RXFP1 receptor agonist analog, preparation method therefor, and use thereof

Abstract

The present invention relates to the technical field of chemical drugs, and provides an RXFP1 receptor agonist analog, a preparation method therefor, and a use thereof. A compound provided by the present invention exhibits good RXFP1 receptor agonist activity and can be used for treating heart failure.

Description

An RXFP1 receptor agonist analogue, its preparation method and uses Technical Field

[0001] This invention belongs to the field of chemical drug technology, specifically relating to an RXFP1 receptor agonist analogue, its preparation method, and its uses. Background Technology

[0002] Relaxin (RLN) is part of the insulin superfamily and comprises seven peptides in humans with high structural similarity but low sequence similarity: RLN1 (H1RLX, RLXH1, or H1), RLN2 (H2RLX, RLXH2, or H2), RLN3 (RXN3, ZINS4, or H3), insulin-like (INSL) peptide 3 (INSL3), INSL4, INSL5, and INSL6. RLN2 is a heterodimer of two peptide chains (A and B chains) with 24 and 29 amino acids respectively, linked by two disulfide bonds, with the A chain further having an intramolecular disulfide bond (see Schwabe & McDonald (1977) Science 197:914-915). RLN2 is produced from its pro-hormone (pro-relaxin) by cleaving its C-peptide.

[0003] Physiologically, RLN2 exhibits a variety of functions, regulating cardiovascular, hepatic, nervous, pancreatic, lung, and renal adaptations, such as vasodilation, anti-fibrotic, and angiogenic effects, although it was initially described as a pregnancy hormone. RLN2 signaling occurs through two distinct classes of G-protein-coupled receptors (GPCRs), namely the leucine-rich repeat-containing GPCRs LGR7 and LGR8, now known as RXFP1 and RXFP2 receptors, respectively.

[0004] Relaxin RLN2 induces activation of RXFP1 in the following ways: 1) upregulation of the endothelin system leading to vasodilation; 2) remodeling of the extracellular matrix by regulating collagen deposition, cell invasion, proliferation, and overall tissue homeostasis; 3) alleviating inflammation by reducing levels of inflammatory cytokines such as TNF-α and TGF-β; and 4) angiogenesis activates VEGF transcription. Understanding the biological effects of relaxin activation of RXFP1 has led to evaluations of relaxin as a treatment for acute heart failure (AHF), preeclampsia, and hypertension. Furthermore, several clinical trials have investigated the therapeutic effects of relaxin in scleroderma, cervical ripening, fibromyalgia, and orthodontics due to its anti-inflammatory and extracellular matrix remodeling functions.

[0005] Most reported relaxin RLN2 mimics are peptides, while small molecule RXFP1 modulators are rarely reported. For example, patent WO2013165606A1 discloses a small molecule relaxin modulator whose compound can selectively activate the RXFP1 receptor, EC... 50 The value is approximately 94 nM; Patent WO2022122773A1 discloses 4-(2-fluoro-4-methoxy-5-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid derivatives and similar compounds as RXFP1 modulators for the treatment of heart failure. These compounds can also selectively activate RXFP1 receptors and can be used to treat heart failure, EC 50 The value is approximately 6.3 nM.

[0006] In summary, although small molecule RXFP1 receptor agonist analogs have been reported in the prior art, the activity and selectivity of these small molecule RXFP1 receptor agonist analogs still need to be optimized, and no related drugs have been marketed yet. Therefore, more small molecule RXFP1 receptor agonist analogs and their preparation methods are still needed. Summary of the Invention

[0007] In view of the problems existing in the prior art, the present invention provides an RXFP1 receptor agonist analog.

[0008] This invention is achieved through the following technical solution: This invention provides an RXFP1 receptor agonist analog, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor agonist analog is shown in general formula (I):

[0009] in:

[0010] Each of R2, R3, or R4 is independently selected from: H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic alkyl;

[0011] The X or Y is independently selected from: -O-, -S-, -NH-, -N(R8)- or -C(R9)(R 10 )-;

[0012] The R8, R9 or R 10 Each is independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy;

[0013] The R5 is independently selected from: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy;

[0014] The R6 is independently selected from: H, halogen, substituted or unsubstituted C1-C6 alkyl;

[0015] Alternatively, R5 and R6, together with the carbon atom they are attached to, may be cyclized into substituted or unsubstituted C3-C8 cycloalkyl groups or substituted or unsubstituted 3-10 heterocyclic alkyl groups.

[0016] The R7 is independently selected from: -COOH, -SO3H, -CON(R) 11 (R) 12 ), substituted or unsubstituted 5-12 heteroaryl groups, C6-C 10 Aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl;

[0017] The R 11 or R 12 All are independently selected from: H, substituted or unsubstituted C1-C6 alkyl groups;

[0018] Alternatively, R6 and R7, together with the carbon atom they are attached to, may be cyclized into substituted or unsubstituted C3-C8 cycloalkyl groups or substituted or unsubstituted 3-10 heterocyclic alkyl groups.

[0019] R1 is independently selected from: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, and substituted or unsubstituted C3-C8 cycloalkyl;

[0020] The W is independently selected from: The n is selected from integers of 0, 1, or 2; the R 13 R 14 or R 15 Each is independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C6-C 12 Aryl, substituted or unsubstituted 5-12 heteroaryl groups;

[0021] The R 16 or R 17 Each is independently selected from: H, C1-C6 alkyl, and C1-C6 haloalkyl;

[0022] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C5-C group.12 Spirocycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;

[0023] Or the R 13 R 14 and R 15 Together with the carbon atom attached thereto, they cyclize into substituted or unsubstituted 5-12 membered bridged cycloalkyl groups;

[0024] Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl;

[0025] The substituents referred to as "substitution" are all independently selected from: -OH, oxo, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups.

[0026] Further, as a preferred embodiment of the present invention, R5 and R6, together with their attached carbon atoms, are cyclized into substituted or unsubstituted 3-10-membered heterocyclic alkyl groups; the substituted or unsubstituted 3-10-membered heterocyclic alkyl groups are selected from: oxoheterocyclic alkyl groups, preferably oxotetrahydropyrrolidinyl or oxotetrahydrofuranyl, more preferably, the substituted or unsubstituted 3-10-membered heterocyclic alkyl groups are selected from:

[0027] Further, as a preferred embodiment of the present invention, R6 is independently selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl; preferably, R6 is independently selected from: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl; more preferably, R6 is independently selected from: methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2OH;

[0028] Furthermore, as a preferred embodiment of the present invention, R5 and R6, together with the carbon atoms attached to them, are cyclized into cyclopropyl groups;

[0029] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analogue has a structure represented by general formula (IIA), general formula (IIB), general formula (IIC), or general formula (IID): The definitions of R1-R7, X, Y and W are the same as those in general formula (I).

[0030] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analogue is selected from the structures represented by formula (IIAA), (IIAB), (IIBA), (IICA), (IICB), (IIDA), or (IIDB):

[0031] The definitions of R1-R7, X, Y and W are the same as those in general formula (I).

[0032] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analogue is selected from the structure shown in formula (IIIA) or (IIIB):

[0033] Wherein, X is selected from -O- or -NH-;

[0034] The Y is independently selected from -NH-;

[0035] R1, R2, and R3 are independently selected from one of the following combinations a)-c):

[0036] a) R1 is selected from: substituted or unsubstituted C1-C3 alkyl groups, and R2 is independently selected from: halogens or -CN; R3 is independently selected from: substituted or unsubstituted C1-C3 alkyl groups, halogens or -CN;

[0037] b) R1 is selected from: -CHF2, R2 is selected from H, halogen, and R3 is independently selected from: halogen or C1-C3 haloalkyl;

[0038] c) R1 is selected from: substituted or unsubstituted C1-C3 alkyl groups, R2 is selected from H and halogens, and R3 is independently selected from: -CHF2;

[0039] The R7 is independently selected from: -COOH or

[0040] The W is independently selected from: The n is selected from integers of 0, 1, or 2; the R 13 R 14 or R 15 Each of the following is independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl; R 16 or R 17 Each is independently selected from: H, C1-C6 alkyl, and C1-C6 haloalkyl;

[0041] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C5-C group. 12 Spirocycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;

[0042] Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl;

[0043] The substituents referred to as "substitution" are all independently selected from: -OH, oxo, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups.

[0044] Furthermore, as a preferred embodiment of the present invention, R1, R2, and R3 are independently selected from one of the following combinations a)-c):

[0045] a) R1 is selected from: C1-C3 alkyl or C1-C3 haloalkyl, and R2 or R3 is independently selected from: halogen;

[0046] b) R1 is selected from: -CHF2, R2 is selected from H, halogen, and R3 is independently selected from: halogen or C1-C3 haloalkyl;

[0047] c) R1 is selected from C1-C3 alkyl or C1-C3 haloalkyl, R2 is selected from H or halogen, and R3 is independently selected from -CHF2.

[0048] Furthermore, as a preferred embodiment of the present invention, X is selected from -O- or -NH-; Y is independently selected from -NH-;

[0049] Each of the R1s is independently selected from: -CH2F, -CHF2, -CF3, -CH3, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl;

[0050] R2 or R3 is independently selected from: F, Cl, -CN, -CH2F, -CHF2, -CF3, -CH3;

[0051] The W is independently selected from: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy.

[0052] Alternatively, YW can be independently selected from:

[0053] The m, p, q, r, s, t, u, v, z1, z2, or z3 are each independently selected from integers of 0, 1, 2, or 3;

[0054] The R 15 Each is independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0055] The R 18 It is independently selected from: C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl.

