp, thiazol-5-yl-alanine, 3-(2-pyridyl)-alanine, 3-(3-pyridyl)-alanine, or 3-(4-pyridyl)-alanine. In certain embodiments, X5', X7', and X11' are each independently -(CH2)p-(C3-C8)alkyl or -(CH2)p-(C3-C8)hydroxyalkyl, where p is 0 to 5. In another particular embodiment, X5', X7', and X11' are each independently Nle, Leu, Ala, Val, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine. In more specific embodiments, X5' is Nle, and / or X7' is Leu and X11' is Val; X6' and X8' are each independently absent or each independently any naturally occurring amino acid or any synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0 to 5, and is selected from cycloalkyl, heterocycloalkyl, aryl, or heterocycloalkyl. or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and alkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, or (C1-C6)alkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is N, O, or S. In more specific embodiments, X6' and / or X8' are absent.

[0093] X13' is an amino acid whose side chain is -(CH2)p-(C3-C8)aryl, where aryl is optionally substituted with one or more substituents, each of which is independently halogen, amine, -OH, S, or (C1-C6)alkyl. In certain embodiments, X14' is Phe or halogen-substituted Phe, such as bromophenyl.

[0094] In certain embodiments, the compound of formula (VI) is compound 79 in Table III below.

[0095] The present disclosure includes compounds of formula (VI), wherein each of X1'-X14' is independently defined using either the more general or more specific definitions provided above for those residues in formula (VI).

[0096] In another particular embodiment, the compound comprises or has the following formula (VII): X1'-X2'-X3'-X4'-c[X5'-X6'-X7'-X8'-X9'-X10']c-X11'-X12'-X13'-X14'-X15'-X16'-X17', During the ceremony, X1' is absent, -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11, a natural amino acid or a synthetic amino acid, the side chain of which is H, -(C1-C12)alkyl, -(CF2)q-CF3, q is 0 to 11, -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -C(O)-(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl or -(CH2)p-(C3-C8)heterocycloalkyl, p is 0 to 5, and cycloalkyl, heterocycloalkyl, aryl or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C and optionally fused with -(C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, where alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which independently includes or has, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, where p is 0-5, -O-(CH2)p-(C3-C8)aryl, where p is 0-3, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S. In certain embodiments, X1 is Pyr, -(CH2)q-CH3 or -(CF2)q-CF3, where q is 0-11. In a more specific embodiment, it is Pyr.

[0097] X2', X3' and X13' are each independently a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. The heteroaryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is one, two or three N, O or S, preferably N. In certain embodiments, X2', X3' and X13' are each independently an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine, optionally substituted with, for example, an aryl, where p is 0-4. In certain embodiments, X2', X3', and X13' are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, or His. In more specific embodiments, X2', X3', and X13' are each independently -CH2-(CH2)p-guanidine, optionally substituted with, for example, aryl, where p is 0-4. In more specific embodiments, X2' and X3' are each independently Arg, aryl-substituted Arg (e.g., -C(O)-(C3-C8)aryl, such as 4-bromobenzoyl), hArg, Nle, Leu, Ala, Val, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), or alpha-methylphenylalanine.In more specific embodiments, X2' and / or X3' are each independently Arg or hArg (substituted or unsubstituted, e.g., Arg substituted with 4 bromobenzoyl), and X13' is Arg.

[0098] X4', X6', X8' and X12' are each independently non-existent or any natural amino acid or synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0-5, and are selected from the group consisting of cycloalkyl, heteroalkyl, and aryl. The cycloalkyl, aryl, or heteroaryl are substituted with one or more substituents, each of which is independently, for example, a halogen, an amino group, a guanidino group, -OH, S, or (C1-C6)alkyl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In a more specific embodiment, X4', X6', X8', and X12' are each independently -(CH2)p-(C3-C8)alkyl or -(CH2)p-(C3-C8)hydroxyalkyl, where p is 0-5. In more specific embodiments, X4', X6', X8' and X12' are each independently Leu, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Ala, Val, Ile, Ser or Thr. In more specific embodiments, X4', X6', X8' and X12' are each independently Ser, Nle or Leu. In more specific embodiments, X4' and / or X12' are Ser, and / or X6' is Nle, and / or X8' is Leu.

[0099] X5' and X10' close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, each independently is Lys, Orn, Dab, Dap, Asp, Glu, or allylGly, and the ring is closed by an amide bridge or an alkene. In certain embodiments, one of X1' and X4' is Glu and the other is Lys. In certain embodiments, they are Lys and Glu or Glu and Lys; X7', X15' and X17' are each independently Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn). In certain embodiments, X7', X15' and X17' are each Pro.

[0100] X9' and X11' are each independently nonexistent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and are selected from cycloalkyl, heterocycloalkyl, aryl, Or the heteroaryl is optionally substituted with at least one amino or guanidino group, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatom in the heteroalkyl, heteroaryl or heterocycloalkyl is one, two or three N, O or S, preferably N. In certain embodiments, X9' and X11' are each independently absent or an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, where p is 0-4. In certain embodiments, X9' is Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, or absent. In more specific embodiments, X9' and X11' are each independently absent, -(CH2)p-imidazole, where p is 0-4, or His.

[0101] X14' is any naturally occurring amino acid or any synthetic amino acid whose side chain is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0 to 5, and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or and optionally fused to two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, where alkyl, heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, or (C1-C6)alkyl, and the heteroatom in the heteroalkyl, heteroaryl, or heterocycloalkyl is N, O, or S. In another particular embodiment, X14' is Nle, Leu, Ala, Ile, Val, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine; in particular embodiments, X14' is -(CH2)p-(C3-C8)alkyl, where p is 0-5, or Ala, Val, Ile, Nle, or Leu; X16' is an amino acid whose side chain is -(CH2)p-(C3-C8)aryl, where aryl is optionally substituted with one or more substituents, each of which is independently halogen, amine, -OH, S, or (C1-C6)alkyl. In certain embodiments, X14' is Phe or halogen-substituted Phe, such as bromophenyl.

[0102] In certain embodiments, the compound of formula (VII) is any one of compounds 74-78 and 89-94 in Table III below. In another particular embodiment, the compound of formula (VII) is any one of compounds 77, 89, 91, and 94 in Table III below.

[0103] The present disclosure includes compounds of formula (VII), where each of X1'-X16' is independently defined using either the more general or more specific definitions provided above for these residues in formula (VIII). In another particular embodiment, the compound comprises or has the following formula (VIII): c[X1'-X2'-X3'-X4']c-X5'-X6'-X7'-X8'-X9'-X10'-X11'-X12'-X13'-X14' During the ceremony, X1' and X4' close the ring, are the same or different, and are aliphatic residues, alkenyl residues, acid residues, or natural or unnatural amino acids, or derivatives thereof, and these moieties are optionally substituted. In certain embodiments, they are residues that bear terminal alkenes or free carboxylic acids or amine functions. In certain embodiments, they are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Asp, Glu, allylGly, Nα-allyl-arginine, Nπ-allyl-histidine, Nγ-allyl-Nγ-nosyl-α,γ-diamino-butanoic acid, Nγ-allyl-α,γ-diamino-butanoic acid, or Nγ-allyl-Nγ-methyl-α,γ-diamino-butanoic acid, whereby the ring is closed by an amide bridge or an alkene. In certain embodiments, each independently Lys, Orn, Dab, Dap, Asp, Glu, or allylGly is present, and the ring is closed by an amide bridge or an alkene, and in certain embodiments, one of X1' and X4' is Glu and the other is Lys. In certain embodiments, they are Lys and Glu or Glu and Lys, X2', X3', X8' and X10' are each independently a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. and heteroaryl is optionally substituted with at least one amino or guanidino group, and cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl or heterocycloalkyl are one, two or three N, O or S, preferably N. In certain embodiments, X2', X3', X8' and X10' are each independently an amino acid whose side chain is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, where p is 0-4. In certain embodiments, X2', X3', X8' and X10' are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, or His. In more specific embodiments, X2', X3', X8' and X10' are each independently -CH2-(CH2)p-guanidine or -(CH2)p-imidazole, where p is 0 to 4. In another specific embodiment, X2', X3' and X10' are each independently -CH2-(CH2)p-guanidine, where p is 0 to 4. In another specific embodiment, X2', X3' and X10' are each independently Arg or hArg, and / or X8' is His.

[0104] X5', X7', X9', and X11' are each independently a natural amino acid or a synthetic amino acid, the side chain of which is H, -(CH2)p-(C3-C8)alkyl, -(CH2)p-(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and cycloalkyl, heterocycloalkyl, , aryl, or heteroaryl are substituted with one or more substituents, each of which is independently, for example, halogen, amino, guanidino, -OH, S, or (C1-C6)alkyl, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in the heteroalkyl, heteroaryl, or heterocycloalkyl are one, two, or three N, O, or S. In another particular embodiment, X5', X7', X9', and X11' are each independently -(CH2)p-(C3-C8)alkyl, where p is 0 to 5. In another specific embodiment, X5', X7', X9', and X11' are each independently Leu, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Ala, Val, Ile, Ser, or Thr. In a more specific embodiment, X5', X7', X9', and X11' are each independently Ser, Nle, Leu, or Val. In a more specific embodiment, X5' is Nle, and / or X7' is Leu, and / or X9' is Ser, and / or X11' is Val.

[0105] X6', X12' and X14' are each independently Gly, Phe, Leu, Ile, Ser, Pro, Aib, Sar, Oic, βAla, Hyp or Hyp(OBn), preferably Pro or Oic. In certain embodiments, X6', X12' and X14' are each Pro.

[0106] X13' is an amino acid whose side chain is -(CH2)p-(C3-C8)aryl, where aryl is optionally substituted with one or more substituents, each of which is independently halogen, amine, -OH, S, or (C1-C6)alkyl. In another particular embodiment, it is Phe or halogen-substituted Phe. In another embodiment, it is Phe.

[0107] In certain embodiments, the compound of formula (VIII) is any one of compounds 72 and 73 in Table III below. In more specific embodiments, it is compound 72.

[0108] In certain embodiments of Formulas (VI)-(VIII), at least 4 (or at least 5, 6, 7, 8, 9, 10, 11 or 12) of the residues (e.g., positions Xn as defined above, where n is 1-14 in Formulas (VI) and (VIII), or 1-17 in Formula (VII)), except for residues that close a ring that differ from the corresponding residues in Elabella(19-32) (SEQ ID NO:85), correspond to residues in Elabella(19-32) (SEQ ID NO:85). For example, compound 79 has 8 residues that correspond to residues in Elabella(19-32) (SEQ ID NO:85).

[0109] In other particular embodiments, the compounds of the present disclosure correspond to macrocyclic analogs of elabella (19-32) PyrRRCMPLHSRVPFP (SEQ ID NO: 85), where the compounds differ from elabella (19-32) by at least two substitutions at the ring-closing positions and by at least one (or 2, 3, 4, 5, 6, 7, or 8) additional substitutions, deletions, and / or insertions. These substitutions, deletions, and / or insertions are defined in the various Xn of formulas (VI)-(VIII) above. The correspondence between these Xn and elabella (19-32) is shown in Table C above, with the "["and"]" symbols used to indicate the positions of the ring-closing residues of formulas (VI)-(VIII) and the compounds of the present disclosure that satisfy these formulas.

[0110] In formulas (I) to (VIII), unless otherwise specified, the bond between two amino acid residues (natural or non-natural) is a peptide bond.

[0111] In another particular embodiment of formulae (I)-(VIII), one of the ring-closing residues' is Lys, Dap, Dab, Orn, and the other is Glu or Asp.

[0112] In one embodiment, one of the terminal (natural or unnatural) amino acid residues used for ring closure is a (natural or unnatural) amino acid having an amine in its side chain prior to ring closure, and the other terminal is a (natural or unnatural) amino acid having a carboxylic acid in its side chain prior to ring closure, where the amine and the carboxylic acid react to form an amide via macrolactamization. More specifically, one of the terminal (natural or unnatural) amino acid residues can be substituted prior to ring closure. After closure, the side chain carboxylic acid activated by the coupling agent reacts with the amino group in the side chain of the other residue to form a peptide bond, for example, using a macrolactamization reaction.

[0113] As used herein, the term "substituted" with respect to the natural or non-natural amino acid or acid residues enumerated above in the structures refers to substitution with halogen (e.g., Cl, F, Br, I), -OH, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)aryl, (C3-C6)aryl(C1-C6)alkyl, (C3-C6)cycloalkyl, hetero(C3-C6)aryl, hetero(C3-C6)aryl(C1-C6)alkyl, hetero(C3-C6)cyclo(C1-C6)alkyl, amino(C1-C6)alkyl, amino(C3-C6)aryl, amino(C3-C6)aryl(C1-C6)alkyl, amino(C3-C6)cycloalkyl, aminohetero(C3-C6)aryl, aminohetero(C3-C6)aryl(C1-C6)alkyl, or aminohetero(C3-C6)cyclo(C1-C6)alkyl.

[0114] In certain embodiments, the size of the macrocycle can be 14 to 24 ring atoms (or 15 to 23, 16 to 22, 17 to 20). In certain embodiments, the size of the macrocycle can be 17 to 20 ring atoms.

[0115] In all of the above compounds, the residues (e.g., X1-Xn) may be in the L or D configuration. In all of the above combinations of two residues, they may be in the LL, LD, DL, or DD configuration.

[0116] Without being so limited, specific compounds of the present disclosure include those satisfying formulas (I)-(VIII). In more specific embodiments, compounds of the present disclosure include those listed in Tables I-III.

[0117] chemical group As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated or unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "(C1-12) alkyl" (or "C1-12 alkyl") refers to any alkyl of up to 12 carbon atoms, including hexyl alkyl and pentyl alkyl isomers, as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl, and methyl. As another example, "(C1-4) alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl, and methyl. As another example, "C1-3 alkyl" refers to n-propyl, isopropyl, ethyl, and methyl. Alkyl includes unsaturated aliphatic hydrocarbons, including alkynes (RC≡CR), and / or alkenes (RC=CR).

[0118] The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo). The term "haloalkyl" refers to an alkyl group, as defined above, in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and / or I). Thus, for example, "C1-10 haloalkyl" (or "C1-C6 haloalkyl") refers to a C1 to C10 straight or branched alkyl group, as defined above, having one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning, except that the halogen substituents are limited to fluoro. Suitable fluoroalkyls include the series (CH2) 0-4 CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).

[0119] The term "heteroalkyl" is given its ordinary meaning in the art and refers to an alkyl group, as described herein, in which one or more carbon atoms are replaced with a heteroatom, such as oxygen, nitrogen, sulfur, or derivatives thereof. Examples of heteroalkyl groups include, but are not limited to, alkoxy, alkyl-substituted amino, thiol, e.g., methionine side groups. Up to two heteroatoms may be consecutive. 2-6 When a prefix such as is used to refer to a heteroalkyl group, the number of carbons (in this example, 2-6) is meant to include the heteroatoms as well.

[0120] The term "aminoalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen or carbon atoms have been replaced with a nitrogen or an amino derivative, such as, but not limited to, guanidine. Thus, for example, "C 1-6 "(or "C1-C6 aminoalkyl") refers to a C1 to C6 straight or branched alkyl group as defined above having one or more amino derivatives (e.g., NH, amide, diazirine, azide, etc.).

[0121] The term "thioalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen or carbon atoms have been replaced with a sulfur atom or a thiol derivative. Thus, for example, "C 1-6 "Thioalkyl" (or "C1-C6 thioalkyl") refers to a C1 to C6 straight or branched alkyl group as defined above having one or more sulfur atoms or thiol derivatives (eg, S, SH, etc.).

[0122] Aminoalkyl and thioalkyl are specific embodiments of, and are encompassed by, the term "heteroalkyl" or substituted alkyl, depending on whether a heteroatom replaces a carbon or hydrogen atom.

[0123] The term "cycloalkyl" refers to a saturated alicyclic hydrocarbon consisting of a saturated 3-8 membered ring optionally fused with additional (1-3) aliphatic (cycloalkyl) or aromatic ring systems, each of which consists of a 3-8 membered ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl (cyp) (e.g., compounds 38-41 and 63-65), cyclohexyl, and cycloheptane.

[0124] The term "heterocyclyl" refers to (i) a 4-7 membered saturated heterocyclyl ring containing 1-3 heteroatoms independently selected from N, O, and S, or (ii) a heterobicyclic ring (e.g., benzocyclopentyl, octahydroindole (e.g., compound 166)). Examples of 4-7 membered saturated heterocyclyl rings within the scope of the present disclosure include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, pyridine, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4- to 7-membered unsaturated heterocyclyl rings within the scope of the present disclosure include monovalent unsaturated heterocyclyl rings that correspond to the saturated heterocyclyl rings listed in the preceding sentence, where a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).

[0125] The term "C(O)" refers to carbonyl. The terms "S(O)2" and "SO2" each refer to sulfonyl. The term "S(O)" refers to sulfinyl.

[0126] The term "aryl" refers to an aromatic (unsaturated) compound consisting of a 3-8 membered ring optionally fused with additional (1-3) aliphatic (cycloalkyl) or aromatic ring systems, each of which consists of a 3-8 membered ring (such as anthracene, indane, Tic, 3-benzothienyllanine, or dihydroindole). In certain embodiments, it refers to phenyl, benzocyclopentyl, or naphthyl.

[0127] The term "heteroaryl" refers to (i) a 3-, 4-, 5-, 6-, 7-, or 8-membered heteroaromatic ring (more specifically, a 3- to 7- or 3- to 6-membered ring) containing 1 to 4 heteroatoms independently selected from N, O, and S, such as thiophenyl, thienyl, pyridine, etc., or (ii) a heterobicyclic ring selected from indolyl, quinolinyl, isoquinolinyl, Tic, dihydroindolylglycine, and quinoxalinyl. Suitable 3-, 4-, 5- and 6-membered heteroaromatic rings include, for example, diazirine, pyridyl (also called pyridinyl), pyrrolyl, diazine (e.g., pyrazinyl, pyrimidinyl, pyridazinyl), triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (e.g., 1, 2, 3 triazolyl), tetrazolyl (e.g., 1, 2, 3, 4 tetrazolyl), oxazolyl, iso-oxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and isothiazolyl. Particularly interesting heteroaryls are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl. Suitable heterobicyclic rings include indolyl.

[0128] The term "aralkyl", more specifically, "(C4-C14)aralkyl" or "C4-14 aralkyl", as used herein, refers to a compound containing a 3-7 membered aryl ring substituted with 1-7 alkyl. In certain embodiments, it refers to benzyl or phenethyl.

[0129] As used herein, unless otherwise specified, the terms "alkyl", "haloalkyl", "aminoalkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroalkyl" and "heteroaryl" as well as terms indicating specific embodiments thereof (e.g., butyl, fluoropropyl, aminobutyl, cyclopropane, morpholine, phenyl, pyrazole, etc.) include substituted embodiments of these groups (i.e., in addition to their halogen and nitrogen substituents, in the case of haloalkyl and aminoalkyl, respectively) as well as unsubstituted embodiments of these groups. Thus, for example, the term "phenyl" includes unsubstituted phenyl as well as fluorophenyl, hydroxyphenyl, methylsulfonylphenyl (or biphenyl), diphenyl, trifluoromethyl-diazirine-phenyl, isopropyl-phenyl, trifluorohydroxy-phenyl. Similarly, the term pyrazole includes unsubstituted pyrazole as well as methylpyrazole. The one or more substituents may be amine, halogen, hydroxyl, C1-6 aminoalkyl, C1-6 heteroalkyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 haloalkyl, aryl, heteroaryl and heterocyclyl groups (and the like).

[0130] It is understood that the particular rings listed above are not limitations on the rings that may be used in the present disclosure; these rings are merely representative.

[0131] Unless expressly stated to the contrary in the specific context, any of the various cyclic rings and ring systems described herein may be attached to the remainder of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results therefrom.

[0132] Isomers, tautomers and polymorphs As used herein, the term "isomer" refers to stereoisomers, including optical isomers (enantiomers), diastereoisomers, as well as other known types of isomers.

[0133] The compounds of the present disclosure have at least 5 asymmetric carbon atoms and therefore can exist in the form of optically pure enantiomers (optical isomers) and as mixtures thereof (racemates).Unless otherwise specified, the present disclosure should be understood to encompass the racemates, enantiomers and / or diastereoisomers of the compounds of the present disclosure and mixtures thereof.Furthermore, certain macrocyclic compounds of the present invention contain an alkene that closes the ring.These compounds have Z and E isomers.

[0134] For further clarity, (S)-H or (S)-CH3 indicates that the stereogenic center bearing the H or CH3 substituent is of (S) stereochemistry.

[0135] Additionally, the present disclosure embraces all geometric isomers: for example, when a compound of the present disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the present disclosure.

[0136] In this disclosure, it is to be understood that the compounds of the present disclosure may exhibit the phenomenon of tautomerism, and that the formulae within this specification may represent only one of the possible tautomeric forms. It is to be understood that the present disclosure encompasses any tautomeric form and is not limited to merely any one tautomeric form utilized within the formulae.

[0137] It is also to be understood that certain compounds of the present disclosure may exhibit polymorphism, and the present disclosure encompasses all such forms.

[0138] salt The present disclosure relates to the compounds of the present disclosure as defined herein above, as well as their salts. As used herein, the term "salt" refers to basic salts formed with inorganic and / or organic bases. The salts for use in pharmaceutical compositions are pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of the present disclosure. The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are pharmacologically acceptable and substantially non-toxic to the subjects to which they are administered. More specifically, these salts retain the biological effectiveness and properties of the anti-atherosclerotic compounds of the present disclosure, and are formed from suitable non-toxic organic or inorganic acids or bases.

[0139] For example, if the compound of the present disclosure is sufficiently acidic, the salts of the present disclosure include base salts formed with inorganic or organic bases. Such salts include alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts, inorganic amine salts such as ammonium or substituted ammonium salts, for example, trimethylammonium salts, as well as chloroprocaine salts, dibenzylamine salts, dicyclohexylamine salts, dicyclohexylamine salts, diethanolamine salts, ethylamine salts (including diethylamine salts and triethylamine salts), ethylenediamine salts, gluconamide salts, and the like. Examples of suitable salts include salts with acid bases (e.g., organic amines), such as samine salts, guanidine salts, methylamine salts (including dimethylamine salts and trimethylamine salts), morpholine salts, morpholine salts, N,N'-dibenzylethylenediamine salts, N-benzyl-phenethylamine salts, N-methylglucamine salts, phenylglycine alkyl ester salts, piperazine salts, piperidine salts, procaine salts, t-butylamine salts, tetramethylammonium salts, t-octylamine salts, tris-(2-hydroxyethyl)amine salts, and tris(hydroxymethyl)aminomethane salts. Preferred salts include salts formed with sodium, lithium, potassium, calcium, and magnesium.

[0140] Such salts can be routinely formed by those skilled in the art using standard techniques.In fact, the chemical modification of pharmaceutical compounds (i.e., drugs) into salts is a technique well known to medicinal chemists (see, for example, H.Ansel et.al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed.1995) pp.196 and 1456-1457, which are incorporated herein by reference).Salts of the compounds of the present disclosure can be formed, for example, by reacting the compounds of the present disclosure with an amount of acid or base, such as an equivalent amount, in a medium, such as an aqueous medium, in which the salt precipitates or is then lyophilized.

[0141] ester The present disclosure relates to the compounds of the present disclosure defined herein above as well as their esters.As used herein, the term "ester" refers to the compounds of the present disclosure or their salts, in which carboxylic acid is converted to corresponding esters by using alcohol and coupling reagent to convert hydroxyl group.The esters used in pharmaceutical compositions are pharmaceutically acceptable esters, but other esters may be useful in the production of the compounds of the present disclosure.

[0142] The term "pharmaceutical acceptable esters" refers to esters of the compounds of the present disclosure that are pharmacologically acceptable and substantially non-toxic to the subjects to which they are administered. More specifically, these esters retain the biological effectiveness and properties of the anti-atherosclerotic compounds of the present disclosure and act as prodrugs that cleave in such a manner as to produce the parent alcohol compound when absorbed into the bloodstream of a warm-blooded animal.

[0143] Esters of the compounds of the present disclosure include, inter alia, carboxylic acid esters obtained by esterification in which the non-carbonyl moiety of the carboxylic acid portion of the following group (1) ester group is selected from linear or branched alkyl (e.g., ethyl, n-propyl, t-butyl, n-butyl, methyl, propyl, isopropyl, butyl, isobutyl, or pentyl), n-hexyl, alkoxyalkyl (e.g., methoxymethyl, acetoxymethyl, and 2,2-dimethylpropionyloxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted with halogen, C1-4 alkyl, or C1-4 alkoxy, or amino).

[0144] Further information on the examples and use of esters for delivery of pharmaceutical compounds is available in Design of Prodrugs.Bundgaard H ed.(Elsevier,1985), which is incorporated herein by reference.See also H.Ansel et.al.,1995 at pp.108-109;Krogsgaard-Larsen,1996 at pp.152-191;Jarkko Rautio,2008;and Pen-Wei Hsieh,2009, all of which are incorporated herein by reference.

[0145] The compounds of the present disclosure can be esterified by a variety of conventional techniques, including that esters are formed from the acid of the molecule by reaction with a coupling agent such as DIC (diisopropylcarbodiimide) and a base such as N-N-dimethylaminopyridine (DMAP) and an alcohol such as methanol (methyl ester), ethanol, a long chain alcohol or benzyl alcohol (benzyl ester). Those skilled in the art will readily understand how to successfully carry out these, as well as other known methods of esterification of acids.

[0146] Esters of the compounds of the present disclosure may form salts, where this is accomplished by conventional techniques as described above.

[0147] solvate The compounds of the present disclosure can exist in unsolvated as well as solvated forms with solvents such as water, ethanol, and the like, and the present disclosure is intended to encompass both the solvated and unsolvated forms.

[0148] "Solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Solvates for use in pharmaceutical compositions are pharma-ceutically acceptable solvates, although other solvates may be useful in the production of compounds of the present disclosure.

[0149] As used herein, the term "pharmaceutical acceptable solvates" refers to solvates of the compounds of the present disclosure that are pharmacologically acceptable and substantially non-toxic to the subjects to which they are administered. More specifically, these solvates retain the biological effectiveness and properties of the anti-atherosclerotic compounds of the present disclosure and are formed from suitable non-toxic solvents.

[0150] Non-limiting examples of suitable solvates include ethanolates, methanolate salts, and the like, as well as hydrates, which are solvates where the solvent molecule is H2O.

[0151] The preparation of solvates is generally known.Thus, for example, Caira, 2004, which is incorporated herein by reference, describes the preparation of the solvates of antifungal fluconazole in ethyl acetate and from water.Similar preparations such as solvates, hemisolvates, hydrates, etc. are described in van Tonder, 2004, Bingham, 2001, both of which are incorporated herein by reference.

[0152] A typical non-limiting process for preparing solvates includes dissolving the compound of the present invention in a desired amount of a desired solvent (organic or water, or a mixture thereof) at a temperature higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals, and then isolating by standard methods. For example, analytical techniques such as IR spectroscopy can be used to show the presence of solvent (or water) in the crystals as solvates (or hydrates).

[0153] Compositions, combinations and kits composition The present disclosure also relates to pharmaceutical compositions comprising the aforementioned compounds of the present disclosure or pharma- ceutically acceptable salts, esters and solvates thereof, and optionally a pharma- ceutically acceptable carrier.

[0154] As used herein, the term "pharmacologically acceptable" refers to molecular entities and compositions that are physiologically tolerable and typically do not produce allergic or similar adverse reactions, such as stomach upset, dizziness, etc., when administered to a subject (e.g., a human). Preferably, as used herein, the term "pharmacologically acceptable" means approved by a federal or state government regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0155] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compounds of the present disclosure may be administered. Sterile water or saline solution and aqueous dextrose and glycerol solutions may be used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. The pharmaceutical compositions of the present disclosure may also contain excipients / carriers such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for varying osmotic pressure, buffers, coating agents, or antioxidants.

[0156] In some embodiments, the compositions provided herein are administered by one or more routes of administration using one or more of a variety of suitable methods. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary depending on the desired outcome. Routes of administration of the disclosed compounds for use as disclosed herein include, but are not limited to, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral administration and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, intrathecal, intraspinal, epidural and intrasternal injection and infusion. Alternatively, the compounds of the present disclosure provided herein are administered orally (see, e.g., U.S. Pat. No. 7,875,648 B2 to Meier), topically, epidermally or mucosally, e.g., via parenteral routes such as intranasal, oral, intravaginal, rectal, sublingual or topical.

[0157] Although not limited thereto, when the compound / pharmaceutical composition of the present disclosure is administered orally, it may take the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions, for example, rectally using a suppository, for example, topically, locally or transdermally using an ointment, cream, gel or solution, or parenterally, for example, intravenously, intramuscularly, subcutaneously, intrathecally or transdermally using an injection solution. Furthermore, administration may be performed sublingually, nasally, or as an ophthalmic preparation or aerosol, for example, in the form of a spray, such as a nasal spray.

[0158] The compounds of the present disclosure may be incorporated into dosage forms together with any of the vehicles commonly used in pharmaceutical preparations. Methods for preparing suitable formulations are well known in the art (see, for example, Remington's Pharmaceutical Sciences, 16th Ed., 1980, A. Oslo Ed., Easton, Pa, which is incorporated herein by reference). Common pharmaceutically acceptable carriers include, but are not limited to, sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters. Aqueous carriers include, but are not limited to, water, alcohol, saline, and buffer solutions. Pharmaceutically acceptable carriers may also include physiologically acceptable aqueous vehicles (e.g., saline) or other known carriers suitable for a particular route of administration.

[0159] For the preparation of tablets, coated tablets, dragees or hard gelatin capsules, the compounds of the present disclosure may be mixed with any known pharma- ceutically inert inorganic or organic excipients and / or carriers. Examples of suitable excipients / carriers include lactose, maize starch or its derivatives, talc or stearic acid or its salts. Suitable excipients for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. However, depending on the nature of the active ingredient, soft gelatin capsules may not require any excipients at all. For the preparation of solutions and syrups, excipients that can be used include, for example, water, polyols, saccharose, invert sugar and glucose.