[0056] Furthermore, as a preferred embodiment of the present invention, the C1-C6 haloalkyl group is independently selected from: Preferably, the C1-C6 haloalkyl group is independently selected from:

[0057] Furthermore, as a preferred embodiment of the present invention, the C1-C6 alkyl group is independently selected from:

[0058] Furthermore, as a preferred embodiment of the present invention, W is independently selected from:

[0059] The R 15 Each is independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl; preferably, R 15 All are independently selected from: H, methyl, ethyl, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The R... 18 Independently selected from: C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl. Preferably, the R 18 Each of the following is independently selected from: H, methyl, ethyl, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, as a preferred embodiment of the present invention, W is independently selected from: The R 15 Each is independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl; preferably, R 15Each of the following is independently selected from: H, methyl, ethyl, -CH2F, -CHF2, -CF3, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, as a preferred embodiment of the present invention, W is independently selected from:

[0060] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analogue is selected from the structures shown in formula (IV), formula (IVA), or (IVB):

[0061] Wherein, R1 is independently selected from: C1-C3 alkyl or C1-C3 haloalkyl;

[0062] The R2 is independently selected from: halogen or -CN;

[0063] The R3 is independently selected from: C1-C3 haloalkyl or halogen;

[0064] The R7 is independently selected from: -COOH or

[0065] The W is independently selected from: The n is selected from integers of 0 or 1; the R 13 R 14 or R 15 Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups; the R 16 or R 17 Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups;

[0066] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C6 cycloalkyl group or a substituted or unsubstituted C5-C group. 12 Spirocycloalkyl;

[0067] Or the R 13 R 14 and R 15 The carbon atom it is attached to cyclizes together to form a substituted or unsubstituted C5-C atom. 12 Bridged cycloalkyl;

[0068] The Y is independently selected from: -NH-;

[0069] Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl;

[0070] The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups.

[0071] Furthermore, as a preferred embodiment of the present invention, the present invention also provides an RXFP1 receptor agonist analog, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor agonist analog is selected from the structure shown in formula (VA) or formula (VB):

[0072] Wherein, R1 is independently selected from: methyl or CH3OCH2CH2-;

[0073] The W is independently selected from: The R 13 R 14 or R 15 Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups; the R 16 or R 17 Each is independently selected from: H, C1-C3 alkyl, and C1-C3 haloalkyl;

[0074] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C6 cycloalkyl group or a substituted or unsubstituted C5-C group. 10 Spirocycloalkyl;

[0075] Or the R 13 R 14 and R 15 The carbon atom it is attached to cyclizes together to form a substituted or unsubstituted C5-C atom. 10 Bridged cycloalkyl;

[0076] The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups.

[0077] Furthermore, as a preferred embodiment of the present invention, the present invention also provides an RXFP1 receptor agonist analog, or its isomer, racemate, or pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor agonist analog is selected from the structure represented by formula (VAA) or formula (VBA):

[0078] Wherein, R1 is independently selected from: methyl or CH3OCH2CH2-;

[0079] The W is independently selected from: The R 13 R 14 or R 15Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups;

[0080] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C6 cycloalkyl group or a substituted or unsubstituted C5-C group. 10 Spirocycloalkyl;

[0081] Or the R 13 R 14 and R 15 The carbon atom it is attached to cyclizes together to form a substituted or unsubstituted C5-C atom. 10 Bridged cycloalkyl;

[0082] The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups.

[0083] Furthermore, as a preferred embodiment of the present invention, the substituted or unsubstituted W is independently selected from:

[0084] The substituted or unsubstituted YW is independently selected from:

[0085] The R 15 or R 16 Independently selected from: H, C1-C3 alkyl, or C1-C3 haloalkyl;

[0086] The m, p, q, r, s, t, u, v, z1, z2, or z3 are each independently selected from integers of 0, 1, 2, or 3;

[0087] Preferably, the substituted or unsubstituted W is independently selected from:

[0088] More preferably, the W is independently selected from:

[0089] The YW is independently selected from:

[0090] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that R1 is independently selected from: substituted or unsubstituted C1-C3 alkyl groups.

[0091] The R2 is independently selected from: halogen or -CN;

[0092] The R3 is independently selected from: C1-C3 haloalkyl or halogen;

[0093] The R7 is independently selected from: -COOH or

[0094] The Y is independently selected from: -NH-;

[0095] The W is independently selected from: The n is selected from integers of 0 or 1; the R 13 R 14 or R 15 Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups; the R 16 or R 17 Each is independently selected from: H or substituted or unsubstituted C1-C3 alkyl groups;

[0096] Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C6 cycloalkyl group or a substituted or unsubstituted C5-C group. 12 Spirocycloalkyl;

[0097] The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups.

[0098] Preferably, the substituted or unsubstituted W is independently selected from:

[0099] Furthermore, as a preferred embodiment of the present invention, R7 is independently selected from: -COOH or

[0100] The R3 is independently selected from: F or -CHF2;

[0101] The R2 is independently selected from: halogen or -CN;

[0102] The R1 is independently selected from: -CH3 or -CHF2;

[0103] The W is independently selected from:

[0104] Further, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analog, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analog is selected from the compounds listed in Table 1A:

[0105] Table 1A

[0106] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analogue, or its isomer, racemate, or pharmaceutically acceptable salt thereof, is characterized in that the RXFP1 receptor agonist analogue is selected from the compounds listed in Table 1B:

[0107] Table 1B

[0108] Furthermore, as a preferred embodiment of the present invention, one or more hydrogen atoms on the RXFP1 receptor agonist analog are coated with the isotope deuterium (… 2 H) substitution.

[0109] Furthermore, as a preferred embodiment of the present invention, the present invention also provides an RXFP1 receptor agonist analog, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms on the RXFP1 receptor agonist analog are coated with the isotope deuterium (… 2 H) substitution, wherein the RXFP1 receptor agonist analogue is selected from the structures shown in Table 1C:

[0110] Table 1C

[0111] Furthermore, as a preferred embodiment of the present invention, the present invention also provides a pharmaceutically acceptable salt of an RXFP1 receptor agonist analog, characterized in that the structure of the RXFP1 receptor agonist analog is shown in general formula (VI):

[0112] Wherein: W is independently selected from:

[0113] The pharmaceutically acceptable salt is independently selected from at least one of the following: lithium, sodium, potassium, calcium, magnesium, aluminum, iron, zinc, or ammonium salts; or the pharmaceutically acceptable salt is independently selected from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, pyridine, methylpyridine, ethanolamine, diethanolamine, ammonium, tetramethylammonium, tetraethylammonium, triethanolamine, and piperazine. At least one of the following: pyridine salt, piperazine salt, morpholine salt, lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucosamine salt, ethylglucosamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, glucosamine salt, sarcosine salt, serine salt, trihydroxymethylaminomethane salt, aminopropylene glycol salt, 1-amino-2,3,4-butanetriol salt, L-lysine salt, ornithine salt, or choline salt.

[0114] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor agonist analog has a structure as shown in general formula (VIA) or general formula (VIB):

[0115] Wherein: W is independently selected from:

[0116] Further, as a preferred embodiment of the present invention, the molar ratio of the RXFP1 receptor agonist analog to the pharmaceutically acceptable salt base molecules is 1 to 3:1; preferably, the molar ratio of the RXFP1 receptor agonist analog to the pharmaceutically acceptable salt base molecules is 3:1, 2:1, or 1:1. More preferably, the molar ratio of the RXFP1 receptor agonist analog to the pharmaceutically acceptable salt base molecules is 2:1 or 1:1.

[0117] Furthermore, as a preferred embodiment of the present invention, the molar ratio of the base molecules of the RXFP1 receptor agonist analog to the pharmaceutically acceptable salt is 1:1 or 2:1, wherein the pharmaceutically acceptable salt is independently selected from sodium, potassium, or calcium salts.

[0118] Furthermore, as a preferred embodiment of the present invention, the molar ratio of the base molecules of the RXFP1 receptor agonist analog to the pharmaceutically acceptable salt is 1:1 or 2:1, and the pharmaceutically acceptable salt of the RXFP1 receptor agonist analog is selected from the structures shown in Table 1D.

[0119] Table 1D

[0120] Furthermore, the present invention also provides a method for preparing an RXFP1 receptor agonist analogue, or an isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, which can be prepared using conventional methods in the art, or by referring to the method of patent WO2022122773A1 and methods known in the art.

[0121] Furthermore, the present invention also provides a pharmaceutical composition characterized in that it comprises an RXFP1 receptor agonist analogue of formula (I), (IIA), (IIB), (IIC), (IID), (IIAA), (IIAB), (IIBA), (IIBB), (IICA), (IICB), (IIDA), (IIDB), (IIIA), (IIIB), (IV), (IVA), (IVB), (VA), (VB), (VAA), (VBA), (VI), (VIA), or (VIB) of the present invention, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0122] Furthermore, the present invention also provides an RXFP1 receptor agonist analogue comprising, or an isomer thereof, or a racemic mixture thereof, as described in formulas (I), (IIA), (IIB), (IIC), (IID), (IIAA), (IIAB), (IIBA), (IIBB), (IICA), (IICB), (IIDA), (IIDB), (IIIA), (IIIB), (IV), (IVA), (IVB), (VA), (VB), (VAA), (VBA), (VI), (VIA), or (VIB) of the present invention. The pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising formula (I), (IIA), (IIB), (IIC), (IID), (IIAA), (IIAB), (IIBA), (IIBB), (IICA), (IICB), (IIDA), (IIDB), (IIIA), (IIIB), (IV), (IVA), (IVB), (VA), (VB), (VAA), (VBA), (VI), (VIA), or (VIB) of the present invention is used in the preparation of a pharmaceutical composition for the prevention or treatment of diseases associated with the RXFP1 receptor.