[0160] For suppositories, and for topical or transdermal application, excipients which may be used include, for example, natural or hardened oils, waxes, fats and semisolid or liquid polyols.

[0161] When parenteral administration is selected as the administration route, the preparation containing the compound of the present disclosure can be provided to the patient in combination with sterilized aqueous or non-aqueous solvent, suspension or emulsion that is pharma- ceutically acceptable.Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic ester.Aqueous carriers include water, aqueous alcoholic solutions, emulsions or suspensions that contain saline, as well as buffered medical parenteral vehicles that contain sodium chloride solution, Ringer's dextrose solution, dextrose + sodium chloride solution, Ringer's solution that contains lactose, or fixed oil.Intravenous vehicles can include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.

[0162] The medicaments / pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for varying osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically active agents.

[0163] In some embodiments, the active compound may be prepared with a carrier that protects the compound from rapid release, such as controlled release formulations, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable biocompatible polymers are used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are patented or generally known to those skilled in the art. For example, see Sustain and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978. In some embodiments, the therapeutic composition is administered with a medical device known in the art. For example, in one embodiment, the therapeutic composition provided herein is administered with a needleless hypodermic injection device.

[0164] Any amount of pharmaceutical composition can be administered to a subject. The dosage depends on many factors, including the age and requirements of the patient and the method of application. Typically, the amount of the compound of the present disclosure contained in a single dose is an amount that effectively prevents, delays or treats the disease or condition to be treated, delayed or prevented without inducing significant toxicity. Thus, a "therapeutically effective amount" or "effective amount" or "therapeutically effective dose" of a particular compound of the present disclosure or a composition thereof can result in a reduction in pain and / or body temperature in a subject. Intravenous administration or oral administration is the preferred form of use.

[0165] The effective amount of the compounds of the present disclosure may also be measured directly. The effective amount may be given daily or weekly, or fractions thereof. Typically, the pharmaceutical compositions of the present disclosure may be administered in an amount of about 0.001 mg up to about 500 mg (e.g., 10 mg, 50 mg, 100 mg, or 250 mg) per kg of body weight per day. The dosage may be provided in either a single or multiple administration regimen. For example, in some embodiments, the effective amount may range from about 1 mg to about 25 grams of the composition per day, about 50 mg to about 10 grams of the composition per day, about 100 mg to about 5 grams of the composition per day, about 1 gram of the composition per day, about 1 mg to about 25 grams of the composition per week, about 50 mg to about 10 grams of the composition per week, about 100 mg to about 5 grams of the composition every other day, and about 1 gram of the composition once per week.

[0166] These are merely guidelines, as the actual dose must be carefully selected and titrated by the attending physician based on each patient's specific clinical factors.The optimal daily dose is determined by methods known in the art and is influenced by factors such as the patient's age and other clinically relevant factors.In addition, the patient may be taking medication for other diseases or conditions.The other medication may be continued during the time that the pharmaceutical composition of the present disclosure is administered to the patient, but in such cases, it is particularly recommended to start at a low dose to determine whether adverse side effects are experienced.

[0167] combination According to another aspect, there is provided a combination of at least one of the compounds described herein with another compound described herein and / or another drug.

[0168] kit According to another aspect of the present disclosure, there is provided a kit comprising a compound as defined herein or a composition as described above, and instructions for its use in the prevention or treatment of cardiovascular disease.

[0169] In certain embodiments of the kit, the kit includes (i) at least one of the compounds described herein, (ii) another drug for the prevention or treatment of cardiovascular disease, (iii) instructions for its use in the prevention or treatment of cardiovascular disease, or (iv) a combination of at least two of (i)-(iii).

[0170] method The present disclosure also relates to a method of preventing or treating a cardiovascular disease or a symptom thereof in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Formulas (I) and (II).

[0171] As used herein, the term "cardiovascular disease" refers to, but is not limited to, heart failure, pulmonary arterial hypertension, cardiac dysfunction in sepsis, cardiac ischemia, and cerebral ischemia.

[0172] As used herein, the term "subject" refers to, but is not limited to, a human or an animal, such as a pet or other animal (e.g., pets such as cats, dogs, horses, and the like, as well as cows, fish, pigs, poultry, and the like).

[0173] As used herein, the term "subject in need thereof" refers to a subject who would benefit from receiving an effective amount of a compound or composition of the present disclosure. In the context of a method for preventing or treating pain, it refers to a subject who is experiencing or at risk of experiencing cardiovascular disease.

[0174] In the context of describing this disclosure (particularly in the context of the claims which follow), the use of the terms "a" and "an" and "the," and similar reference words, should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0175] The terms "including," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise specified.

[0176] The recitation of ranges of values ​​herein, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range, and each separate value is incorporated herein as if it were individually recited herein. All subsets of values ​​within a range are also incorporated herein as if they were individually recited herein.

[0177] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0178] The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the disclosure and does not pose a limitation on the scope of the disclosure unless otherwise claimed.

[0179] No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0180] Thus, the term "about" has its ordinary meaning. In one embodiment, it can mean ±10% of the numerical value it qualifies.

[0181] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0182] Other objects, advantages and features of the present disclosure will become more apparent upon reading the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.

[0183] The present disclosure is further illustrated by the following non-limiting examples.

[0184] Example 1: material and method Reagents and equipment All amino acids, HATU, DEPBT, DIPEA, piperidine, DIAD and triphenylphosphine were purchased from Chem-Impex (Illinois, USA). Wang resin (capacity 0.4-0.7 mmol / g) was ordered from Rapp-Polymer (Tuebingen, Germany). Second generation Hoveyda-Grubbs catalyst was obtained from Sigma-Aldrich (Ontario, Canada). Other solvents and reagents were purchased from Fischer Scientific (Ontario, Canada) and used as received.

[0185] Thin-layer chromatography (TLC) was performed on glass plates precoated with silica gel 60F254 (Merck, Darmstadt, Germany) and visualized with UV light (254 nm) and KMnO4 spray. Purification of organic molecules was performed by flash chromatography using a Biotage Isolera One system (Charlotte, North Carolina, US). High-resolution electrospray mass spectrometry (HRMS) data was recorded using a maXis ESI-Q-Tof instrument (Billerica, USA). Analytical LC was performed using a UPLC-MS system from Waters (Milford, USA) (column Acquity UPLC® CSH™ C18 (2.1×50 mm) packed with 1.7 μm particles). 1 H and 13 C NMR spectra (298 K) were recorded at 400 MHz and 100 MHz on a Bruker Ascend 400 or 600 MHz on a Bruker 600 MHz Varian INOVA spectrometer, respectively. Chemical shifts are in parts per million (ppm). Residual solvent signals were used as internal standards.

[0186] Fmoc-based amino acid synthesis N α -Fmoc-(N π Synthesis of (-allyl)-L-histidine-OH. Methyl N α -(((9H-fluoren-9-yl)methoxy)carbonyl)-N τ-Trityl-L-histidinate (Fmoc-L-His(Trt)-OMe 103). To a suspension of Fmoc-L-His(Trt)-OH (1 eq., 3.1 g, 5 mmol) and 1-hydroxy-benzotriazole monohydrate (HOBt·H2O, 1.1 eq., 1.05 g, 5.5 mmol) in 30 mL of DCM, 1-ethyl-2-diaminopropyl-carbodiimine chloride (EDC·HCl, 1.1 eq., 743 mg, 5.5 mmol) was added. A small amount of MgSO4 (approx. 100 mg) was added to absorb water and the mixture was stirred at room temperature for 10 min. Methanol (1 mL) was added and the reaction was carried out overnight at room temperature. The organic phase was washed twice with water and once with brine, dried over MgSO4 and filtered. The organic solvent was removed under vacuum and the product was purified by flash chromatography using DCM-MeOH (95:5) as eluent. The product was obtained as a white solid, 2.33 g, 73% yield. The product characteristics are identical to those reported (Ahn et al., 2013).

[0187] Methyl N α -(((9H-fluoren-9-yl)methoxy)carbonyl)-N π -Allyl-L-histidinate (N α -Fmoc-(N π-Allyl)-L-Histidine-OMe 104). To a solution of freshly distilled Tf2O (1.1 equiv., 686 μL, 4.0 mmol) in 26 mL of DCM pre-cooled at -78 °C was added (dropwise for 15 min) a mixture of allyl alcohol (1.1 equiv., 278 μL, 4.0 mmol) and diisopropylethylamine (DIPEA, 1.2 equiv., 855 μL, 4.4 mmol) in 18 mL of DCM. The reaction mixture was stirred at -78 °C for 30 min and slowly transferred to a solution of Fmoc-His(Trt)-OMe (1 equiv., 2.32 g, 3.7 mmol) dissolved in 30 mL of DCM pre-cooled at -78 °C. After 10 min, the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Residual acid was neutralized by vigorous mixing with 10 mL of saturated NaHCO3. The organic phase was washed twice with saturated NaHCO3, dried over MgSO4, filtered and evaporated to dryness. The trityl group was cleaved by treating the crude product with a solution of TFA / TIPS (2 mL / 0.5 mL) in 20 mL of DCM for 2 h at room temperature. The mixture was evaporated to dryness, the residual acid was neutralized with 40 mL of saturated NaHCO3 and the product was extracted with EtOAc. Purification was carried out using flash chromatography with DCM-MeOH (0->10% MeOH gradient in 10 CV). The product was obtained as a white foam, 1.1 g, 70% yield. 1H NMR (400MHz, CDCl3) δ (ppm) 8.58 (s, 1H), 7.74 (d, J = 7.5Hz, 2H), 7.55 (d, J = 7.3Hz, 2H), 7.38 (t, J = 7.4Hz, 2H), 7.29 (t, J = 7.4Hz, 2H), 7.18 (s, 1H), 6.09 (d, J = 7.2Hz, 1H, protonamide), 5.96 -5.76(m,1H),5.36(d,J=10.2Hz,1H),5.16(d,J=17.0Hz,1H),4.76-4.60(m,2H),4.59-4.4 9(m,1H),4.37(d,J=5.5Hz,2H),4.16(t,J=6.5Hz,1H),3.75(s,3H),3.28-3.05(m,2H).13C NMR(101MHz,CDCl3)δ(ppm)170.64,156.16,143.66,143.59,141.41,135.31,129.86,129.78,127. 95,127.25,125.09,121.37,120.15,119.42,67.27,53.21,52.85,49.13,47.09,26.35.HRMS[M+Na + ]:454.1750 (calculated value 454.1737).

[0188] N α -(((9H-fluoren-9-yl)methoxy)carbonyl)-N π -Allyl-L-histidine (N α -Fmoc-(N π Nα-Fmoc-(Nπ-allyl)-L-histidine-OH 105). To a solution of Nα-Fmoc-(Nπ-allyl)-L-histidine-OMe (602 mg, 1.4 mmol) in 27 mL of dioxane, 27 mL of HCl 2M was added and the mixture was refluxed for 10 h. The solution was neutralized to pH 6 using NaOH 1M. The mixture was extracted twice with DCM. TLC was used to monitor the completion of the extraction process. The combined organic phase was washed with brine, dried over MgSO4, and filtered. The organic solvent was removed under vacuum and the crude product was purified by flash chromatography using DCM-MeOH as eluent (gradient 5%→20% MeOH+1% AcOH in 10 CV). 450 mg of product was obtained, 77% yield. 1H NMR(400MHz,MeOD-d4)δ(ppm)8.91(s,1H),7.78(d,J=7.5Hz,2H),7.62(t,J=6.8Hz,2H),7 .38(t,J=7.4Hz,2H),7.35-7.25(m,3H),6.04(ddd,J=22.4,10.8,5.6Hz,1H),5.40(d,J=10 .3Hz,1H),5.24(d,J=17.1Hz,1H),4.87(d,J=4.5Hz,2H),4.53(dd,J=9.4,4.6Hz,1H),4.3 7(d,J=6.7Hz,2H),4.18(t,J=6.6Hz,1H),3.38-3.30(m,1H),3.10(dd,J=15.9,9.6Hz,1H). 13 C NMR(101MHz,MeOD-d4)δ(ppm)173.27,158.40,145.16,145.07,142.60,136.54,132.85,132 .08,128.83,128.16,126.12,120.96,119.36,67.88,53.63,50.24,48.36,26.82.HRMS[M+Na + ]:418.1759(Calculated value 418.1759).

[0189] Synthesis and characterization of Tyr(OBn) analogues (S)-2-Amino-3-(3-cyclopentyl-4-hydroxyphenyl)-propanoic acid (cypTyr 107). To a 250 mL round bottom flask containing L-tyrosine (1 equiv, 4.0 g, 22 mmol), H3PO4 85% (7.8 equiv, 20 mL, 173 mmol) and 3 mL of cyclopentanol (1.5 equiv, 2.9 g, 33 mmol) were added and the suspension was stirred and heated at 100 °C overnight. After 16 h, the reaction mixture was cooled, diluted in 100 mL of ice water, and the acid was neutralized with KOH (15.6 equiv, 19.3 g, 345 mmol). The product was precipitated by adding NaHCO3 until pH 5-7. The precipitate was filtered and washed with cold water. The solid was dried under a fume hood for 1 day to deliver 4.96 g of crude product as a mixture of mono- and di-alkylated tyrosines (off-white solid), which was used as is in the next step.

[0190] Methyl (S)-2-amino-3-(3-cyclopentyl-4-hydroxyphenyl)-propanoate (cypTyr-OMe, 108). The crude mixture of compound 107 (4.0 g) was dissolved in anhydrous methanol (73 eq., 45 mL, 1.1 mol) in a 250 mL round bottom flask under inert atmosphere. The solution was cooled to 0° C., then thionyl chloride (3 eq., 3.3 mL, 46 mmol) was added slowly to the flask. The mixture was stirred at room temperature overnight. After 15 h, the methanol was evaporated under reduced pressure and the mixture was diluted with cold saturated NaHCO3 (15 mL). The product was extracted three times with ethyl acetate (EtOAc, 20 mL each). The combined organic phase was washed once with brine (20 mL), dried over anhydrous MgSO4, and filtered. The EtOAc was evaporated under reduced pressure to give 3.85 g of a brown-orange oil. The resulting product was purified using flash chromatography on a normal phase silica gel cartridge with gradient elution of 0→7% MeOH in DCM. The mono- and di-alkylated products were completely separated to give the mono-alkylated product 15 as a clear viscous oil (1.2 g), 26% yield (two steps). 1 H NMR(400MHz,MeOD-d4)δ(ppm)6.93(d,J=2.0Hz,1H),6.79(dd,J1=8.0,2.0Hz,1H),6.67(d,J=8.4Hz,1H),3.6 7(s,3H),3.64(t,J=6.4Hz,1H),3.32-3.22(m,1H),2.92-2.81(m,2H),2.03-1.94(m,2H),1.86-1.50(m,6H). 13 C NMR (101MHz, MeOD-d4) δ (ppm) 176.6, 155.4, 133.8, 12.9, 128.6, 128.4, 116.1, 56.9, 52.5, 41.2, 40.6, 34.2, 34.1, 26.6.

[0191] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-cyclopentyl-4-hydroxyphenyl)-propanoate (Boc-cypTyr-OMe 109). Compound 108 (1 eq., 1.2 g, 0.7 mmol) was dissolved in 30 mL of a mixture of THF / H2O (1:1) in a 250 mL round-bottom flask. NaHCO3 (2 eq., 114 mg, 1.4 mmol) was added to the flask and stirred until completely dissolved. Di-tert-butyl-dicarbonate (1.5 eq., 223 mg, 1.0 mmol) was added and the reaction was carried out at room temperature for 1 h. To neutralize the solution, aqueous HCl 1M (1.4 mL, 1.4 mmol) was added and the THF was evaporated in vacuum. The final product was extracted from the aqueous phase three times with EtOAc (20 mL each). The combined organic phase was washed once with brine (20 mL) and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed in vacuo. The product was purified by flash chromatography using a gradient of 20-30% EtOAc in hexane to give 16 as a pale yellow oil (1.64 g), 84% yield. 1 H NMR(400MHz,CDCl3)δ(ppm)6.90(d,J=2.0Hz,1H),6.77(dd,J=8.1,2.2Hz,1H),6.64(d,J=8.0Hz,1H),4.99(d,J=8.2Hz,1H),4.54(dd,J=13.7,5.7Hz, 1H),3.71(s,3H),3.28-3.14(m,1H),3.00(d,J=5.2Hz,2H),2.10-1.93(m, 2H),1.86-1.73(m,2H),1.73-1.63(m,2H),1.61-1.51(m,2H),1.42(s,9H). 13 C NMR(101MHz,CDCl3)δ(ppm)172.76,155.33,152.92,132.27,128.07,127.56,1 27.38,115.41,80.14,54.64,52.35,38.94,37.74,33.07,33.02,28.43,25.49.

[0192] Methyl (S)-3-(4-(benzyloxy)-3-cyclopentylphenyl)-2-((tert-butoxycarbonyl)amino)-propanoate (Boc-cypTyr(OBn)-OMe 110). Compound 109 (1 eq., 203 mg, 559 μmol) was dissolved in dry acetonitrile (5 mL) and K2CO3 (1.2 eq., 92.6 mg, 670 μmol) was added to the mixture, followed by benzyl bromide (1.3 eq., 130 mg, 760 μmol). The mixture was refluxed for 18 h. After the reaction was complete, the acetonitrile was evaporated in vacuum. The crude product was redissolved in 15 mL of EtOAc and washed three times with water (15 mL each) and 20 mL of brine. The organic phase was collected, dried over MgSO4, filtered, and the solvent was removed in vacuum. The crude product was purified by flash chromatography using hexane-EtOAc (8:2) as isothermal eluent to give a clear sticky oil (158 mg), 58% yield. 1 H NMR ( 400MHz, CDCl3)δ(ppm)7.42-7.24(m,5H),6.95(d,J=1.8Hz,1H),6.86(dd,J = 7.8,1.5Hz,1H),6.80(d,J=8.4Hz,1H),5.04(s,2H),4.95(d,J=8.1Hz,1H),4.54(q,J=7.7Hz,1H), 3.70(s,3H),3.38(quint,J=8.4Hz,1H),3.02(m,2H),2.01(m,2H),1.79-1.50(m,6H),1.42(s,9H). 13 C NMR(101MHz,CDCl3)δ(ppm)172.7,155.8,155.3,137.7,135.3,128.7,128.1,128.0 ,127.9,127.8,127.3,111.9,80.0,70.3,54.7,52.4,39.1,37.8,33.2,28.5,25.7.

[0193] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-cyclopentyl-4-(cyclopentyloxy)phenyl)-propanoate (Boc-cypTyr(OCyp)-OMe 111). From 109 (1.00 g, 2.77 mmol), 111 (640 mg, 1.48 mmol, 54% yield) was obtained using a protocol similar to the synthesis of 110. 1 H NMR(400MHz,CDCl3)δ(ppm)6.89(s,1H),6.83(d,J=7.6Hz,1H),6.71(d,J=8.0Hz,1H),5.05-4.84(m,1H),4.82-4 .64(m,1H),4.60-4.41(m,1H),3.69(s,3H),3.21(quint,J=7.6Hz,1H),2.99(d,J=4.4Hz,2H)2.08-1.28(m,25H). 13 C NMR(101MHz,CDCl3)δ(ppm)172.7,155.2,155.0,135.3,128.1,127.1,126. 9,112.4,79.9,79.1,54.6,52.3,39.5,37.7,33.0,32.9,28.5,25.7,24.2.

[0194] Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-cyclopentyl-4-propoxyphenyl)-propanoate (Boc-cypTyr(OPr)-OMe 112). From 109 (900 mg, 2.48 mmol), using a similar protocol to the synthesis of 110, 112 (521 mg), 52% yield was obtained. 1H NMR (600 MHz, CDCl3) δ (ppm) 6.90 (d, J = 1.2 Hz, 1H), 6.84 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.92 (d, J = 7.8 Hz, 1H), 4.51 (q, J = 7.8 Hz, 1H), 3.87 (t, J = 5.4 Hz, 2H), 3.69 (s,3H),3.28(quint,J=8.4Hz,1H),2.99(d,J=6.6Hz,2H),2.01-1.93(m,2H),1.79(sext ,J=6.0Hz,2H)1.76-1.70(m,2H),1.68-1.48(m,4H),1.40(s,9H),1.02(t,J=7.2Hz,3H). 13 C NMR(101MHz,CDCl3)δ(ppm)172.7,156.2,155.3,135.0,128.0,127.4,127. 3,111.4,80.0,69.8,54.7,52.4,39.3,37.8,33.1,28.5,25.8,23.0,11.0.

[0195] (S)-3-(4-(benzyloxy)-3-cyclopentylphenyl)-2-((tert-butoxycarbonyl)amino)-propanoic acid (Boc-cypTyr(OBn)-OH 113). To a solution of compound 110 (921 mg, 2.03 mmol) in 10 mL of THF was added LiOH (583 mg, 24.4 mmol, pre-dissolved in 10 mL of water). The mixture was stirred at room temperature for 3 h. Once the conversion was complete (following TLC), the pH was adjusted to 5 with HCl 1M and the THF was removed in vacuo. The pH of the aqueous phase was adjusted to 2 and the product was extracted three times with ethyl acetate (20 mL each). The combined organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo to give a white solid (860 mg), 96% yield. The product was pure enough to continue to the next step without purification. 1H NMR(400MHz,CDCl3),δ(ppm)7.46-7.36(m,4H),7.36-7.29(m,1H),6.95(d,J=7.8Hz,1H),6.83(d,J=8.3Hz,1H),5.06(s,2H),4.95(d,J=7.9Hz,1H) ,4.60(dd,J=12.4,5.6Hz,1H),3.50-3.31(m,1H),3.22-2.96(m,2H),2.0 9-1.95(m,2H),1.84-1.72(m,2H),1.71-1.55(m,4H),1.49-1.28(m,10H). 13 C NMR(101MHz,CDCl3)δ(ppm)177.05,155.80,155.46,137.61,135.32,128.63,128.14,127.84,127.77, 127.34,127.26,111.92,80.29,77.48,77.16,76.84,70.23,54.46,39.05,37.23,33.10,28.42,25.61.

[0196] (S)-2-((tert-butoxycarbonyl)amino)-3-(3-cyclopentyl-4-(cyclopentyloxy)phenyl)-propanoic acid (Boc-cypTyr(OCyp)-OH 114). From 111 (640 mg, 1.48 mmol), 114 (656 mg, 1.57 mmol, 100%) was obtained using the same protocol as for the synthesis of 113. 1 H NMR(400MHz,CDCl3)δ(ppm)6.98(s,1H),6.92(d,J=7.9Hz,1H),6.75(d,J=8.4H z,1H),4.91(d,J=7.9Hz,1H),4.74(p,J=4.0Hz,1H),4.56(d,J=6.6Hz,1H),3.32 -3.17(m,1H),3.16-2.91(m,2H),1.95(dd,J=10.3,5.3Hz,2H),1.90-1.82(m,4 H),1.81-1.71(m,4H),1.70-1.59(m,4H),1.59-1.50(m,2H),1.48-1.28(m,9H). 13C NMR(101MHz,CDCl3)δ(ppm)177.03,155.52,155.03,135.42,128.20,127.13,126. 71,112.48,80.29,79.11,54.49,39.56,37.16,33.03,32.85,28.42,25.71,24.16.

[0197] (S)-2-((tert-butoxycarbonyl)amino)-3-(3-cyclopentyl-4-propoxyphenyl)-propanoic acid (Boc-cypTyr(OPr)-OH 115). From 112 (521 mg, 1.28 mmol), 115 (467 mg, 1.19 mmol, 93% yield) was obtained using the same protocol as for the synthesis of 113. 1 H NMR(400MHz,CDCl3)δ(ppm)6.97(s,1H),6.91(d,J=8.0Hz,1H),6.72(d,J=8Hz,1H),4.94-4.79(m,1H),4.57-4.45(m,1H),3.88(t, J=6Hz,2H),3.29(quint,J=8Hz,1H),3.13-2.91(m,2H),2.05-1.89(m,2H),1.85-1.46(m,8H),1.40(s,9H),1.02(t,J=7.6Hz,3H). 13 C NMR(101MHz, CDCl3), δ(ppm)177.0,156.3,155.6,135.1,128.2,127.4,127.2,111.5,80.4,69.8,54.6,39.4,37.3,33.1,28.5,25.8,23.0,11.0.

[0198] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(benzyloxy)-3-cyclopentylphenyl)-propanoic acid (Fmoc-cypTyr(OBn)-OH 116). Compound 113 (1 eq, 860 mg, 1.96 mmol) was dissolved in 20 mL of a mixture TFA-DCM (1:1) and stirred at room temperature for 2 h. TFA and DCM were evaporated in vacuo to give a green-brown solid. The residual acid was neutralized with saturated NaHCO3 solution and 20 mL of THF was added to solubilize the solid residue. NaHCO3 (3 eq, 493 mg, 5.87 mmol) was dissolved in 10 mL of water and added to the mixture, followed by Fmoc-Cl (1.1 eq, 607 mg, 2.07 mmol). The reaction was carried out at room temperature for 2 h. The THF was evaporated in vacuo and the aqueous phase was acidified with aqueous HCl 1N to pH 3 and extracted three times with EtOAc (15 mL). The combined organic phase was washed with brine and dried over MgSO4. The organics were evaporated in vacuo to give the crude product. The product was purified by flash chromatography using a gradient of 0-30% EtOAc + 0.25% AcOH in hexane to give a pale yellow oil (752 mg), yield (68%). 1 H NMR(400MHz,CDCl3),δ(ppm)7.76(d,J=7.5Hz,2H),7.55(t,J=7.9Hz,2H),7.46-7.27(m,10H),7. 06(s,1H),6.91(d,J=8.2Hz,1H),6.81(d,J=8.3Hz,1H),5.20(d,J=8.2Hz,1H),5.03(s,2H),4.69( dd,J=13.5,5.8Hz,1H),4.46-4.32(m,2H),4.20(t,J=7.0Hz,1H),3.45-3.31(m,1H),3.17(dd,J=1 4.1,5.3Hz,1H),3.09(dd,J=14.0,6.1Hz,1H),2.01(s,2H),1.82-1.69(m,2H),1.68-1.51(m,5H). 13C NMR(101MHz,CDCl3),δ(ppm)176.67,155.94,143.89,143.85,141.42,137.53,135.49,128.65,127.99,127.88,127.42,127.3 9,127.29,127.24,127.20,125.23,120.13,111.99,70.22,67.33,54.81,47.24,39.13,37.27,33.13,25.62,25.60.HRMS[M+Na + ]584.2405 (calculated value 584.2407).

[0199] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyclopentyl-4-(cyclopentyloxy)phenyl)-propanoic acid (Fmoc-cypTyr(OCyp)-OH 117). From 114 (600 mg, 1.44 mmol), 117 (321 mg, 593 μmol, 41% yield) was obtained using a protocol similar to that for the synthesis of 116. 1 H NMR(400MHz,CDCl3)δ(ppm)7.76(d,J=7.5Hz,2H),7.56(t,J=7.9Hz,2H),7.40(t,J=7.4Hz,2H), 7.30(t,J=7.4Hz,2H),7.01(s,1H),6.90(d,J=8.1Hz,1H),6.74(d,J=8.3Hz,1H),5.22(d,J=8.2 Hz,1H),4.79-4.64(m,2H),4.38(t,J=6.9Hz,2H),4.21(t,J=7.0Hz,1H),3.30-2.93(m,3H),2.0 3-1.91(m,2H),1.85(d,J=4.6Hz,4H),1.82-1.71(m,4H),1.70-1.59(m,4H),1.60-1.48(m,2H). 13C NMR(101MHz,CDCl3)δ(ppm)176.79,155.97,155.15,143.91,141.41,135.54,128.06,127.84,127.19,126.40,1 25.25,120.10,112.52,79.11,67.33,54.82,47.24,39.63,37.23,33.02,32.86,25.71,25.68,24.17.HRMS[M+H + ]540.2762 (calculated value 540.2745).

[0200] (S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-cyclopentyl-4-propoxyphenyl)-propanoic acid (Fmoc-cypTyr(OPr)-OH 118). From 115 (467 mg, 1.19 mmol), 118 (438 mg, 853 μmol, 71% yield) was obtained using a protocol similar to that for the synthesis of 116. 1 H NMR(400MHz,CDCl3)δ(ppm)7.76(d,J=7.6Hz,2H),7.55(t,J=7.8Hz,2H),7.40(t,J=7.4Hz,2H),7.30(t,J=7.4Hz,2H) ,7.02(s,1H),6.91(d,J=8.2Hz,1H),6.73(d,J=8.3Hz,1H),5.19(d,J=8.2Hz,1H),4.68(dd,J=13.6,5.8Hz,1H),4.43- 4.33(m,2H),4.20(t,J=7.0Hz,1H),3.88(t,J=6.3Hz,2H),3.39-3.24(m,1H),3.16(dd,J=14.1,5.3Hz,1H),3.08(dd,J =14.0,6.2Hz,1H),2.09-1.90(m,2H),1.87-1.71(m,4H),1.70-1.61(m,2H),1.60-1.50(m,2H),1.04(t,J=7.4Hz,3H). 13C NMR(101MHz,CDCl3)δ(ppm)176.65,156.32,155.97,143.90,141.41,135.11,127.91,127.85,127.34,127.20,126. 78,125.24,120.11,111.42,69.65,67.34,54.83,47.24,39.33,37.26,33.02,25.66,25.63,22.89,10.94.HRMS[M+H + ]514.2602 (calculated value 514.2588).

[0201] General protocol for solid phase synthesis Following more specific protocols provided in Examples 2-4, the following provides a general protocol for the solid phase synthesis of the analogs disclosed herein.