[0123] Furthermore, as a preferred embodiment of the present invention, the RXFP1 receptor-related disease is selected from heart failure.

[0124] In the chemical structure of the compound described in this invention, the bond... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations;

[0125] In the chemical structure of the compound described in this invention, the bond... This indicates that the key can be a single key. or double bond

[0126] In the chemical structure of the compounds described in this disclosure, the bonds... The configuration is not specified, meaning it can be either Z configuration or E configuration, or both configurations can be included simultaneously;

[0127] In the chemical structure of the compound described in this invention, the bond... Indicates a connection key;

[0128] In the chemical structure of the compound described in this invention, "abs" indicates the absolute configuration;

[0129] The compounds and intermediates of the present invention may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization. Examples of lactam-lactamimide equilibrium are between A and B as shown below.

[0130] All compounds in this invention may be designated as type A or type B. All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0131] For clarity, this article defines the general terminology used in the description of compounds.

[0132] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0133] The term "alkyl" refers to a branched, unbranched, or cyclic saturated hydrocarbon chain containing a specified number of carbon atoms. The alkyl group is preferably C16-264-3 ... 1- C6 alkyl, the C 1- The number of carbon atoms in a C6 alkyl group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1- C6 alkyl groups are preferably C1-C2, C1-C3, C1-C4, or C1-C5 alkyl groups; examples of such alkyl groups include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, and 1-ethylbutyl.

[0134] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above, and non-limiting examples of hydroxyalkyl groups include: -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)2, -CHOHCH2OH, etc.

[0135] The term "halogenated alkyl" means that the hydrogen atom on the alkyl group can be replaced by one or more halogen atoms, preferably C16. 1- C6 haloalkane, wherein the C 1- The number of carbon atoms in the C6 haloalkyl group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1- C6 haloalkyl groups are preferably C1-C2, C1-C3, C1-C4, or C1-C5 haloalkyl groups; examples of such haloalkyl groups include: -CH2F, -CHF2, -CH2Cl, -CHCl2, -CF3, -CCl3, -CHFCH2F, -CHClCH2F, -CF2CHF2, -CH2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, -CCl2CHCl2, -CH2CH Cl2, -CH2CCl3, -CHClCH3, -CH2CH2Cl, -CCl2CH3, -CH2CCl2CHCl2, -CH2Br, -CHBr2, -CHBr2, -CBr3, -CHBrCH2Br, -CHClCH2F, -CBr2CHBr2, -CH2CHBr2, -CH2CBr3, -CHBrCH3, -CH2CH2Br, -CBr2CH3, -CH2CBr2CHBr2, etc., in one embodiment, C 1- C6 haloalkyl groups include C6 groups with fluorine substitution. 1- C6 alkyl, chlorinated C 1- C6 alkyl, bromine-substituted C1- C6 alkyl, in one embodiment, C 1- C6 haloalkyl groups include C6 groups with fluorine substitution. 1- C6 alkyl; in another embodiment, C 1- C4 haloalkyl groups include C4 groups with fluorine substitution. 1- C4 alkyl; in another embodiment, C 1- C3 haloalkyl groups include C3 fluorinated alkyl groups. 1- C3 alkyl.

[0136] The term "alkoxy" refers to an alkyl group in which one or more carbon atoms are replaced by oxygen, such as -O-(alkyl), wherein the definition of alkyl is as described above. The number of carbon atoms in the C1-C6 alkoxy group is selected from 1, 2, 3, 4, 5 or 6, and the alkoxy group is preferably C1-C6 alkoxy. The C1-C6 alkoxy group is preferably C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy. Further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0137] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are substituted by halogens; the haloalkoxy group is preferably C64-C ... 1- C6 haloalkoxy group, wherein the C 1- The number of carbon atoms in the C6 haloalkoxy group is selected from 1, 2, 3, 4, 5, or 6, wherein the C... 1- The preferred C6 haloalkoxy group is a C1-C2, C1-C3, C1-C4, or C1-C5 haloalkoxy group. Further, the haloalkoxy group is specifically selected from -OCHF2, -OCHCl2, -OCHBr2, -OCF3, -OCCl3, -OCBr3, -OCH2CH2F, -OCH2CH2Cl, -OCHFCH2F, -OCHClCH2F, -OCHBrCH2F, -OCF2CHF2, -OCH2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, - OCF2CH3, -OCH2CF2CHF2, -OCCl2CHCl2, -OCH2CHCl2, -OCH2CCl3, -OCHClCH3, -OCH2CH2Cl, -OCCl2CH3, -OCH2CCl2CHCl2, -OCH2CH2Br, -OCBr2CHBr2, -OCH2CHBr2, -OCH2CBr3, -OCHBrCH3, -OCH2CH2Br, -OCBr2CH3, -OCH2CBr2CHBr2, etc., in one embodiment, C 1- C6 haloalkoxy groups include C with fluorine substitution. 1- C6 alkoxy, chlorinated C1- C6 alkoxy, bromine-substituted C 1- C6 alkoxy; in another embodiment, C 1- C4 haloalkyl groups include C4 groups with fluorine substitution. 1- C4 alkoxy; in yet another embodiment, C 1- C3 haloalkyl groups include C3 fluorinated alkyl groups. 1- C3 alkoxy group.

[0138] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring structure having a specified number of ring atoms, wherein the cycloalkyl group is preferably C16-26-3 ... 3- C8 cycloalkyl, the C 3- C8 cycloalkyl groups are C3, C4, C5, C6, C7, or C8 cycloalkyl groups having 3 to 8 carbocyclic members, wherein the C 3- C8 cycloalkyl groups are preferably derived from: C 3- C7 cycloalkyl, C 3- C6 cycloalkyl, C 3- C5 cycloalkyl or C 3- In one embodiment, the cycloalkyl group is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0139] The term "heterocyclic alkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms independently selected from N, O, and S; the number of heteroatoms is 1, 2, 3, or 4; the heterocyclic alkyl group is preferably a 3-10 membered heterocyclic alkyl group; the number of carbon atoms in the 3-10 membered heterocyclic alkyl group is selected from 2, 3, 4, 5, 6, 7, 8, or 9, and the 3-10 membered heterocyclic alkyl group is preferably selected from: 3-9 membered heterocyclic alkyl groups, 3-8 membered heterocyclic alkyl groups, 3-7 membered heterocyclic alkyl groups, 3-6 membered heterocyclic alkyl groups, 3-5 membered heterocyclic alkyl groups, or 3-4 membered heterocyclic alkyl groups. In one embodiment, examples of the heterocyclic alkyl group include, but are not limited to: aziridine propane, ethylene oxide, aziridine butane, oxadiazine, and pyrrolidine. Tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine, diazacycloheptyl, high-piperazinyl, oxaziridine, thiazoyl, 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,6-diaza-spiro[3.3]heptyl. More specific examples of heterocyclic alkyl groups are pyrrolidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirheptanyl, diazaheptanyl, high-piperazinyl, oxazheptanyl, thiazolyl and 2,6-diaza-spiro[3.3]heptyl.

[0140] The term "oxoheterocyclic alkyl" refers to a heterocyclic alkyl group in which one or two carbon atoms are substituted by a bridging oxygen (C=O) group. Examples of such oxoheterocyclic alkyl groups include, but are not limited to: 2- or 3-oxopyrrolidone-1-yl, 2,3- or 4-oxopyridinyl-1-yl, 3-oxomorpholino-4-yl, 2-oxo-piperazinyl-1-yl, 2-oxotetrahydropyran-3-yl, 3-oxothiomorpholino-4-yl, and 2-imidazolium-1-yl. Preferably, the oxoheterocyclic alkyl group is selected from:

[0141] The term "aryl" refers to a set of 6- to 14-membered monocyclic or polycyclic aromatic rings, in which all ring atoms are carbon atoms. Generally, aryl groups are 6-membered monocyclic, 10- to 12-membered bicyclic, or 14-membered fused tricyclic aromatic ring systems. The C4 group used in this paper... A Aryl and C A-BThe aryl group indicates that A and B represent the number of carbon atoms in the ring system. The aryl group is preferably C6-C. 12 Aryl, further preferred: C6-C 10 Aryl, C6-C8 aryl, or C6-C7 aryl; in one embodiment, the aryl group is specifically selected from phenyl, naphthyl, anthraceneyl, phenanthrene, etc.

[0142] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring structure comprising one or more (preferably 1, 2, 3, or 4) heteroatoms independently selected from O, N, and S, and a specified number of carbon atoms. Specifically, the aromatic ring structure may have 5 to 12 ring members. The heteroaryl is preferably a 5- to 12-membered heteroaryl, more preferably a 5- to 10-membered heteroaryl, more preferably a 5- to 8-membered heteroaryl, and most preferably a 5-, 6-, 7-, or 8-membered heteroaryl. The heteroaryl may be, for example, a five- or six-membered monocyclic ring or a fused bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings or, as another example, two fused five-membered rings. Each ring may contain up to four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. The heteroaryl ring typically contains up to four heteroatoms, more typically up to three heteroatoms, and more typically up to two heteroatoms, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl ring (including any amino substituents in the ring) will be less than five.