[0202] Peptides were synthesized on solid phase at 0.1 mmol scale using Fmoc-based chemistry. The first amino acid was loaded onto the resin using the Mitsunobu reaction. Briefly, amino acid (0.3 equiv, 0.3 mmol), triphenylphosphine (3 equiv, 0.3 mmol, 79 mg) and 300 mg of Wang resin were mixed together in 4 mL of DCM for 5 min. Diisopropyl azodicarboxylate (DIAD, 3 equiv, 0.3 mmol, 59 μL) was added dropwise and the mixture was shaken overnight. Excess reagent was removed by washing twice with 5 mL of DCM. Amino acid loading was quantified by measuring the UV absorbance of the dibenzofulvene-piperidine adduct resulting from Fmoc deprotection. Loading was typically 0.25-0.35 mmol / g. When the desired loading was achieved, the resin was capped with 4 mL of a solution of DCM-acetic anhydride-DIPEA (4:1:0.2) for 1 h. The resin was washed with 5 mL of each solvent, DMF-DCM-iPrOH-DCM-iPrOH-DCM, for 3 min (also known as the washing protocol). The next amino acid was added to the sequence in two steps: 1 / Fmoc deprotection and 2 / amide coupling. The resin was always washed using the washing protocol described above between the two steps. Fmoc deprotection was achieved by treating the resin with 5 mL of piperidine 20% / DMF for 10 min. For the coupling step, HATU (5 eq., 0.5 mmol, 190 mg) and amino acid (5 eq., 0.5 mmol) were dissolved in 5 mL of DMF and transferred to the resin, then DIPEA (5 eq., 0.5 mmol, 87 μL) was added to initiate the coupling reaction. The reaction was run for 30 min and excess reagents were removed by filtration. The deprotection and coupling steps were repeated to synthesize the linear precursor peptide. The resin was washed using a washing protocol, washed again with diethyl ether, and dried in vacuum overnight before the cyclization step.

[0203] Fmoc-N on resin γ -Allyl-N γSynthesis of o-nosyl-α,γ-diamino-butanoic acid (Fmoc-Alnb-OH). Fmoc-L-Dab(Alloc)-OH was introduced at His7 position by SPPS to serve as the starting residue for the synthesis of Fmoc-Alnb-containing peptides (Figure 5). The Alloc group was removed by treating the resin with a solution of Pd(PPh3)4 (0.25 equiv., 29 mg, 0.025 mmol), phenylsilane (25 equiv., 311 μL, 2.5 mmol) in DCM for 30 min under inert atmosphere. The resin was washed with 5 mL of DCM and then 5 mL of DMF for 5 min each. In a 20 mL vial, o-nosyl chloride (NsCl, 86 mg, 0.4 mmol) was dissolved in 5 mL of NMP and sym-collidine (55 μL, 0.4 mmol) was added. This mixture was transferred to the resin and stirred at room temperature for 30 min. The resin was filtered and the nosylation reaction was repeated once. The resin was washed with a washing sequence and dried in vacuum before the allylation step. The allylation step was performed by the Fukuyama-Mitsunobu reaction. In a 12 mL cartridge, the thoroughly dried resin was swollen with 4 mL of anhydrous THF for 5 min and filtered. A mixture of allyl alcohol (68 μL, 1 mmol), PPh3 (106 mg, 0.4 mmol) in 3 mL of anhydrous THF was poured onto the resin and mixed for 5 min, after which DIAD was added dropwise (0.079 mL, 0.4 mmol, diluted in 1 mL of anhydrous THF). The mixture was stirred at room temperature for 20 min. The resin was filtered and the allylation reaction was repeated once. The conversion was monitored by UPLC-MS. After the resin was washed with a washing protocol, peptide elongation was performed by SPPS.

[0204] Macrocycles via ring-closing metathesis. Prior to metathesis, Fmoc-L-allylglycine-OH or Boc-L-allylglycine (for truncated analogs) were incorporated at the Pro3 position, while the allyl-containing residue AA (L-allylglycine, N π -Allyl-L-histidine or N γ -Allyl-N γ-nosyl-α,γ-L-diaminobutyric acid) was introduced at His7 position during solid-phase peptide synthesis (Figure 3A). The general sequence should be Fmoc / Boc-allylglycine-Arg(Pbf)-Leu-Ser(OtBu)-AA-Lys(Boc)-Gly-Pro-(C-terminus)-resin. Dry resin (0.1 mmol peptide) and Hoveyda-Grubbs catalyst 2nd generation (0.023 mmol, 15 mg) were added to a dry 10 mL microwave tube. A Teflon cap was added and the tube was filled with argon through a needle by vacuum and filling cycles in a small vacuum chamber. After argon purging, 4 mL of dichloroethane was added and the reaction mixture was heated at 120 °C for 10 min at 300 W in a Discover SP microwave oven (CEM, Matthews, USA). Solvent and reagents were removed by filtration. The resin was washed with a washing protocol. The progress of the reaction was monitored by LC-MS. If the ratio between cyclic and linear peptides was less than 6, the metathesis step was repeated until the cyclic peptide was enriched to the desired amount (cyclic / linear peptide ratio >6). The resin was washed using a washing protocol before being used in the next step (cleavage of the final product or addition of Pyr-Arg).

[0205] Macrolactamization. Prior to lactamization, Lys(Alloc) or Dap(Alloc) was introduced at the Pro3 position and Fmoc-Asp(OAll)-OH was incorporated at the His7 position. On the dry resin (0.1 mmol peptide), the Alloc protecting group was removed by treating the resin with a solution of Pd(PPh3)4 (0.25 equiv, 29 mg, 0.025 mmol) and phenylsilane (25 equiv, 311 μL, 2.5 mmol) in DCM for 30 min under argon atmosphere. The resin was washed with 5 mL of DCM and 5 mL of DMF for 5 min each. Macrocyclization was performed using DEPBT (5 equiv, 150 mg, 0.5 mmol) and DIPEA (5 equiv, 0.5 mmol, 87 μL). The coupling reagent and DIPEA were dissolved in 5 mL of DMF before being transferred to the resin and the cyclization reaction was carried out overnight. The resin was washed with a washing protocol before proceeding to the next step (Fmoc deprotection / peptide elongation).

[0206] Post-cyclization modifications. Macrocycles 7 and 8 were synthesized from macrocycle 5 on resin. After a metathesis step and addition of Pyr(Boc)-Arg(Pbf)- to the N-terminus to give 5 (with the protecting group still on board), deprotection of the o-nosyl group (repeated once more to ensure complete deprotection) using a mixture of mercaptoethanol (8 equiv., 57 μL, 0.8 mmol), DBU (5 equiv., 0.5 mmol, 76 μL) for 15 min gave macrocycle 7. The resin was washed with a washing protocol before final cleavage. Macrocycle 8 was synthesized from 7 on resin (with the protecting group) by reductive amination using NaBH(OAc)3 (20 equiv., 423 mg, 2 mmol) in a mixture of formaldehyde 37% in water (40 equiv., 324 μL, 4 mmol), THF-TMOF (1:1) overnight. Excess NaBH(OAc)3 was quenched with 3 mL of MeOH. After gas evolution ceased, the resin was washed with MeOH, followed by a washing protocol. Note that part of the peptide was cleaved during the reductive amination, which reduced the yield.

[0207] Final cleavage and purification. Final cleavage from the resin and simultaneous removal of protecting groups were performed using a cocktail of trifluoroacetic acid (TFA) / triisopropylsilane (TIPS) / water (95:2.5:2.5). The cleavage reaction was carried out for 2 h (if the peptide had 0-1 arginine) or 4 h (if the peptide had 2 arginines). The mixture was filtered through a glass wool plug to remove solid particles and the solution was slowly dripped into 30 mL of methyl tert-butyl ether (pre-cooled at 0 °C) to precipitate the product. The crude peptide was isolated by centrifugation (3000 rpm, 10 min), resuspended in 1 mL of acetic acid (AcOH) 10% and allowed to stand for 10 min. Two layers were separated: residual ether layer (top) versus aqueous layer (bottom). The aqueous layer was isolated and 1 mL of AcOH 10% was added to extract the residual peptide from the ether layer. This refinement helped to further purify the mixture and facilitate purification. The aqueous extracts were combined and filtered before purification. The macrocyclic peptide was purified on a HPLC-MS system from Waters (Milford, USA) (column XSELECT™ CSH™ Prep C18 (19×100 mm) packed with 5 μm particles, UV detector 2998, MS SQ detector 2, sample manager 2767, and binary gradient module) using a binary solvent system (acetonitrile / water + 0.1% formic acid). The pure fractions (confirmed by UPLC-MS) were combined and lyophilized to obtain a white solid. The purity of the peptides was assessed using a Waters (Milford, USA) UPLC / MS system using an Acquity UPLC® CSH™ C18 column (2.1×50 mm) packed with 1.7 μm particles with the following gradient: acetonitrile and water containing 0.1% HCOOH (0→0.2 min: 5% acetonitrile, 0.2→1.5 min: 5%→95%, 1.5→1.8 min: 95%, 1.8→2.0 min: 95%→5%, 2.0→2.5 min: 5%). All peptides were >95% pure, except for 21 (91%), 24 (93%), 32 (93%) and 33 (90%). HRMS spectra were obtained using a Bruker (Billerica, USA) maXis ESI-Q-Tof instrument using electrospray injection.

[0208] cell culture HEK293 cells stably expressing YFP-tagged human APJ were cultured in DMEM medium supplemented with 10% FBS in a humid atmosphere at 37 °C while maintaining 5% CO. Selection pressure for APJ-expressing cells was maintained by adding the antibiotic G418 (400 μg / mL), whereas penicillin / streptomycin (0.1%) was used to prevent bacterial contamination.

[0209] Binding experiments Binding experiments were performed on cell membranes of HEK293 stably expressing YFP-tagged human APJ receptor. Cells were stored frozen at -80°C and quickly thawed (1 min at 37°C) immediately before the experiment. Thawed cells were resuspended in 5 mL of EDTA solution (1 mM EDTA, 50 mM Tris-HCl, pH 7.4), transferred to a 10 mL Falcon tube, and centrifuged at 3500g for 15 min at 4°C to extract cell membranes. The precipitate (cell membranes) was suspended in binding buffer (50 mM Tris-HCl, 0.2% BSA, pH 7.4). Binding assays were performed in 96-well plates. 15 μg of membrane protein was mixed with 0.2 nM radiolabeled [ 125 I][Nle75, Tyr77][Pyr 1 ]-Apelin-13 (820 Ci / mmol) 3 and 10 in a total volume of 200 μL -5 ~10 -11 The cells were incubated for 1 h at room temperature with test ligands at concentrations ranging from 1 M. The incubation mixture was filtered through a glass fiber filter (Millipore, preabsorbed with PEI 0.5% for 2 h at 4°C) to remove unbound ligand, and the filter membrane was washed three times with 170 μL of cold binding buffer (4°C). Gamma emission was measured (80% efficiency) using a 1470 Wizard gamma counter from PerkinElmer (Waltham, USA). Nonspecific binding did not exceed 5% of the total signal (10 -5 IC represents the concentration of ligand tested. 50Values ​​were determined by transferring 50% of the radiolabeled ligand from the receptor and using GraphPad Prism 8 to determine the results. 1 ]-Apelin-13K D The dissociation constant, K, was determined by saturation binding assay and is 1.8 nM. i The value was calculated using the Cheng-Prusoff equation 50 The mean ± SEM of two to three independent experiments was calculated from the mean ± SEM of the 14-kDa correlation coefficient, and the results are expressed as the mean ± SEM of two to three independent experiments, each performed in duplicate (Yung-Chi et al., 1973).

[0210] Gα i1 BRET assay for activation and β-arrestin2 recruitment HEK293 cells were cultured in high glucose DMEM medium with 10% FBS, 100 U / mL penicillin / streptomycin, 2 mM glutamine, and 20 mM HEPES at 37°C in a T175 flask under a humidified chamber with 5% CO2. After 24 hours, PEI was used to transfect human APJ, Gα i1 -RlucII(91), GFP10-Gγ2, and Gβ1 (BRET-based Gα i1 Cells were transfected with plasmids encoding APJ-GFP10 (for Gα activation assay) or APJ-GFP10 and RlucII-β-arretin2 (for BRET-based β-arretin2 recruitment assay) (Murza et al., 2015, Gales et al., 2006, REGNman et al., 2012). Prior to the assay, cells were transferred to white 96-well plates BD Bioscience (Mississauga, Canada) at a concentration of 50,000 cells / well for 24 h and incubated overnight at 37 °C. Cells were then washed with phosphate-buffered saline (PBS) and 90 μL of Hank's balanced salt solution was added to each well. Cells were then incubated at 37 °C (Gα i1 ) for 5 min or at room temperature for 30 min (β-arretin 2), -5 M~10 -11After stimulation, 5 μM of coelanthrazine 400A was added to each well and BRET was performed on a GeniosPro plate reader (Tecan, Austria). 2 The plates were read using the filter set. BRET ratios were calculated using the em / RlucII em Data were plotted and analyzed using GraphPad Prism 8. 50 Values ​​were determined. Each data point represents the mean ± SEM of at least three different experiments, each performed in triplicate.

[0211] Rat plasma stability Plasma was obtained from male Sprague-Dawley rats by collecting blood in heparin tubes and centrifuging at 13,000 rpm to remove blood cells. Isolated plasma was stored at -80°C and thawed immediately before testing. In a 96-well plate, 6 μL of peptide solution at 1 mM was incubated with 27 μL of plasma at 37°C in an oven equipped with an orbital shaker. The wells were sealed using tightly fitted caps to avoid water evaporation during incubation. At 0, 1, 2, 4, 6, and 24 hours, the plasma was inactivated with 140 μL of ACN-EtOH solution (1:1) containing 0.25 mM N,N-dimethylbenzamide (internal standard) and the wells were resealed with tightly fitted caps. At 24 hours, when all the plasma was inactivated, the caps were removed and the mixture was transferred to a 96-well filtration plate Impact™ Protein Precipitation (Phenomenex, California, US). A 96-well UPLC plate was placed at the bottom to collect the samples. Both plates were centrifuged at 500g for 10 min at 4°C to accelerate the filtration. The collected filtrate was diluted with 80 μL of water and analyzed in an Acquity UPLC-MS system class H (column Acquity UPLC® Protein BEH C4 (2.1×50 mm), 1.7 μm particles with pores 300 Å). The amount of remaining peptide was plotted in an exponential one-phase decay curve using GraphPad Prism 8, which allows the calculation of peptide half-life. Results are shown as the mean ± SEM of at least three independent experiments, each performed in duplicate.

[0212] In vivo pharmacokinetics Male Sprague-Dawley rats aged 8-10 weeks were used in this study. 24 hours before the experiment, a jugular catheter (Silastic® Laboratory tubing; ID 0.02 × OD 0.037) was surgically inserted for intravenous injection (iv, 3 mg / kg for analogs 42, 43 or Ape13 in 0.9% saline, approximately 350 μL) and blood collection. Animals were placed in a containment chamber prior to intravenous injection to facilitate blood sampling. Blood samples (0.2 mL, corresponding to 0.1 mL of plasma after centrifugation) were collected 5, 10, 30, 60, 120 and 240 minutes after intravenous administration ([Pyr 1

[0113] -Apelin-13: 1, 2, 5, 10, 15 min) into K2-EDTA microtubes (Sarstedt, Numbrecht, Germany). These samples were immediately stored on crushed ice and then centrifuged at 13000 rpm for 5 min at 4°C to isolate plasma (upper layer). The resulting plasma was transferred to polypropylene tubes and immediately frozen at -80°C.