[0143] Examples of five-membered monocyclic heteroaryl groups include (but are not limited to) pyrrole, furanyl, thiophene, imidazolyl, furazonyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of six-membered monocyclic heteroaryl groups include (but are not limited to) pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include (but are not limited to) imidazothiazolyl and imidazothiazolyl. Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include (but are not limited to) benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolazinyl, purine (e.g., adenine, guanine), indazoleyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl. Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include (but are not limited to) quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cenolinyl, phthalazinyl, naphthidyl, and pteridinyl. The specific heteroaryl group is those heteroaryl groups derived from thienyl, pyrroleyl, benzothienyl, benzofuranyl, indolyl, pyridyl, quinolinyl, imidazolyl, oxazolyl, and pyrazinyl.

[0144] The term "halogen" is selected from F, Cl, Br, or I;

[0145] The term "bridged cycloalkyl" refers to a polycyclic aromatic hydrocarbon group consisting of two non-directly bonded carbon atoms shared by any two rings. It may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C5-C2). 20 Bridged cycloalkyl group. The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 5 to 14 carbon atoms (i.e., a 5 to 14-membered bridged cycloalkyl group), and more preferably a bridged cycloalkyl group having 5 to 10 carbon atoms (i.e., a 5 to 10-membered bridged cycloalkyl group). Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of the "bridged alkyl group" include, but are not limited to: bicyclic [1.1.1]pentyl, bicyclic [2.1.1]hexyl, (1s,4s)-bicyclic [2.2.1]heptyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, (1s,5s)-bicyclic [3.3.1]nonyl, bicyclic [3.3.1]nonyl, bicyclic [2.2.2]octyl, (1r,5r)-bicyclic [3.3.2]decyl, and bicyclic [3.3.2]decyl. Its connection point can be at any position;

[0146] The term "bridged heterocyclic alkyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Examples of the "bridged heterocyclic alkyl" include, but are not limited to:

[0147] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group in which the rings are linked by a common carbon atom (called the spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the spirocycloalkyl group is 5- to 12-membered, and more preferably 5- to 10-membered. Depending on the number of shared spiro atoms, spirocycloalkyl groups are classified as monospirocycloalkyl, dispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or dispirocycloalkyl. Representative examples of monospirocycloalkyl groups include, but are not limited to, the following substituents:

[0148] The term "heterospirocycloalkyl" refers to the aforementioned spirocycloalkyl containing at least one heteroatom selected from O, N, and S, preferably a spirocycloalkyl containing at least one heteroatom of O or N, preferably a 5-12-membered heterospirocycloalkyl, more preferably a 5-9-membered heterospirocycloalkyl, in some embodiments the heterospirocycloalkyl is selected from 5-12-membered nitrogen-containing heterospirocycloalkyl, in other embodiments the heterospirocycloalkyl is selected from 5-9-membered nitrogen-containing heterospirocycloalkyl, wherein representative examples of nitrogen-containing heterospirocycloalkyl include, but are not limited to, the following substituents:

[0149] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0150] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0151] The term "stereoisomer" refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0152] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0153] The term "racemate" refers to a mixture of two equimolar enantiomers that lack optical activity.

[0154] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reactions with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, gluconate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, p-pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and N+(C1-4 alkyl)4 salts. This invention also envisions the formation of quaternary ammonium salts from any compound containing an N-group. Water-soluble, oil-soluble, or dispersed products can be obtained via quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates.

[0155] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. Substances that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; a mixture of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethyl cellulose. Sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0156] The term "excipient" generally refers to the carrier, diluent, and / or medium required to formulate an effective pharmaceutical composition.

[0157] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0158] The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0159] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0160] The atoms in the compounds of this invention are isotopes. Isotope derivatization can typically prolong half-life, reduce clearance rate, stabilize metabolism, and enhance in vivo activity. Furthermore, one embodiment is included, wherein at least one atom is replaced by an atom having the same number of atoms (protons) but different mass numbers (protons and neutrons). Examples of isotopes included in the compounds of this invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each comprising... 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomical examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with quantity and are not radioactive, therefore they can be used safely. When the atoms constituting the compounds of this invention are isotopes, the isotopes can be converted according to common methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0161] For example, the compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0162] Furthermore, one or more hydrogen atoms in the compound of the present invention are coated with the isotope deuterium ( 2 The compounds of this invention, after being substituted with H), have the effects of prolonged half-life, reduced clearance rate, metabolic stabilization, and increased in vivo activity.

[0163] The preparation methods of the isotope derivatives typically include phase-transfer catalysis. For example, a preferred deuteration method employs a phase-transfer catalyst (e.g., tetraalkylammonium salt, NBu4HSO4). Using a phase-transfer catalyst to exchange the methylene protons of a diphenylmethane compound results in the introduction of higher levels of deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with Lewis acids such as aluminum trichloride using sodium deuterated borate.

[0164] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0165] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0166] The advantages of this invention over the prior art include, but are not limited to:

[0167] The RXFP1 receptor agonist analogue of the present invention has a lower EC50 compared with the prior art. 50 value. Attached Figure Description

[0168] 1) Figure 1 shows the effect of compounds 17BC and 24BC of the present invention on renal blood flow in monkeys. Detailed Implementation

[0169] The present invention will be further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0170] Example 1

[0171] Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0172] The specific synthesis route is as follows:

[0173] Step A: Synthesis of ethyl 8-methyl-1,4-dioxaspirin[4,5]decane-8-carboxylate

[0174] At room temperature, ethyl 1,4-dioxaspirin[4.5]decane-8-carboxylate (50 g, 233 mmol) was dissolved in tetrahydrofuran (500 mL), nitrogen gas was purged, the temperature was lowered to -50°C, and lithium diisopropylamino (140 mL, 280 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise. After stirring for 30 minutes, methyl iodoform (38 g, 268 mmol) was added, and the reaction was kept warm and stirred for 4 hours until the reaction was basically complete.

[0175] The reaction was quenched by slowly adding saturated ammonium chloride aqueous solution (500 mL) below -20°C, extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 3 times), dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to obtain 32 g of ethyl 8-methyl-1,4-dioxaspirin[4.5]decane-8-carboxylic acid.

[0176] Step B: Synthesis of 1-methyl-4-oxocyclohexane-1-carboxylic acid

[0177] At room temperature, 32 g (140 mmol) of ethyl 8-methyl-1,4-dioxaspirin[4.5]decane-8-carboxylate was dissolved in 400 mL of ethanol, and 210 mL (2 mol / L) of sodium hydroxide aqueous solution was added. The mixture was heated to 80°C and refluxed overnight until the ethyl carboxylate was substantially hydrolyzed. The mixture was then cooled to 0°C with ice water, and the pH was adjusted to 1-2 with concentrated hydrochloric acid. The mixture was slowly brought to room temperature and stirred for 30 minutes until the reaction was substantially complete.

[0178] Extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 1 time), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 17.5 g of 1-methyl-4-oxocyclohexane-1-carboxylic acid.

[0179] Step C: Synthesis of 1-methyl-4-oxocyclohexane-1-carboxynaphthalene-1-ylmethyl ester

[0180] At room temperature, 1-methyl-4-oxocyclohexane-1-carboxylic acid (17.5 g, 112 mmol) was dissolved in acetonitrile (500 mL), and 1-chloromethylnaphthalene (20.8 g, 118 mmol), sodium iodide (1.65 g, 11 mmol) and potassium carbonate (18.6 g, 134 mmol) were added. The suspension was heated to 60 degrees Celsius and reacted overnight. The reaction was basically complete.

[0181] The reaction mixture was cooled to room temperature, diluted with water (500 mL), extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 29.9 g of 1-methyl-4-oxocyclohexane-1-carboxylic acid naphth-1-ylmethyl ester.

[0182] Step D: Synthesis of naphth-1-ylmethyl(1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid ester

[0183] At room temperature, 29.9 g (101 mmol) of 1-methyl-4-oxocyclohexane-1-carboxynaphthalene-1-ylmethyl ester was dissolved in tetrahydrofuran (300 mL), water (300 mL) was added, and sodium borohydride (3.8 g (101 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour until the reaction was complete.

[0184] The mixture was cooled to 0°C with ice water, quenched with 1 mol / L dilute hydrochloric acid, extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 27 g of racemic product. The product was slurried twice with 150 mL (ethyl acetate / n-hexane = 1 / 10), the solid was filtered off, and the mother liquor was concentrated to give 10.8 g of oily naphth-1-ylmethyl(1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid ester. The solid was another isomer.

[0185] Step E: Synthesis of methyl 3,4-difluoro-2-methoxybenzoate

[0186] At room temperature, 20 g of 3,4-difluoro-2-hydroxybenzoic acid (115 mmol) was dissolved in 500 mL of N,N-dimethylformamide, and potassium carbonate (40 g, 288 mmol) and iodomethane (49 g, 345 mmol) were added. The suspension was heated to 60°C and reacted overnight. The reaction was monitored by TLC and found to be almost complete.

[0187] The reaction mixture was cooled to room temperature, diluted with water (800 mL), extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 15.1 g of methyl 3,4-difluoro-2-methoxybenzoate.

[0188] Step F: Synthesis of methyl 3,4-difluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate

[0189] At room temperature, methyl 3,4-difluoro-2-methoxybenzoate (15.1 g, 75 mmol) was dissolved in 2-methyltetrahydrofuran (500 mL), and pinacol diboronate (21 g, 83 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1 g, 3.8 mmol) and methoxy(cyclooctadiene)iridium dimer (1.2 g, 1.9 mmol) were added. The mixture was purged with nitrogen three times and heated to reflux for 5 hours until the reaction was substantially complete.