[0213] Sample preparation Peptides were extracted using a combination of protein precipitation and solid-phase extraction steps. Plasma samples were thawed on ice. After vortexing (60 s), 100 μL of sample was removed and 300 μL of cold acetonitrile was added to precipitate plasma proteins. Samples were then vortexed (60 s) and centrifuged at 4500 rpm for 10 min at 4°C. The supernatant was then isolated and passed directly through HLB Prime for further washing. The filtrate was diluted 10-fold in 0.1% formic acid / water and filtered through a 0.22 μm syringe filter before LC / MS / MS analysis.

[0214] mass spectrometry Samples were analyzed on a Sciex Qtrap 6500+ equipped with microflow liquid chromatography (Eksigient M3 microflow) and a UPLC HSS-T3 column (1 mm x 100 mm, 1.8 μm, equipped with a 0.2 μm frit prefilter). The solvent flow rate was set at 50 μL / min, the column temperature was maintained at 40 °C, and the injection volume was 3 μL. The mobile phase was 0.1% formic acid / water (A) and 0.1% formic acid / acetonitrile (B). The elution gradient started with 2% eluent B, increased to 95% for 8 min, maintained at 95% for 2 min, and then returned to initial conditions for 2 min over a total run time of 13 min. Optimized parameters for peptide fragmentation were obtained by directly injecting analytical standard solutions of Ape13, 42, and 43 at 100 ng / mL. The analysis used two daughter traces (transitions), the most abundant for quantification and the second most abundant for confirmation.

[0215] In vivo blood pressure measurement animal Adult male Sprague-Dawley rats (Charles River Laboratories, St-constant, Quebec, Canada), 8-10 weeks of age, were maintained on a 12-h light / 12-h dark cycle with free access to food and water. Animal experimental protocols were approved by the Animal Care Committee of Sherbrooke University and adhered to the policies and directives of the Canadian Animal Care Committee.

[0216] Blood pressure testing Male Sprague-Dawley rats (8-10 weeks old) were anesthetized with a ketamine / xylazine injection (87 / 13 mg / kg im) and placed in supine position on a thermostat pad. Their right carotid artery was catheterized with a PE 50 (filled with heparinized saline) and connected to a Micro-Med transducer (model TDX-300, Calabasas, USA) and a Micro-Med blood pressure analyzer (model BPA-100c). Vehicle (isotonic saline) was administered by intravenous bolus followed 5 min later by injection of either Ape13, compounds 9, 20, 29, 42 or 43 (administered at 19.5 and 65 nmol / kg, volume 0.25 mL over 10 s) through another catheter (PE10) inserted in the left jugular vein. This iv catheter was flushed with saline (0.2 mL) immediately after each injection.

[0217] Electrocardiography Transthoracic echocardiography was performed in Sprague-Dawley rats under isoflurane anesthesia (2%, 1.5 mL / min, Baxter) using a Vevo 3100 ultrasound machine with an MX250 transducer (FUJIFILM, VisualSonic, ON, Canada) before (baseline) and 3, 6, and 24 h after subcutaneous injection of peptides (0.2 and 2 μmol / kg). Two-dimensional short-axis views of the LV were obtained at the papillary muscle level and M-mode tracings were recorded. From these images, heart rate (HR) was calculated and LV end-diastolic (LVEDd) as well as LV end-systolic diameter (LVESd) were measured by state-of-the-art methods according to the American Society of Echocardiography guidelines. Fractional shortening (FS) was calculated by the following formula: FS=([LVEDd-LVESd / LVEDd]×100%). Cardiac output (CO) was assessed from the LV long-axis views. Stroke volume (SV) was calculated according to Simpson's method by tracing the endocardial border at end systole and end diastole, and given as CO=SV×HR.

[0218] Example 2: Synthesis of Apelin 13 Analogs of Table I Ninety-seven analogs were designed and synthesized with various types of macrocyclic linkers, including saturated hydrocarbon chains (13), lactam groups (14, 17), histidine mimetics (15), sulfonamides (16), secondary amines (18), and tertiary amines (19) (Figure 2A).

[0219] The precursor linear peptides were synthesized using classical solid-phase peptide synthesis (SPPS) and Fmoc chemistry. To construct the macrocycles, the Pro3 and His7 residues were replaced by unnatural amino acids that were part of the linker. For compound 97, allylglycine residues were introduced at both positions and cyclization was prepared using ring-closing metathesis (RCM) (Figure 3A). Compound 13 was obtained from 97 by hydrogenation using 10% Pd / C catalyst (Green et al., 2013). Compounds 14, 17, 46 and 47 were synthesized by macrolactamization with Dap(Alloc) or Lys(Alloc) at the Pro3 position and Asp(OAll) at the His7 position, respectively, according to a previously described protocol (Alcaro et al., 2004). Macrocycles 15, 16, 18 and 19 were also prepared using RCM (Figure 3B). For this purpose, allylglycine was introduced at the Pro3 position and N π -Allyl-histidine (Alh for 15) or N γ -Allyl-N γ -nosyl-α,γ-diamino-butanoic acid (Alnb for 16, 17, 18) was placed at His8 position. As described in our previous work (Trrunn et al., 2018), the Pro3→allylglycine mutation was localized between Arg2 and Arg4, making cyclization of the peptide impossible after introduction of Arg2, likely due to steric hindrance and catalytic chelation by the arginine residue. For this reason, cyclization was performed before adding the Pyr1-Arg2 moiety (Figure 3B).

[0220] Conversions in the RCM step were generally >50%, but in some cases, like compound 14, the yields were around 20-25% in the best cases, and N πLonger heating (100 °C, 2 h) was required due to the presence of -allyl-histidine. A possible explanation is that the imidazole ring of histidine may act as a chelating agent and poison the Hoveyda-Grubs catalyst.

[0221] Intermediate Fmoc-LN π Fmoc-Alh-OH was prepared in three steps from Fmoc-L-His(Trt)-OH 102 (Figure 4). The key step was the addition of N-alkylation of the imidazole ring (103) using in situ generated allyl triflate. π The sterically hindered trityl (Trt) protecting group was introduced at the N τ Stay in position and press N π In the next step, the methyl ester 104 was hydrolyzed using 2M HCl in dioxane water (1:1) under reflux conditions to give the Fmoc-LN π -Allyl-histidine-OH 105 was obtained.

[0222] The synthesis of analogs 16, 18, and 19 required the residue Fmoc-Alnb-OH (Figure 3B), which was easily prepared from Fmoc-Dab(Alloc)-OH on solid phase. The Alloc protecting group was selectively removed using Pd(PPh3)4 and PheSiH3 as scavengers. Nosylation of the γ-amine group was performed with o-nosyl chloride and sym-collidine, followed by allylation using the Fukuyama-Mitsunobu reaction to give the Fmoc-Alnb-containing peptides (Figure 5).

[0223] To reduce the size of the Ape13 analogs, the N- and C-termini of the macrocycle analogs were progressively truncated. The truncated peptides were synthesized using the same protocol as above (Figure 3A-B). In the last series, the C-terminal Nle11 residue was replaced with a non-natural amino acid. Among the non-natural residues, we included several Tyr(OBn) analogs, such as cypTyr(OBn), dcypTyr(OBn), cypTyr(OPr), and cypTyr(OCyp), because the incorporation of Tyr(OBn) was previously found to increase affinity for the binding pocket (Murza et al., 2015). The cyclopentyl group (Cyp) was found to affect the binding and signaling properties of Tyr(OBn)-containing peptides in our previous study (Tran et al., 2021). This was introduced onto tyrosine (106) using two equivalents of cyclopentanol in 85% phosphoric acid under reflux conditions to form precursor 107 (Figure 6). This intermediate underwent a series of transformations (esterification of 107, Boc protection of 108, alkylation of 109, ester hydrolysis of 110-112, Boc removal and Fmoc protection of 113-115) to give Fmoc-cypTyr(OBn)-OH (116), Fmoc-cypTyr(OCyp)-OH (117) and Fmoc-cypTyr(OPr)-OH (118), which were suitable for SPPS.

[0224] Compounds 20–45, 48–59 were prepared using a method similar to that used for the synthesis of 97. Briefly, the first amino acid was loaded onto Wang resin using the Mitsunobu reaction (loading 0.3 mmol / g). Linear peptides were synthesized using Fmoc-based chemistry and macrocyclization was carried out using Hoveyda-Grubbs catalyst II (120 °C, 10 min). Unnatural amino acids bearing terminal alkenes, e.g., Lys(N-butenyl), Lys(N-All), Orn(N-butenyl), Dab(N-butenyl), were prepared on-resin from Lys(Aloc), Orn(Aloc) and Dab(Aloc) using chemistry similar to the synthesis of Fmoc-Alnb-OH described above. [ka]

[0225] For modifications at the N-terminus, the Fmoc protecting group was removed after cyclization and the free amino group was derivatized by either acetylation or guanidinylation (using 1H-pyrazole-1-carboxamidine hydrochloride, CAS: 4023-02-3) as in compounds 21, 23, 4, 47, 49. For compounds 15, 16, 20, 28-29 and 34-45, see Figures 7-8.

[0226] Example 3: Synthesis of Apelin 17 Analogs of Table II Step 1: Load onto 400 mg of resin 2-chlorotrityl (loading 0.35 mmol / g). First, the resin was swollen and washed with DCM. 2.5 equivalents of amino acid and DIPEA were dissolved in 4 mL of DCM and the solution was poured onto the resin. The mixture was mixed overnight. Unreacted 2-chlorotrityl chloride was capped using 5 mL of the mixture DCM-MeOH-DIPEA (7:2:1). The resin was washed with DMF-DCM-iPrOH-DCM-iPrOH-DCM for 3 min for each solvent after each reaction (capping, Fmoc deprotection, amide coupling).

[0227] Step 2: Amino acid coupling Fmoc was removed by treating the resin with 20% piperidine in DMF for 10 min. The resin was drained and the deprotection step was repeated once more. The next amino acid was added by reacting the free N-terminal amine with 5 equivalents of the corresponding Fmoc-protected amino acid, 5 equivalents of HATU and 5 equivalents of DIPEA. Glu(OAll) and Lys(Alloc) were incorporated into their corresponding positions on the peptide sequence.

[0228] Step 3: Deprotection of allyl and aryl groups The dried resin was transferred to a 10 mL microwave tube and swelled in 5 mL of DCM. The mixture was closed with a cap and bubbled under argon for 10 min before adding PheSiH3. Tetrakis(triphenylphosphine)palladium (Pd(Ph3)4) was added to the reaction mixture when the cap was opened slightly and the argon flow was increased. The mixture was bubbled with argon for 2 min and stirred at room temperature for 30 min. The resin was washed with the washing sequence: DMF-DCM-MeOH-DCM-MeOH-DCM (3 min with 5 mL of each solvent).

[0229] Step 4: Peptide cyclization To a solution of 5 equivalents of DEPBT in 4 mL of DMF, DIPEA was added. This solution was transferred to the reactor containing the resin and the mixture was shaken overnight. Ac-Lys(Boc)-Phe-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Pro-Arg(Pbf)-Leu-c[Glu-HIs(Trt)-Lys(Boc)-Lys]c-Pro-Nle-Pro-cypTyr(OBn)-resin (precursor of analog 76).

[0230] Step 5: Final cleavage, deprotection and purification 5 mL of cleavage cocktail of TFA-TIPS-H2O (95:2.5:2.5) was prepared and mixed well. The resin was transferred to a 20 mL vial and the cleavage cocktail was added. The mixture was stirred for 5 h. The resin was filtered and the filtrate was added dropwise in pre-cooled TBME to precipitate the peptide. The suspension was centrifuged to pull down the solid (3000 rpm x 10 min at 4 °C). The supernatant was removed and the residual ether was evaporated under a gentle air stream for 30 min. The resulting solid was solubilized in 1900 μL of 10% acetic acid in water and filtered through a PTFE 0.22 um filter into an LC-MS preparative vial (max. 3 mL). The peptide was purified by preparative HPLC-MS using a gradient of 10-25% ACN (+0.1% formic acid) in 15 min. The pure fractions were lyophilized to give 3 mg of a white powder (analog 76).

[0231] Example 4: Synthesis of Ela Bella Analogues of Table II material Fmoc-protected (L)-amino acids, 2-chlorotrityl chloride resin and [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (HATU) were purchased from Matrix Innovation (Canada). N,N-diisopropylethylamine (DIPEA) and unnatural amino acids were purchased from Chem Impex (USA). Piperidine was purchased from ACP (Canada). All other solvents were purchased from Sigma-Aldrich (Canada) or Fisher Scientific (USA) and were of the highest commercially available purity. All reagents and starting materials were used as received. Peptide elongation was performed using a Symphony™ X peptide synthesizer from Gyros Protein Technology (USA).

[0232] Step 1: Loading of 2-chlorotrityl chloride resin To load the first amino acid of the sequence, 2-chlorotrityl chloride resin (0.25 mmol / g, 400 mg) was treated with Fmoc-protected amino acid (1 eq.), N,N-diisopropylethylamine (DIPEA, 2 eq.) in dichloromethane (DCM, 4 mL). The mixture was shaken on an orbital shaker at room temperature for 2 h, then the resin was washed successively with DCM (2×5 mL), 2-propanol (1×5 mL), DCM (1×5 mL), 2-propanol (1×5 mL), DCM (2×5 mL) for 3 min. A capping solution of DCM / MeOH / DIPEA (7 / 2 / 1, 5 mL) was then added, and the mixture was shaken at room temperature for 1 h and washed with the solvent sequence described above.

[0233] Step 2: Peptide elongation Peptide synthesis was performed with a typical Fmoc solid phase peptide synthesis (SPPS) procedure. 2-Chlorotrityl chloride resin (0.25 mmol / g, 400 mg, loaded with the first amino acid of the sequence) was placed in a peptide synthesizer reactor and swollen in N,N-dimethylformamide (DMF) (3×6 min, 4.5 mL). Note that during coupling, deprotection, and washing steps, the resin was mixed via N2 bubbling. The Fmoc group was then deprotected with 20% piperidine / DMF (2×5 min, 4.5 mL), and then the subsequent Fmoc-protected amino acid (5 eq.) was attached with DIPEA (10 eq.) in DMF / NMP (4.5 mL) in the presence of HATU (5 eq.), and the reaction was allowed to proceed for 30 min. The Fmoc group was then deprotected at each step using piperidine (20% in DMF). The resin was washed after each coupling and Fmoc deprotection step with DMF (4×1 min 30 sec, 4.5 mL).

[0234] Step 3: Allyl / Aloc deprotection In a typical procedure, after coupling of the last amino acid in the sequence, the allyl / Aloc protecting group was selectively deprotected with tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (0.2 equiv.) and phenylsilane (PhSiH3) (20 equiv.) in argon-degassed DCM (5 mL) and the reaction was allowed to proceed for 30 min.) The resin was then washed with DMF (3 × 1 min 30 s, 4.5 mL) and DCM (5 × 6 min, 4.5 mL).

[0235] Step 4: Macrolactamization-Cleavage / Deprotection Macrolactamization was then carried out with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (5 eq.) and DIPEA (5 eq.) in DMF (5 mL) for 16 h. After resin washing (DMF, 5 × 1 min 30 s, 4.5 mL), the macrocycle was cleaved from the resin and the protecting groups were removed with a mixture of TFA (trifluoroacetic acid) / HO / TIPS (triisopropylsilane) 95 / 2.5 / 2.5, v / v (2 mL / 0.2 g of resin) for 4 h at room temperature. The crude was precipitated in tert-butyl methyl ether (TBME) at 0 °C, centrifuged, and the supernatant was removed or the crude was directly evaporated under vacuum. The crude was then redissolved in 7:3 HO / acetonitrile (ACN) and lyophilized before purification by reversed-phase HPLC.

[0236] Step 4: Ring-closing metathesis (RCM)-cleavage / deprotection Ring-closing metathesis (RCM) was then carried out in DCE (4 mL) at 50 °C for 1 h in a CEM microwave using Hoveyda Grubbs 2nd generation catalyst (0.2 equiv.) and benzoquinone (1 equiv.). The resin was then washed with DCM (3x), MeOH (3x) and DCM (3x) and dried before the cleavage step. The resin and protecting groups were removed using a mixture of TFA (trifluoroacetic acid) / HO / TIPS (triisopropylsilane) 95 / 2.5 / 2.5, v / v (2 mL / 0.2 g of resin) for 4 h at room temperature. The crude was precipitated in tert-butyl methyl ether (TBME) at 0 °C, centrifuged and the supernatant was removed or the crude was directly evaporated under vacuum. The crude was then redissolved in 7:3 HO / acetonitrile (ACN) and lyophilized before purification by reverse-phase HPLC.

[0237] Step 5: Purification and characterization The crude product was resuspended in 7:3 HO / acetonitrile (ACN) and purified on a preparative HPLC-MS system from Waters (Milford, USA) (column XSELECT™ CSH™ Prep C18 (19×100 mm) packed with 5 μm MP particles, UV detector 2998, MS SQ detector 2, sample manager 2767 and binary gradient module) using acetonitrile and water + 0.1% formic acid as eluents. Pure fractions were lyophilized to give the final product as a white solid. For purity assessment, compounds were analyzed on a Waters (Milford, USA) UPLC-MS system using an Acquity UPLC® CSH™ C18 column (2.1×50 mm) packed with 1.7 μm particles with the following gradient: acetonitrile and water containing 0.1% HCOOH (0→0.2 min: 5% acetonitrile, 0.2→1.5 min: 5%→95%, 1.5→1.8 min: 95%, 1.8→2.0 min: 95%→5%, 2.0→2.5 min: 5%).

[0238] The synthetic schemes for the compounds of Table III are also shown in Figures 9A-B, 10 and 11A-B.

[0239] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0240] [Table 2]

[0241] [Table 3-1] [Table 3-2] [Table 3-3]

[0242] Example 8: Binding affinity and other biological properties of apelinergic compounds Various properties of the apelinergic compounds of the present disclosure have been determined and are presented below in Tables I-III.

[0243] Dissociation constant K i is the binding affinity (K i This reflects the binding (nM) and corresponds to the concentration of ligand that displaces 50% of the radiolabeled Pil-Apelin-13. 125 I][Nle 75 , Tyr 77 ][Pyr 1 ]-Ape13 was measured on membranes prepared from HEK293 cells stably expressing human APJ (hAPJ) by competitive binding assay.

[0244] EC 50 Gαi1 measurement by BRET-based biosensor in HEK293 cells expressing the hAPJ receptor i1 The concentration of ligand that elicits 50% of the maximal response of activation is determined.

[0245] EC 50 β-arrestin2 measurements determine the concentration of ligand that elicits 50% of the maximal response of b-arrestin2 recruitment by a BRET-based biosensor in HEK293 cells expressing the hAPJ receptor.

[0246] The half-life in vitro data represent the proteolytic stability of the analogs after incubation in rat plasma at several time points up to 24 hours at 37°C. The percentage of remaining analog was calculated by taking the ratio between the AU of the compound and the AUC of the internal standard. The half-life was estimated from the curves. [Table I-1] [Table I-2] [Table I-3] [Table II] [Table III-1] [Table III-2]

[0247] Example 9: Apelin 13 analogues for receptor binding on mutant APJ receptors The extracellular surface of the APJ receptor possesses several negatively charged residues on its N-terminal tail and extracellular loops, such as EE20, D23, D92, D94, D172, E174, D184, and E194 (Ma et al., 2017). To investigate their role in receptor binding of macrocycle analogs, the affinity of compounds 20 (N-terminal acetylation), 22 (absence of N-terminal amine), and 24 (Arg4Nle) was determined on the APJ E20A and D23A mutant receptors, since these mutations were previously shown as potential binding sites for the cationic moiety of apelin (Table IV). The results showed that the affinities of 20, 22 and 24 were not affected by these mutations (<2.5-fold change) compared to that of Ape13 (2.4- to 7.7-fold decrease), suggesting that E20 and D23 of APJ may not play a significant role in the binding of these macrocycle analogues, but may be important in conferring higher affinity to compounds with a positive charge in the N-terminal portion. [Table IV]

[0248] Example 10: Functional activity of apelin-13 analogues K i All apelin 13 analogs with a titer <20 nM were tested for their ability to activate downstream signaling pathways of the APJ receptor. To this end, a BRET-based biosensor was used to measure the activity of G proteins (Gα i1 ) activation and β-arrestin2 recruitment were monitored. Remarkably, this analysis reveals that some of the macrocycles behave as partial agonists, while others show biased signaling for some of the studied pathways (Figure 12, Panels A-B, Table V). [Table V-1] [Table V-2]

[0249] Example 11: In vitro plasma stability The plasma stability of compounds with an affinity of less than 20 nM for the APJ receptor was evaluated (Table V above). The first generation macrocyclic analogs 97, 13, 15, 16, 18 and 19 showed good stability in rat plasma, with t values ​​ranging from 2 to 5 hours. 1 / 2 This shows a significantly higher (t 1 / 2 0.4 hours). Peptides with polar groups on the linker (18, 19t 1 / 2 , 2.0-2.2 hours) has a shorter half-life (vs. 97, 13, 15, 16t 1 / 2 , 4.0-4.7 h), suggesting that the linker affects the stability of the macrocycle.

[0250] Truncation of the N-terminal tail (Pyr1-Arg2) slightly reduced plasma stability compared to compound 97, which may be due to exposure of the N-terminal amine, making the compound more vulnerable to aminopeptidases. Nevertheless, analogs 20, 23 and 28 still exhibited half-lives of more than 3 hours. The macrocyclic analogs were always more stable than their linear analogs. Somewhat surprising was the effect of truncation of the C-terminus (Pro12-Phe13 removal), which also reduced peptide stability. Indeed, analog 29, truncated at both the C-terminus and N-terminus (t 1 / 2 0.9 h) was 3-fold less stable than the N-terminally truncated 20 and the full-length analog 13 (t 1 / 2 The C-terminus of Ape13 is known to be cleaved at the penultimate position by metalloproteases such as ACE2 and PRCP (Yang et al., 2017). However, this cleavage site was removed in these truncated analogs.

[0251] The peptide stability of analog 29 was improved by introducing a D-amino acid at the C-terminal Nle11 position. D-amino acids are not commonly used by the body and proteolytic enzymes have not evolved for their recognition (Feng et al., 2016), which explains why macrocycles 42, 43, 44, and 45, which have D-1Nal, D-2Nal, D-Tyr(OBn) and D-Tyr substitutions, respectively, are much more stable than the parent compound 29, with half-lives ranging from 2.4 to >24 h. 43 is the most stable compound in this series, exhibiting a half-life of >24 h.

[0252] Example 12: In vivo pharmacokinetics The most potent cleaved macrocycle (42) and the most stable analog (43) were selected for in vivo pharmacokinetic profiling. The compounds were administered intravenously to rats via the jugular vein at 3 mg / kg, and blood was collected at 5, 10, 15, 20, 30, 60, 120, and 240 min after injection, followed by LC / MS-MS analysis (Figure 13). As expected, 42 and 43 were stable and detectable in rat plasma up to 2 hours after injection, while Ape13 disappeared completely after 5 minutes. Compound 42 showed a half-life of 24 minutes and a plasma clearance of 2.29 mL / min / kg (Table VII). Notably, analog 43 had an in vivo t1 / 2 of 220 minutes, resulting in a circulating concentration of 8.6 μg / mL 4 hours after injection (compared to 36.1 μg / mL at 5 minutes). Due to the long half-life and low plasma clearance (0.34 mL / min / kg), this compound suggests the possibility of using Ape13 analogs as cardioprotective agents with a single bolus injection. [Table VII]

[0253] Example 13: Effects on blood pressure We evaluated the ability of compounds 15, 20, 29, 42, and 43 to regulate blood pressure in rat plasma. Their effects on blood pressure were evaluated at two doses, 19.6 and 65 nmol / kg. The dose of 19.6 nmol / kg corresponds to the maximal effect of Ape13, while the higher dose of 65 nmol / kg was chosen to see if less potent analogs could produce an effect.

[0254] The truncated analog gradually lost its effect on blood pressure as its size decreased, as well as the ability to recruit β-arrestin 2 (Besserer-Offroy et al., 2018). Compound 15 (β-arr2 EC 50Ape13, which has a truncated N-terminal tail (33 nM, Emax 115%), produced a similar reduction in blood pressure (ΔMABP -40 mmHg) as Ape13, although the response was slightly longer, likely due to its longer half-life and higher potency in mobilizing β-arr2 (Figure 14). In contrast, analog 20, which has a truncated N-terminal tail (β-arr2 EC 50 143nM, E max Analog 29, which has both N- and C-terminal truncations (β-arr2 EC 50 743nM, Emax 69%) had little effect on blood pressure (ΔMABP -13mmHg), whereas 43 (β-arr2 EC 50 Compound 42 inhibited APJ binding (31, K i 0.6nM vs. Ape13, K i 0.6 nM) and β-arrestin 2 recruitment (42, EC 50 31nM vs. Ape13, EC 50 Despite similar potency to Ape13 (ΔMABP -24 mmHg), Ape13 induced a smaller decrease in blood pressure (ΔMABP -24 mmHg) than Ape13. The difference is the lower maximal efficacy of 42 on β-arretin 2 mobilization (E max 70%), indicating its partial agonist activity on this pathway. Similarly, compound 43 has partial efficacy (E max 55%) and low efficacy (43, EC 50 232 nM), which most likely explains its lack of efficacy on blood pressure.

[0255] Example 14: Effects on cardiac function Using echocardiography, we studied the cardiac effects of macrocycles 42 and 43, which show small size, good affinity for APJ and improved in vitro and in vivo half-lives. Also, both compounds inhibited Gα i1It should also be noted that 42 is more potent (6.2-7.5-fold) than 43 for those pathways, whereas they are full agonists with good potency for β-arretin, whereas they are partial agonists for β-arretin.

[0256] To show whether peptides with higher stability could maintain their cardiovascular effects after a single bolus administration, Ape13 and the two macrocycles 42 and 43 were administered to rats by subcutaneous injection (sc) at two doses: 0.2 μmol / kg (low) and 2 μmol / kg (high for the macrocycles, approximately 2 mg / kg). Left ventricular fractional shortening (FS), an index of cardiac contractility, as well as cardiac output (CO), an indication of overall cardiac performance, were monitored (Figure 15A-B). Three hours after injection, no observable effect was detected for Ape13 at 0.2 μmol / kg, while 42 showed a significant increase in FS only, and 43 showed a significant increase in both FS and CO, consistent with its long half-life.

[0257] At the highest dose tested, 2 μmol / kg, Ape13, 42 and 43 all showed significant improvements in FS and CO up to 22–27% from baseline 3 h after injection. Thus, previous studies have shown that very high doses of Ape13 (50 mg / kg or approximately 32 μmol / kg, sc) may help overcome its short half-life and ensure therapeutically effective concentrations (Onorato et al., 2019). However, most of the tested compounds lost efficacy 6 h after injection due to metabolism and elimination. Only 43 at the highest dose (2 μmol / kg) showed significant effects on FS (17% increase) and CO (16% increase from baseline) at 6 h. These results are consistent with those of 42 (in vivo t 1 / 2 24 min) and 43 (in vivo t 1 / 2This is consistent with the pharmacokinetic profile of 42 at 4 h (220 min). Even at higher doses (3 mg / kg or approximately 3 μmol / kg), we expect that 42 will be completely cleared from plasma in 4 h (Table VII), while 43 will decline by less than three half-lives at 6 h and remain in sufficient concentrations to have an observable effect. Thus, a longer in vivo half-life would result in more prolonged cardiac effects, especially for macrocycle 43.

[0258] The scope of the claims should not be limited by the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the description as a whole.