[0190] The reaction mixture was cooled to room temperature, diluted with water (500 mL), extracted with ethyl acetate (500 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 6) to give 18.5 g of methyl 3,4-difluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate.

[0191] Step G: Synthesis of methyl 3,4-difluoro-5-hydroxy-2-methoxybenzoate

[0192] At room temperature, methyl 3,4-difluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzoate (18.5 g, 56 mmol) was dissolved in 2-methyltetrahydrofuran (200 mL), acetic acid (10.1 g, 169 mmol) was added, the mixture was cooled to 0–5°C with ice water, and an aqueous solution of hydrogen peroxide (7.65 g, 67.5 mmol, 30% by mass) was added dropwise. The mixture was slowly heated to room temperature and allowed to react overnight until the reaction was essentially complete.

[0193] The reaction was quenched by adding saturated sodium thiosulfate aqueous solution (100 mL), extracted with ethyl acetate (200 mL × 2 times), the organic phases were combined, washed with saturated brine (300 mL × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5) to give 10.4 g of methyl 3,4-difluoro-5-hydroxy-2-methoxybenzoate.

[0194] Step H: Synthesis of methyl 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphth-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

[0195] At room temperature, 10 g (33.5 mmol) of naphth-1-ylmethyl(1r,4r)-4-hydroxy-1-methylcyclohexane-1-carboxylic acid ester was dissolved in tetrahydrofuran (300 mL), methyl 3,4-difluoro-5-hydroxy-2-methoxybenzoate (9.5 g, 43.6 mmol) and triphenylphosphine (13.2 g, 50.3 mmol) were added, the mixture was cooled to 0–5 °C with ice water, and diisopropyl azodicarbonate (10.2 g, 50.3 mmol) was added dropwise. The mixture was slowly heated to room temperature and stirred for 3 hours. The reaction was monitored by TLC until it was substantially complete.

[0196] The solvent was replaced with ethyl acetate, concentrated, and the white solid was filtered off. The mother liquor was concentrated, and the crude product was purified by column chromatography (eluent: dichloromethane / n-hexane = 1 / 2) to give 6.7 g of methyl 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphth-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate.

[0197] Step I: Synthesis of 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphth-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

[0198] At room temperature, methyl 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthyl-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate (6.7 g, 13.4 mmol) was dissolved in tetrahydrofuran (100 mL), and lithium hydroxide aqueous solution (0.96 g, 40.2 mmol, dissolved in 100 mL of water) was added. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by TLC to be essentially complete.

[0199] Adjust the pH to 3-4 with 1 mol / L dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2 times), combine the organic phases, wash with saturated brine (100 mL × 2 times), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 5.5 g of 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphth-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid.

[0200] Step J: Synthesis of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0201] At room temperature, 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthyl-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (5.5 g, 11.4 mmol) was dissolved in dichloromethane (50 mL), and (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester (2.3 g, 13.7 mmol) and N,N-diisopropylethylamine (7.4 g, 56.9 mmol) were added. The mixture was cooled to 0–5°C with ice water, and 1-n-propylphosphonic anhydride (21.7 g, 34.2 mmol, 50% ethyl acetate solution) was added dropwise. The mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC and found to be essentially complete.

[0202] The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (50 mL × 2 times), the organic phases were combined, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 6.1 g of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester was obtained.

[0203] Step K: Synthesis of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

[0204] At room temperature, methyl (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (6.1 g, 9.7 mmol) was dissolved in tetrahydrofuran (50 mL), and an aqueous solution of lithium hydroxide (0.7 g, 29.1 mmol, dissolved in 100 mL of water) was added. The mixture was stirred at room temperature for 5 hours, and the reaction was monitored by TLC to be essentially complete.

[0205] Adjust the pH to 3-4 with 1 mol / L dilute hydrochloric acid, extract with ethyl acetate (100 mL × 2 times), combine the organic phases, wash with saturated brine (100 mL × 2 times), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 4.8 g of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

[0206] Step L: Synthesis of naphth-1-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0207] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1 g, 1.6 mmol) was dissolved in dichloromethane (20 mL), and (1-methylcyclobutyl)methylamine hydrochloride (0.28 g, 2.1 mmol) and N,N-diisopropylethylamine (1 g, 8 mmol) were added. The mixture was cooled to 0–5°C with ice water, and 1-n-propylphosphonic anhydride (3 g, 4.8 mmol, 50% ethyl acetate solution) was added dropwise. The mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC and found to be essentially complete.

[0208] The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2 times), the organic phases were combined, washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 0.78 g of naphth-1-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0209] Step M: Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0210] At room temperature, 0.78 g (1.12 mmol) of naphth-1-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (20 mL), wet palladium / carbon (0.2 g, 10% palladium / 55% water) was added, and hydrogen gas was introduced. The reaction was carried out at room temperature for 15 hours, and the reaction was monitored by LC-MS until the reaction was complete.

[0211] Palladium / carbon was filtered off, the sample was washed with ethanol (10 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.67 g of the product (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.17 min, [M+H] + =563.04.

[0212] NMR data for compound 7B: 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=8.4Hz,1H),7.98(t,J=6.0Hz,1H),7.39(dd,J=9.1,2.1 Hz,1H),4.33(tt,J=9.6,4.2Hz,1H),4.16(t,J=8.4Hz,1H),3.94(d,J=1.5Hz,3H),3.10-2 .97(m,2H),2.67(d,J=8.4Hz,1H),2.26(d,J=3.5Hz,1H),2.15-2.04(m,4H),1.99-1.88(m ,2H),1.82-1.65(m,3H),1.58-1.39(m,6H),1.37-1.16(m,6H),1.14(s,3H),0.96(s,3H).

[0213] Example 2

[0214] Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0215] The specific synthesis route is as follows:

[0216] Step A: Synthesis of (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

[0217] At room temperature, norborneol olefinic anhydride (1.64 g, 10.0 mmol) was dissolved in anhydrous diethyl ether (100 mL), and hydrogenated quinidine (anthraquinone-1,4-diyl) diether (0.85 g, 1.0 mmol) was added. The mixture was cooled to -30°C, and methanol (3.2 g, 100.0 mmol) was slowly added dropwise. The mixture was kept at this temperature and stirred for 48 hours until the reaction was essentially complete.

[0218] Add 60 mL of 1 mol / L dilute hydrochloric acid aqueous solution, extract with ethyl acetate (200 mL × 2 times), combine the organic phases, wash with saturated brine (100 mL × 3 times), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to give 1.6 g of (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

[0219] This synthetic method is referenced in A Highly Enantioselective Catalytic Desymmetrization of Cyclic Anhydrides with Modified Cinchona Alkaloids, J. Am. Chem. Soc. 2000, 122, 9542-9543.

[0220] Step B: Synthesis of (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0221] At room temperature, (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (20 g, 100 mmol) was added to toluene (500 mL), and N,N-diisopropylethylamine (15.5 g, 120 mmol) was slowly added. The mixture was cooled to 0-5 degrees Celsius with ice water, and diphenyl azidophosphate (27.5 g, 100 mmol) was slowly added dropwise. The mixture was then slowly brought to room temperature and allowed to react overnight. The reaction was monitored by TLC and found to be essentially complete.

[0222] Wash with saturated citric acid aqueous solution (200 mL × 2 times), 1 mol / L sodium hydroxide aqueous solution (200 mL × 2 times), saturated brine (200 mL × 1 time), dry with anhydrous sodium sulfate, filter to obtain toluene solution, add benzyl alcohol (21.6 g, 200 mmol), heat to 90 degrees and react for 3 hours until the reaction is basically complete.

[0223] The solution was slowly cooled to room temperature, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 18 g of (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-en-2-carboxylic acid methyl ester, LC-MS: RT = 1.82 min, [M+H] + =302.1.

[0224] Step C: Synthesis of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0225] At room temperature, methyl (18 g, 60 mmol) of (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid was dissolved in methanol (300 mL), wet palladium / carbon (1.8 g, 10% palladium / 55% water) was added, and hydrogen gas was introduced. The reaction was carried out at room temperature for 15 hours until the reaction was complete.

[0226] Palladium / carbon was filtered off, followed by rinsing with methanol (50 mL), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: methanol / dichloromethane = 1 / 9) to give 9.1 g of the oily product (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester. LC-MS: RT = 0.4 min, [M+H] + =170.15.

[0227] Step D: Synthesis of (1S,2S,3R4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0228] At room temperature, 5 g (10.3 mmol) of 3,4-difluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthyl-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid and 2.7 g (16.0 mmol) of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester were dissolved in dichloromethane (100 mL), N,N-diisopropylethylamine (6.9 g (53.5 mmol)) was added, the temperature was lowered to 0°C, propylphosphonic anhydride (13.6 g (21.4 mmol, 50% ethyl acetate solution) was added, the temperature was slowly raised to room temperature, and the reaction was stirred for 1 hour. The reaction was monitored by TLC until it was complete.

[0229] The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 2 times), the organic phases were combined, washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 5.2 g of (1S,2S,3R4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester was obtained.

[0230] Step E: Synthesis of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzoylamino)bicyclo[2.2.1]heptane-2-carboxylic acid

[0231] At room temperature, methyl (1S,2S,3R4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthyl-2-methoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (5.2 g, 8.2 mmol) was dissolved in tetrahydrofuran (100 mL), and an aqueous solution of lithium hydroxide (1.16 g, 48.6 mmol) (200 mL) was added. The mixture was stirred at room temperature for 15 hours, and the reaction was monitored by TLC until the reaction was complete.