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(Item 1) A compound of formula (II) [ka] During the ceremony, X1 is absent or is X7-X8; X7 is -(CH2)q-CH3 or -(CF2)q-CF3, q is 0 to 11; a natural amino acid, a synthetic amino acid, the side chain of which is H; -(C1-C12)alkyl, -(CF2)q-CF3, where q is 0 to 11; -(C3-C8)heteroalkyl, -(CH2)p-(C3-C8)aryl, -(CH2)p-(C3-C8)heteroaryl, -(CH2)p-(C3-C8)cycloalkyl, or -(CH2)p-(C3-C8)heterocycloalkyl, where p is 0 to 5; and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is one or two (C3-C8)aryl, (C3-C8)heteroaryl. and optionally fused to an alkyl, heteroaryl, aryl, (C3-C8)cycloalkyl or -(C3-C8)heterocycloalkyl, wherein said alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents, each of which is independently, for example, halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, and wherein a heteroatom in said heteroalkyl, heteroaryl or heterocycloalkyl is N, O or S; X8 is absent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is aryl is optionally substituted with at least one amino or guanidino group; said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused with one or two (C-C)aryl, (C-C)heteroaryl, (C-C)cycloalkyl or -(C-C)heterocycloalkyl; and the heteroatoms in said heteroalkyl, heteroaryl or heterocycloalkyl are 1, 2 or 3 N, O or S; Y is absent, NH2-, Ac-NH-, guanidine, or H; A is -(CH)-, -(CH)NH=C(NH)N-CH-CH=CH- (preferably allyl-glycine or N-allyl-arginine), where n is 2, 3 or 4, or -CH=CH-(CH)-, where m is 0, 1 or 2; B is not present or [ka] wherein R is O, P, m-alkyl, halogen or nitro, and n is 1, 2 or 3; [ka] wherein R is H, C3-C7 alkyl, benzyl or arylalkyl, and n is 1, 2 or 3; [ka] wherein n is 1, 2, 3 or 4 and m is 0 or 1; or [ka] In the formula, X9 is CH or N; X2 and X3 are each independently nonexistent or a natural or synthetic amino acid, the side chain of which is -CH2-(CH2)p-NH2, --CH2-(CH2)p-guanidine, -(CH2)p-(C3-C8)cycloalkyl, -(CH2)p-(C3-C8)heterocycloalkyl, -(CH2)p-(C3-C8)aryl, or -(CH2)p-(C3-C8)heteroaryl, where p is 0 to 5, and the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with at least one amino or guanidino group, said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally fused to one or two (C-C)aryl, (C-C)heteroaryl, (C-C)cycloalkyl or -(C-C)heterocycloalkyl, and said heteroatoms in said heteroalkyl, heteroaryl or heterocycloalkyl are 1, 2 or 3 N, O or S; X4 is a natural or unnatural amino acid having a positively charged or uncharged side chain; X5 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp, or Hyp(OBn); X6 is X 10 -X 11 -X 12 where: X 10is any naturally occurring or synthetic amino acid whose side chain is H, -(CH)p-(C3-C8)alkyl, -(CH)p-(C3-C8)heteroalkyl, -(CH)p-(C3-C8)cycloalkyl, -(CH)p-(C3-C8)heterocycloalkyl, -(CH)p-(C3-C8)aryl, -(CH)p-(C3-C8)heteroaryl, -CH2-(CH2)p-NH2, -CH2-(CH2)p-guanidine, where p is 0 to 5, and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which may be independently selected from, for example, a halogen, an amino group, a guanidino group, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5, and said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and said heteroatoms in said heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S). In certain embodiments, X 10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0-5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each substituent being independently O-(C1-C6)alkyl, -(CH2)p-(C3-C8)aryl, -O-(CH2)p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p is 0-5. In certain embodiments, it is not Ala. In more specific embodiments, X 10is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr; X 11 is absent or is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp, or Hyp(OBn). In certain embodiments, it is absent or is Pro, X 12 is absent or is Phe, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 2) - X2 and X3 are each independently an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0 to 4; and / or -X 10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0 to 5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each substituent being independently -OH, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 3) - X2 and X3 are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine; - X4 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), - X5 is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), and / or -X 10 is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)-N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 4) - X2 and X3 are each independently Lys, Arg, hArg, Nle, Leu, Phe, or Cha; - X4 is Gly, and / or - the compound according to item 3, wherein X5 is Pro; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 5) - X1 is not present, - Y is NH2, Ac-NH-, guanidine or H, A is -CH=CH-(CH)-, where m is 0, 1 or 2; - B does not exist, [ka] R is O, P, m-alkyl, halogen or nitro and n is 1, 2 or 3; [ka] , X9 is CH or N, and / or -X 10 is an amino acid whose side chain is -(CH2)p-(C3-C8)alkyl, or -(CH2)p-(C3-C8)aryl, where p is 0 to 5, and the aryl is optionally fused to one or two (C3-C8)aryl, and the aryl is optionally substituted with one or more substituents, each substituent being independently -OH, -O-(C1-C6)alkyl, -(CH2)p'-(C3-C8)aryl, -O-(CH2)p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 6) X 10 is Nle or D-1Nal, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. 2. - X1 is X7 to X8, and / or - a compound according to any one of items 1 to 4, wherein Y is absent, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 7) - the compound according to item 7, wherein X1 is X7-X8, X8 is an amino acid, the side chain of which is -CH2-(CH2)p-guanidine, -CH2-(CH2)p-NH2, or -(CH2)p-imidazole, preferably -CH2-(CH2)p-guanidine or -CH2-(CH2)p-NH2, where p is 0 to 4; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 8) - the compound according to item 7 or 8, wherein A is -(CH2)n- or -CH=CH-(CH2)m-, where m is 0, 1 or 2; or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 9) A compound of any one of formulas (I) to (VIII), or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 10) The compound according to item 9, which is any one of compounds 3 to 4, 9 to 29, 35 to 46, 62 to 70, 72 to 79, 84, and 89 to 94, preferably any one of compounds 11, 13, 15 to 16, 18 to 20, and 42 to 44: [Table 4-1] [Table 4-2] or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 11) 11. The compound according to item 10, which is any one of compounds 13 to 25, 27 to 29, 35 to 37 and 42 to 45, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 12) A pharmaceutical composition comprising a compound, stereoisomer, mixture, pharma- ceutically acceptable salt, ester or solvate according to any one of items 1 to 11, and at least one pharma- ceutically acceptable carrier or excipient. (Item 13) A method of using a compound of any one of formulas (I) to (IV), or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester, or solvate thereof, for treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound. (Item 14) Item 14. The method according to item 13, wherein the compound is any one of compounds 3 to 4, 9 to 29, and 35 to 46 defined in item 10, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester, or solvate thereof. (Item 15) Item 14. The method according to item 13, wherein the compound is a compound of formula (II) as defined in any one of items 1 to 8. (Item 16) The method according to item 15, wherein the compound is any one of compounds 13 to 25, 27 to 29, 35, 36 to 37 and 42 to 45 defined in item 10, preferably any one of compounds 13, 15 to 16, 18 to 20, 23 and 42 to 44, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof. (Item 17) 17. The method according to item 16, wherein the compound is compound 42 or 43, or a stereoisomer or mixture thereof, or a pharma- ceutically acceptable salt, ester or solvate thereof.

Claims

1. A compound of formula (II) [Chemistry 18] During the ceremony, X １ is not present or X ７ -X ８ and X ７ is -(CH ２ )q-CH ３ Or - (CF ２ ) q-CF ３ , q is 0 to 11, natural amino acids, synthetic amino acids, the side chain of which is H, -(C1-C12) alkyl, -(CF ２ ) q-CF ３ , where q is 0 to 11; -(C3-C8)heteroalkyl; -(CH ２ ) p-(C3-C8)aryl, —(CH ２ )p-(C3-C8)heteroaryl, —(CH ２ ) p-(C3-C8)cycloalkyl, or —(CH ２ )p-(C3-C8)heterocycloalkyl, where p is 0-5, wherein said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and said alkyl, heteroaryl, aryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more substituents, each substituent independently being halogen, amine, -OH, S, -(C1-C6)alkyl, -O-(C1-C6)alkyl, -(CH ２ )p-(C3-C8)aryl, —O—(CH ２ ) p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, wherein the heteroatom in said heteroalkyl, heteroaryl, or heterocycloalkyl is N, O, or S; X ８ is a non-existent, natural or synthetic amino acid, the side chain of which is -CH ２ - (CH ２ ) p-NH ２ , -CH ２ - (CH ２ ) p-guanidine, -(CH ２ ) p-(C3-C8)cycloalkyl, —(CH ２ )p-(C3-C8)heterocycloalkyl, —(CH ２ ) p-(C3-C8)aryl, or —(CH ２ )p-(C3-C8)heteroaryl, wherein p is 0-5, said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group, said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and the heteroatoms in said heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S; Y is absent or NH ２ -, Ac-NH-, guanidine, or H; A is -(CH ２ ) n-, -(CH ２ )nNH=C(NH ２ ) N-CH ２ -CH=CH-, where n is 2, 3, or 4, or -CH=CH-(CH ２ ) m-, where m is 0, 1 or 2; B does not exist, or 【Chemistry 19】 wherein R is O, P, m-alkyl, halogen, or nitro, and n is 1, 2, or 3; 【Chemistry 20】 wherein R is H, C3-C7 alkyl, benzyl, or arylalkyl, and n is 1, 2, or 3; 【Chemistry 21】 wherein n is 1, 2, 3, or 4 and m is 0 or 1; or 【Chemistry 22】 In the formula, X ９ is CH or N; X ２ and X ３ are each independently a non-existent, natural or synthetic amino acid, the side chain of which is -CH ２ - (CH ２ ) p-NH ２ , --CH ２ - (CH ２ ) p-guanidine, -(CH ２ ) p-(C3-C8)cycloalkyl, —(CH ２ )p-(C3-C8)heterocycloalkyl, —(CH ２ ) p-(C3-C8)aryl, or —(CH ２ )p-(C3-C8)heteroaryl, wherein p is 0-5, said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with at least one amino or guanidino group, said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused to one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and said heteroatoms in said heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S; X ４ is a natural or unnatural amino acid with a positively charged or uncharged side chain, X ５ is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), X ６ is X １０ -X １１ -X １２ where: X １０ is any natural or synthetic amino acid, the side chain of which is H, —(CH ２ ) p-(C3-C8) alkyl, —(CH ２ )p-(C3-C8)heteroalkyl, —(CH ２ ) p-(C3-C8)cycloalkyl, —(CH ２ )p-(C3-C8)heterocycloalkyl, —(CH ２ ) p-(C3-C8)aryl, —(CH ２ ) p-(C3-C8)heteroaryl, —CH ２ - (CH ２ ) p-NH ２ , or -CH ２ - (CH ２ )p-guanidine, where p is 0-5, and the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is substituted with one or more substituents, each of which is independently selected from, for example, halogen, amino, guanidino, —OH, S, —(C1-C6)alkyl, —O—(C1-C6)alkyl, —(CH ２ )p'-(C3-C8)aryl, —O—(CH ２ )p'-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p' is 0 to 5, and said cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally fused with one or two (C3-C8)aryl, (C3-C8)heteroaryl, (C3-C8)cycloalkyl, or -(C3-C8)heterocycloalkyl, and said heteroatoms in said heteroalkyl, heteroaryl, or heterocycloalkyl are 1, 2, or 3 N, O, or S, and optionally X １０ is an amino acid, the side chain of which is -(CH ２ ) p-(C3-C8) alkyl, or —(CH ２ )p-(C3-C8)aryl, where p is 0-5, said aryl is optionally fused with one or two (C3-C8)aryl, said aryl is optionally substituted with one or more substituents, each substituent being independently O-(C1-C6)alkyl, -(CH ２ )p-(C3-C8)aryl, —O—(CH ２ )p-(C3-C8)aryl, -(C3-C8)cycloalkyl, or -O-(C3-C8)cycloalkyl, where p is 0 to 5; and optionally, X １０ is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)—N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr; X １１ is absent or is Gly, Phe, Leu, lie, Ser, Aib, Pro, Sar, Oic, βAla, Hyp, or Hyp(OBn), and optionally X is absent or is Pro; X １２ is absent or is Phe, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

2. -X ２ and X ３ are each independently an amino acid, the side chain of which is —CH ２ - (CH ２ ) p-guanidine, —CH ２ - (CH ２ ) p-NH ２ , or -(CH ２ ) p-imidazole, preferably —CH ２ - (CH ２ ) p-guanidine, or —CH ２ - (CH ２ ) p-NH ２ where p is 0 to 4; and / or -X １０ is an amino acid, the side chain of which is -(CH ２ ) p-(C3-C8) alkyl, or —(CH ２ )p-(C3-C8)aryl, where p is 0-5, said aryl is optionally fused to one or two (C3-C8)aryl, said aryl is optionally substituted with one or more substituents, each substituent being independently selected from -OH, -O-(C1-C6)alkyl, -(CH ２ )p'-(C3-C8)aryl, —O—(CH ２ 2. The compound of claim 1, wherein p' is 0 to 5; or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

3. -X ２ and X ３ are each independently Lys, Orn, Dab (2,4-diaminobutyric acid), Dap (2,3-diaminopropionic acid), Arg, hArg, His, Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine) or alpha-methylphenylalanine; -X ４ is Gly, Phe, Leu, Ile, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), -X ５ is Gly, Phe, Leu, lie, Ser, Aib, Pro, Sar, Oic, βAla, Hyp or Hyp(OBn), and / or -X １０ is Nle, alpha-methylleucine, cycloleucine, tert-leucine, cyclohexylalanine (e.g., (3-cyclohexyl-L-alanine), alpha-methylphenylalanine, Phe, Tic ((S)—N-Fmoc-tetrahydroisoquinoline-3-carboxylic acid), Tyr, 1Nal, 2Nal, TyrOBn, cypTyr(OBn), dcypTyr(OBn), cypTyr(OCyp), cypTyr(OPr), D-1Nal, D-2Nal, D-TyrOBn, or D-Tyr; or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

4. -X ２ and X ３ are each independently Lys, Arg, hArg, Nle, Leu, Phe, or Cha; -X ４ is Gly, and / or -X ５ The compound of claim 1, wherein is Pro. or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

5. -X １ But it doesn't exist, - Y is NH ２ , Ac—NH—, guanidine, or H; - A is -CH=CH-(CH ２ ) m-, where m is 0, 1 or 2; - B does not exist, 【Chemistry 23】 wherein R is O, P, m-alkyl, halogen, or nitro, and n is 1, 2, or 3; or 【Chemistry 24】 In the formula, X ９ is CH or N, and / or -X １０ is an amino acid, the side chain of which is -(CH ２ ) p-(C3-C8) alkyl, or —(CH ２ )p-(C3-C8)aryl, where p is 0-5, said aryl is optionally fused to one or two (C3-C8)aryl, said aryl is optionally substituted with one or more substituents, each substituent being independently selected from -OH, -O-(C1-C6)alkyl, -(CH ２ )p'-(C3-C8)aryl, —O—(CH ２ 2. The compound of claim 1, wherein p' is 0 to 5; or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

6. X １０ 6. The compound of claim 5, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein is Nle or D-1Nal.

7. -X １ But, X ７ ~X ８ and / or The compound according to claim 1, wherein Y is absent. or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

8. -X １ But, X ７ -X ８ and X ８ is an amino acid, the side chain of which is —CH ２ - (CH ２ ) p-guanidine, —CH ２ - (CH ２ ) p-NH ２ , or -(CH ２ ) p-imidazole, preferably —CH ２ - (CH ２ ) p-guanidine, or —CH ２ - (CH ２ ) p-NH ２ 8. The compound of claim 7, wherein p is 0 to 4. or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

9. - A is -(CH ２ )n- or -CH=CH-(CH ２ 8. The compound of claim 7, wherein m is 0, 1, or 2. or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

10. A compound of any one of formulas (I) to (VIII), or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof:

11. The compound according to claim 10, which is any one of compounds 3 to 4, 9 to 29, 35 to 46, 62 to 70, 72 to 79, 84, and 89 to 94, preferably any one of compounds 11, 13, 15 to 16, 18 to 20, and 42 to 44: Table 5-1 Table 5-2 In the formula, X represents allylglycine, dX represents D-allylglycine, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.

12. The compound according to claim 11, which is any one of compounds 13 to 25, 27 to 29, 35 to 37, and 42 to 45, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester, or solvate thereof.

13. A pharmaceutical composition comprising a compound, stereoisomer, mixture, pharmaceutically acceptable salt, ester or solvate according to any one of claims 1 to 12, and at least one pharmaceutically acceptable carrier or excipient.

14. A composition for use in treating cardiovascular disease, comprising a compound of any one of formulas (I) to (IV), or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester, or solvate thereof; or A composition for use in treating cardiovascular disease, comprising a compound of formula (II) as defined in any one of claims 1 to 4.

15. The composition according to claim 14, wherein the compound is any one of compounds 3 to 4, 9 to 29, and 35 to 46 as defined in claim 10, optionally any one of compounds 13, 15 to 16, 18 to 20, 23, and 42 to 44, preferably compound 42 or 43, or a stereoisomer or mixture thereof, or a pharmaceutically acceptable salt, ester, or solvate thereof.

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