[0232] Most of the tetrahydrofuran was concentrated, the pH was adjusted to 4-5 with 1 mol / L dilute hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100 mL × 2 times). The organic phases were combined, washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 3.6 g of (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzoylamino)bicyclo[2.2.1]heptane-2-carboxylic acid was obtained.

[0233] Step F: Synthesis of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0234] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthyl-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzoylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (0.5 g, 0.8 mmol) and (1-methylspiro[2.2]pentane-1-yl)methylamine hydrochloride (130 mg, 0.96 mmol) were dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (0.52 g, 4 mmol) was added, the temperature was lowered to 0°C, propylphosphohydrin (1.53 g, 2.4 mmol, 50% ethyl acetate solution) was added, the temperature was slowly raised to room temperature, and the reaction was stirred for 2 hours. The reaction was monitored by TLC until it was complete.

[0235] The reaction mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL × 2 times), the organic phases were combined, washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 0.39 g of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0236] Step G: Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0237] At room temperature, 0.39 g (0.56 mmol) of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (10 mL), wet palladium / carbon (50 mg, 10% palladium / 55% water) was added, the mixture was substituted and hydrogen gas was introduced, and the reaction was carried out at room temperature for 3 hours. The reaction was monitored by LC-MS until it was complete.

[0238] Palladium / carbon was filtered off, the sample was washed with ethanol (10 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.22 g of the product (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.18 min, [M+H] + =563.02.

[0239] NMR data for compound 7A: 1 H NMR (400MHz, DMSO-d6) 1H NMR (400MHz, DMSO-d6) δ12.33 (bs, 1H), δ9.74 (d, J = 7.1Hz, 1H), 8.08 (s, 1H), 7.42 (dd, J = 9. 1,2.1Hz,1H),4.33(ddd,J=14.7,8.1,4.3Hz,2H),3.98(d,J=1.5Hz,3H),3.20(dd,J=13.3, 6.6Hz,1H),3.02-2.88(m,2H),2.45(d,J=18.5Hz,2H),2.08(d,J=13.4Hz,2H),1.98-1.89( m,2H),1.87-1.69(m,5H),1.63-1.51(m,4H),1.47-1.28(m,7H),1.13(s,3H),1.03(s,3H).

[0240] Example 3

[0241] Synthesize (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0242] The specific synthesis route is as follows:

[0243] Step A: Synthesis of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0244] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1 g, 1.6 mmol) and (1-methylspiro[2.2]pentan-1-yl)methylamine (0.27 g, 2.4 mmol) were dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (0.65 g, 8 mmol) was added. The mixture was cooled to 0°C, and propylphosphohydrin (3 g, 4.8 mmol, 50% ethyl acetate solution) was added. The mixture was slowly heated to room temperature and stirred for 2 hours. The reaction was monitored by LC-MS until complete.

[0245] The reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 mL × 2 times), the organic phases were combined, washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 0.8 g of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0246] Step B: Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0247] At room temperature, 0.8 g (1.1 mmol) of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (20 mL), and wet palladium / carbon (50 mg, 10% palladium / 55% water) was added to replace the ester and hydrogen gas was introduced. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored by LC-MS until the reaction was complete.

[0248] Palladium / carbon was filtered off, the mixture was washed with ethanol (10 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.39 g of the product (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.17 min, [M+H] + =575.04.

[0249] NMR data for compound 9B: 1H NMR (400MHz, DMSO-d6) δ8.71(dd,J=8.4,3.4Hz,1H),7.94(q,J=5.3Hz,1H),7.39(ddd,J=9.1,5.0,2.1Hz,1H),4.33(dt, J=9.8,5.4Hz,1H),4.15(t,J=8.3Hz,1H),3.94(d,J=3.0Hz,3H),3.12-2.89(m,2H),2.65(d,J=8.4Hz,1H),2.25(d,J=3. 7Hz,1H),2.08(dd,J=21.5,8.1Hz,4H),1.92(dt,J=12.6,4.1Hz,2H),1.47(ddq,J=18.4,9.1,5.0,4.1Hz,4H),1.33-1.1 9(m,5H),1.13(s,3H),0.92(d,J=5.6Hz,3H),0.82-0.77(m,1H),0.76-0.68(m,1H),0.58(ddd,J=12.7,10.5,5.4Hz,4H).

[0250] Example 4

[0251] Synthesis of (1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (compound 17A)

[0252] Step A: Synthesis of (S)-2-(benzylamino)-3,3-dimethylbut-1-ol

[0253] At room temperature, (S)-2-amino-3,3-dimethylbut-1-ol (10.3 g, 100.0 mmol) was dissolved in 1,2-dichloroethane (200 mL), and benzaldehyde (11.7 g, 110.0 mmol) was added. After stirring at room temperature for 30 minutes, sodium borohydride (4.2 g, 11.0 mmol) was slowly added, and the reaction was carried out at room temperature for 15 hours until the reaction was basically complete.

[0254] The mixture was cooled to 0 degrees Celsius with ice water, and the reaction was quenched by adding 50 mL of 1 mol / L dilute hydrochloric acid solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1) to give 12 g of (S)-2-(benzylamino)-3,3-dimethylbut-1-ol.

[0255] Step B: Synthesis of (4S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline-2-oxide

[0256] At room temperature, (S)-2-(benzylamino)-3,3-dimethylbut-1-ol (12 g, 57.9 mmol) was added to dichloromethane (200 mL), followed by the slow addition of N,N-diisopropylethylamine (16.4 g, 127 mmol). The mixture was cooled to 0-5°C with ice water, and then thionyl chloride (7.6 g, 63.7 mmol) was slowly added. The mixture was then slowly brought to room temperature and allowed to react overnight. TLC monitoring showed that the reaction was essentially complete.

[0257] Dilute with water (200 mL), separate the organic phase, wash with saturated brine (200 mL × 1 time), dry with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2) to give 13 g of (4S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline-2-oxide.

[0258] Step C: Synthesis of (S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline 2,2-dioxide

[0259] At room temperature, (4S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline-2-oxide (13 g, 36.8 mmol) was dissolved in acetonitrile (200 mL), water (200 mL) was added, along with ruthenium trichloride (0.65 g, 1.8 mmol) and sodium periodate (11.9 g, 55.2 mmol). The reaction was carried out at room temperature for 15 hours until the reaction was complete.

[0260] Extracted with ethyl acetate (200 mL × 2 times), the organic phases were combined, washed with saturated brine (200 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2). 12 g of (S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline 2,2-dioxide was obtained.

[0261] Step D: Synthesis of (S)-N-benzyl-1-fluoro-3,3-dimethylbut-2-amine

[0262] At room temperature, (S)-3-benzyl-4-(tert-butyl)-1,2,3-oxathiazoline 2,2-dioxide (12 g, 44.6 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0-5°C with ice water, and tetrabutylammonium fluoride (14 g, 44.6 mmol) was added. The mixture was slowly heated to room temperature and reacted overnight. The solvent tetrahydrofuran was removed by vacuum distillation, and the oily residue was dissolved in diethyl ether (200 mL). 20% sulfuric acid aqueous solution (50 mL) was added, and the mixture was stirred at room temperature for 3 hours until the reaction was substantially complete.

[0263] The reaction mixture was cooled to 0-5°C with ice water, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL × 2 times). The organic phases were combined, washed with saturated brine (100 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2). 7 g of (S)-N-benzyl-1-fluoro-3,3-dimethylbut-2-amine was obtained.

[0264] Step E: Synthesis of (S)-1-fluoro-3,3-dimethylbut-2-amine hydrochloride

[0265] (S)-N-benzyl-1-fluoro-3,3-dimethylbut-2-amine (7 g, 33.4 mmol) was dissolved in methanol (100 mL) at room temperature, and wet palladium / carbon (700 mg, 10% palladium / 55% water) was added to replace the precipitate and hydrogen gas was introduced. The reaction was carried out at room temperature for 24 hours, and TLC was monitored until the reaction was complete.

[0266] Palladium / carbon was filtered off, and the mixture was rinsed with methanol (20 mL). A solution of dioxane chloride (10 mL, 4 mol / L) was added, and a white solid precipitated. The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (20 mL). The cake was dried under vacuum at 50 °C to obtain 5 g of (S)-1-fluoro-3,3-dimethylbut-2-amine hydrochloride.

[0267] Step F: Synthesis of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0268] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthyl-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzoylamino)bicyclo[2.2.1]heptane-2-carboxylic acid (0.5 g, 0.8 mmol) and (S)-1-fluoro-3,3-dimethylbut-2-amine hydrochloride (149 mg, 0.96 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (0.52 g, 4 mmol) was added. The mixture was cooled to 0°C, and propylphosphoanhydride (1.53 g, 2.4 mmol, 50% ethyl acetate solution) was added. The mixture was slowly heated to room temperature and stirred for 2 hours. The reaction was monitored by TLC until complete.

[0269] The reaction mixture was diluted with water (20 mL), extracted with dichloromethane (20 mL × 2 times), the organic phases were combined, washed with saturated brine (20 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 0.41 g of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0270] Step G: Synthesis of (1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0271] At room temperature, 0.41 g (0.57 mmol) of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (10 mL), wet palladium / carbon (50 mg, 10% palladium / 55% water) was added, the mixture was substituted and hydrogen gas was introduced, and the reaction was carried out at room temperature for 3 hours. The reaction was monitored by LC-MS until it was complete.

[0272] Palladium / carbon was filtered off, the sample was washed with ethanol (10 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.15 g of the product (1S,4S)-4-(2,3-difluoro-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.7 min, [MH] - =581.09.

[0273] NMR data for compound 17A: 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),9.78(d,J=7.0Hz,1H),8.11(d,J=9.6Hz,1H),7.41(dd,J=9. 1,2.1Hz,1H),4.56(ddd,J=46.7,9.6,3.7Hz,1H),4.43-4.24(m,3H),4.02-3.87(m,4H),3.00(dd,J =11.0,4.2Hz,1H),2.47(d,J=12.6Hz,2H),2.08(d,J=12.9Hz,2H),2.00-1.87(m,2H),1.72-1.53( m,3H),1.44(ddd,J=19.6,14.7,9.5Hz,3H),1.32(tt,J=9.4,4.7Hz,4H),1.13(s,3H),0.90(s,9H).

[0274] Example 5

[0275] Synthesis of (1S,4S)-4-(2,3-difluoro-5-((1S,2R,3S,4R)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid (compound 17B)

[0276] (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy) was prepared according to the method of Example 1.

[0277] (S)-1-fluoro-3,3-dimethylbut-2-amine hydrochloride was prepared by the method described in Example 4. (2.2.1)-benzamido(2,2.1)-5-en-2-carboxylic acid.

[0278] Step A: Synthesis of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0279] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1 g, 1.6 mmol) was dissolved in dichloromethane (20 mL), and (S)-1-fluoro-3,3-dimethylbut-2-amine hydrochloride (0.30 g, 1.92 mmol) and N,N-diisopropylethylamine (1 g, 8 mmol) were added. The mixture was cooled to 0–5°C with ice water, and 1-n-propylphosphonic anhydride (3 g, 4.8 mmol, 50% ethyl acetate solution) was added dropwise. The mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC and found to be essentially complete.

[0280] The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2 times), the organic phases were combined, washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 0.92 g of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(neopentamino)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0281] Step B: Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0282] At room temperature, 0.92 g (1.28 mmol) of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (30 mL), and wet palladium / carbon (100 mg, 10% palladium / 55% water) was added to replace the ester and hydrogen gas was introduced. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored by LC-MS until the reaction was complete.

[0283] Palladium / carbon was filtered off, the sample was washed with ethanol (20 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.44 g of the product (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: [MH]- = 581.09, RT = 2.7 min.

[0284] NMR data for compound 17B: 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=8.2Hz,1H),8.06(d,J=9.5Hz,1H),7.39(dd,J=9.1,2.1Hz,1H),4.52-4.10(m,4H),3.96-3.81(m,4 H),2.76(d,J=8.4Hz,1H),2.14-2.01(m,4H),1.93(d,J=12.5Hz,2H),1.62-1.44(m,4H),1.36-1.16(m,6H),1.13(s,3H),0.90(s,9H).

[0285] Example 6

[0286] Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0287] Step A: Synthesis of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(neopentamino)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester

[0288] At room temperature, (1S,2S,3R,4R)-3-(3,4-difluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphth-1-ylmethoxy)carbonylcyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1 g, 1.6 mmol) was dissolved in dichloromethane (20 mL), and pentylamine (0.18 g, 2.1 mmol) and N,N-diisopropylethylamine (1 g, 8 mmol) were added. The mixture was cooled to 0–5°C with ice water, and 1-n-propylphosphonic anhydride (3 g, 4.8 mmol, 50% ethyl acetate solution) was added dropwise. The mixture was slowly heated to room temperature and stirred for 1 hour. The reaction was monitored by TLC and found to be essentially complete.

[0289] The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2 times), the organic phases were combined, washed with saturated brine (50 mL × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5). 1.0 g of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(neopentamino)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was obtained.

[0290] Step B: Synthesis of (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0291] At room temperature, 1.0 g (1.12 mmol) of naphth-2-ylmethyl(1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(neopentamino)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid ester was dissolved in ethanol (30 mL), and wet palladium / carbon (100 mg, 10% palladium / 55% water) was added to replace the ester and hydrogen gas was introduced. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored by LC-MS until the reaction was complete.

[0292] Palladium / carbon was filtered off, the sample was washed with ethanol (20 mL), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to give 0.34 g of the product (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.21 min, [M+H] +=551.13.

[0293] NMR data for compound 24B: 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=8.3Hz,1H),7.92(t,J=6.2Hz,1H),7.38(dd,J=9.1,2.1Hz,1 H),4.33(tt,J=9.5,4.1Hz,1H),4.15(t,J=8.3Hz,1H),3.94(d,J=1.5Hz,3H),2.90(dd,J=13.0, 6.3Hz,1H),2.81(dd,J=13.1,6.1Hz,1H),2.70(d,J=8.4Hz,1H),2.26(d,J=3.6Hz,1H),2.17-2 .00(m,4H),1.99-1.87(m,2H),1.63-1.38(m,4H),1.38-1.16(m,5H),1.14(s,3H),0.77(s,9H).

[0294] Example 7

[0295] Compounds 1, 3-6, 7BD, 8-16, 18-22, 24BD, 28, 30-32, 36-44, their isomers, and deuterated compounds were prepared according to the methods in Examples 1, 2, 3-6, and Patent Publication No. CN116547270A. The structural and characterization data (mass spectrometry and liquid chromatography retention times) of the compounds are as follows:

[0296] NMR data for compound 19: 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=8.7Hz,1H),7.36(dd,J=9.0,2.1Hz,1H),4.33(tt,J=9.7,4.1Hz,1 H),4.23(t,J=8.5Hz,1H),4.10(q,J=8.6Hz,2H),3.94(d,J=1.4Hz,3H),3.76(d,J=9.9Hz,1H),3.59( d,J=9.9Hz,1H),2.56(s,1H),2.27(d,J=3.7Hz,1H),2.14-2.05(m,5H),1.96(tdd,J=13.6,9.3,3.8H z,4H),1.88-1.79(m,1H),1.72(p,J=7.5Hz,2H),1.60-1.40(m,4H),1.34-1.19(m,5H),1.14(s,3H).

[0297] NMR data for compound 20: 1 H NMR(400MHz,DMSO d6)δ8.71(d,J=8.3Hz,1H),7.99(t,J=5.8Hz,1H),7.38(dd,J=9.1,2.1Hz,1H),4.33(dt,J=9 .8,5.2Hz,1H),4.14(t,J=8.4Hz,1H),3.93(d,J=1.4Hz,3H),3.13-3.00(m,2H),2.62(d,J=8 .4Hz,1H),2.36(s,1H),2.24(d,J=3.6Hz,1H),2.07(ddd,J=29.2,12.2,6.9Hz,4H),1.98-1. 85(m,2H),1.55(s,7H),1.46(ddt,J=12.5,6.4,3.0Hz,2H),1.34-1.15(m,6H),1.13(s,3H).

[0298] NMR data for compound 30: 1 H NMR(400MHz,DMSO d6)δ8.42(d,J=8.3Hz,1H),7.73(t,J=5.9Hz,1H),7.08(dd,J=9.1,2.1Hz,1H),4.02(dt,J=9.9 ,5.4Hz,1H),3.84(t,J=8.4Hz,1H),3.63(d,J=1.5Hz,3H),2.62(qd,J=13.5,5.8Hz,2H),2.33(d ,J=8.4Hz,1H),1.94(d,J=3.6Hz,1H),1.85-1.68(m,4H),1.61(d,J=12.4Hz,2H),1.30-1.06(m ,4H),1.03-0.85(m,5H),0.82(s,3H),0.59(s,3H),0.00(q,J=2.9Hz,2H),-0.13--0.26(m,2H).

[0299] NMR data for compound 31: 1H NMR (400MHz, DMSO) d6)δ8.69(d,J=8.4Hz,1H),8.08(t,J=6.1Hz,1H),7.39(dd,J=9.1,2.1Hz,1H),4 .32(d,J=10.1Hz,2H),4.18(d,J=6.4Hz,2H),3.95(d,J=1.5Hz,3H),3.23-3.10( m,2H),2.66(d,J=8.4Hz,1H),2.27(d,J=3.6Hz,1H),2.15-2.02(m,4H),1.99-1. 88(m,2H),1.76-1.64(m,6H),1.59-1.40(m,4H),1.36-1.18(m,5H),1.14(s,3H).

[0300] NMR data for compound 32: 1 H NMR(400MHz,DMSO d6)δ8.45(d,J=8.6Hz,1H),7.35(dd,J=9.1,2.1Hz,1H),4.48-4.12(m,4H),4.00-3.84(m,4H),3.68(d,J=10.1Hz,1H),2.83- 2.52(m,5H),2.27(d,J=3.8Hz,1H),2.17-2.02(m,3H),2.00-1.85(m,3H),1.61-1.37(m,4H),1.35-1.17(m,5H),1.12(s,3H).

[0301] Example 8

[0302] Synthesis of sodium (1S,4S)-4-(2,3-difluoro-5-((1S,2R,3S,4R)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0303] At room temperature, purified (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid (1.0 g, 1.71 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydroxide (68.4 mg, 1.71 mmol) was added. The aqueous solution (30 mL) was stirred at room temperature for 0.5 hours, and then the tetrahydrofuran was evaporated under reduced pressure. The solution was then freeze-dried at -80°C to obtain sodium (1S,4S)-4-(2,3-difluoro-5-((1S,2R,3S,4R)-3-((S)-1-fluoro-3,3-dimethylbut-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: [MH] - =581.09,RT=2.7min.

[0304] Compound NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=8.1Hz,1H),8.12(d,J=9.5Hz,1H),7.35(dd,J=9.1,2.1Hz ,1H),4.39-4.29(m,1H),4.26-4.11(m,3H),3.90(d,J=1.3Hz,4H),2.77(d,J=8.4Hz,1H),2.2 6(d,J=3.5Hz,1H),2.14(dd,J=12.4,8.1Hz,3H),2.03(d,J=10.0Hz,1H),1.87-1.74(m,2H),1 .69-1.43(m,4H),1.31-1.14(m,3H),1.03(td,J=12.9,3.6Hz,2H),0.97(s,3H),0.90(s,9H).

[0305] Example 9

[0306] Synthesis of sodium (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0307] At room temperature, (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid (1.0 g, 1.81 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium hydroxide (72.4 mg, 1 mL) was added. An aqueous solution (30 mL) of 81 mmol was stirred at room temperature for 0.5 hours, and the tetrahydrofuran was evaporated under reduced pressure. The solution was then freeze-dried at -80°C to obtain sodium (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 2.21 min, [M+H] + =551.13.

[0308] Compound NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=8.3Hz,1H),7.95(t,J=6.2Hz,1H),7.34(dd,J=9.1,2.1Hz,1H),4.18(dt, J=16.4,6.6Hz,2H),3.93(d,J=1.4Hz,3H),2.90(dd,J=13.0,6.3Hz,1H),2.81(dd,J=13.0,6.1Hz,1H),2.71( d,J=8.4Hz,1H),2.25(d,J=3.6Hz,1H),2.15(dt,J=12.9,3.5Hz,3H),2.04(d,J=9.9Hz,1H),1.79(dd,J=12. 3,4.6Hz,2H),1.66-1.46(m,4H),1.21(dt,J=13.2,9.1Hz,3H),1.06-0.98(m,2H),0.96(s,3H),0.76(s,9H).

[0309] Example 10

[0310] Synthesis of potassium (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylate

[0311] At room temperature, (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid (1.0 g, 1.81 mmol) was dissolved in tetrahydrofuran (30 mL), and potassium hydroxide (101.4 mg, 1 mL) was added. A 30 mL aqueous solution of 0.81 mmol was stirred at room temperature for 0.5 hours, and the tetrahydrofuran was evaporated under reduced pressure. The solution was then freeze-dried at -80°C to obtain potassium (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 2.21 min, [M+H] + =551.13.

[0312] Example 11

[0313] Synthesis of calcium (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylate

[0314] At room temperature, (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid (1.0 g, 1.81 mmol) was dissolved in tetrahydrofuran (30 mL), and calcium hydroxide (67.05 mg, 0. A 905 mmol aqueous solution (30 mL) was stirred at room temperature for 0.5 hours, and the tetrahydrofuran was evaporated under reduced pressure. The solution was then freeze-dried at -80°C to obtain (1S,4S)-4-(2,3-difluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(neopentylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid calcium. LC-MS: RT = 2.21 min, [M+H] + =551.13.

[0315] Example 12

[0316] Compounds 17AC and 24AC were prepared according to the methods described in Examples 8-11 and Patent Publication No. CN116547270A. The structural and characterization data (mass spectrometry and liquid chromatography retention times) of the compounds are as follows:

[0317] Experiment 13: In vitro activity test of RXFP1 receptor modulator in humans

[0318] This experiment used the CHO-K1 cell line stably transfected with the human RXFP1 receptor, and evaluated the activity of compounds by detecting the cAMP produced after stimulating the RXFP1 receptor coupled with Gs protein.

[0319] Main reagents: cAMP detection kit (Cisbio), 1M HEPES (Invitrogen), HBSS (Invitrogen), BSA (Sigma), IBMX (Sigma).

[0320] Test procedure:

[0321] (1) Compound preparation: The test compound was dissolved in DMSO and diluted 4 times to 10 concentration gradients. 250 nL of each concentration was transferred to the test plate (OptiPlate-384 well plate) using Echo.

[0322] (2) Test buffer: 1X stimulation buffer, 500μM IBMX, deionized water;

[0323] (3) Cell preparation: After thawing the frozen cells (RXFP1 cAMP cells), wash them twice with HBSS and then resuspend them in stimulation buffer.

[0324] (4) Add 10 μL of cell suspension containing 10,000 cells to each well of the test plate, centrifuge at 1000 rpm for 5 seconds, and then incubate at 37°C for 60 minutes.

[0325] (5) Add 10 μL of detection reagent to each well of the test plate, centrifuge at 1000 rpm for 5 seconds, and incubate at 23°C for 60 minutes;

[0326] (6) Use an EnVision microplate reader to read the plate.

[0327] Data Analysis: The response values ​​for each concentration were calculated using the following formula, and then curve fitting was performed using Graphpad software to obtain the EC50 values. 50 value.

[0328] %Effect=100×(Sample Raw Value-Low Control Average) / (High Control Average-Low Control Average)

[0329] Table 1. Data on human RXFP1 receptor agonist activity assay

[0330] The structural formula of Example 1 in CN116547270A is:

[0331] The structural formula of Example 36 in CN116547270A is:

[0332] As can be seen from the data in Table 1, the compounds of the present invention have excellent agonistic activity against the RXFP1 receptor and are significantly superior to the molecules in Examples 1 and 36 of Patent CN116547270A.

[0333] Example 14: Pharmacokinetic Study of Compound in Rat

[0334] 14.1 Experimental Materials

[0335] SD rats: male, 180-250g, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd.

[0336] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0337] Instrument: AB SCIEX QTRAP 5500+.

[0338] 14.2 Experimental Methods

[0339] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or gavage administration to rats, 200 μL of venous blood was collected in EDTA-K2 anticoagulant tubes at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, and 24 h (an additional 5 min for the IV group). The blood was centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test sample was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipetted and added to 90 μL of blank plasma. The mixture was vortexed to prepare plasma samples with concentrations equivalent to 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold at 5 min, 15 min, and 30 min after intravenous administration), add 150 μL of propranolol (50 ng / mL) in acetonitrile solution, vortex to mix, add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and collect the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0340] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0341] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0342] 14.3 Data Processing

[0343] After LC-MS detection of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The test results are shown in Table 2.

[0344] Table 2: Pharmacokinetics of the compounds of the present invention in rats Note: " / " indicates that it has not been tested.

[0345] The structural formula of Example 35 in CN116547270A is:

[0346] As shown in Table 2, the compounds of this invention all exhibit good pharmacokinetic characteristics in SD rats, with low exposure levels and low C60 levels. max It has a high value, high bioavailability, good absorption, and low exposure and C. max The values ​​are significantly better than those of the molecules in Examples 1 and 35 of Patent CN116547270A.

[0347] Example 15: Pharmacokinetic Study of Compound in Beagle Dogs

[0348] 15.1 Experimental Materials

[0349] Beagle: Male, 8-13kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0350] Reagents: physiological saline, EDTA-2K, acetonitrile, methanol, formic acid, and propranolol (internal standard) are all commercially available.

[0351] Instrument: AB SCIEX QTRAP 5500+

[0352] 15.2 Experimental Methods

[0353] The compound was dissolved in a DMSO-PEG-400-physiological saline (5:60:35, v / v / v) system. After intravenous or gavage administration to beagle dogs, 200 μL of venous blood was collected in EDTA-K2 anticoagulant EP tubes at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h (an additional 5 min for the IV group). The blood was centrifuged at 12000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A precise amount of the test substance was dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the test substance stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 10 μL of each of the above standard solutions was accurately pipetted and added to 90 μL of blank plasma. The mixture was vortexed to prepare plasma samples equivalent to concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. Two samples were analyzed for each concentration to establish a standard curve. Take 30 μL of plasma (diluted 5-fold at 5 min, 15 min, and 30 min after intravenous administration), add 150 μL of propranolol (50 ng / mL) in acetonitrile solution, vortex to mix, add 100 μL of purified water, vortex again, centrifuge at 4000 rpm for 5 min, and collect the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0354] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0355] Mobile phase: water (0.1% formic acid) - acetonitrile. Gradient elution is performed according to the table below.

[0356] 15.3 Data Processing

[0357] After LC-MS was used to detect the blood drug concentration, the pharmacokinetic parameters were calculated using WinNonlin 6.1 software and the non-compartmental model method. The results are shown in Table 3.

[0358] Table 3. Beagle Comparison Data

[0359] As shown in Table 3, the series of compounds of this invention all have good pharmacokinetic characteristics in beagle dogs, with good absorption and high absolute bioavailability.

[0360] Example 16: Detection of changes in renal blood flow in cynomolgus monkeys using the compound

[0361] 1. Experimental Methods

[0362] Animal selection and adaptation: Six healthy male cynomolgus monkeys were selected for adaptation through veterinary health assessment. The animals were housed individually with free access to water, fed three times a day at fixed times and in fixed quantities, and kept in a 12-hour light / 12-hour dark cycle. They were adapted for 7 days before medication.

[0363] Animal grouping: During the adaptation period, a B-ultrasound renal artery blood flow test was performed as baseline data. Animals were grouped according to body weight and renal artery blood flow, into a 17 BC treatment group and a 24 BC treatment group.

[0364] Dosage regimen: 17BC and 24BC were filled into gastric-soluble capsules of the same size, with strengths of 50 mg and 100 mg respectively, and administered by gavage. The number of capsules was adjusted based on pre-administration body weight to ensure an actual dose of approximately 60 mg / kg and 30 mg / kg respectively. Each group was administered the drug sequentially at doses of 60 mg / kg and 30 mg / kg. Each dose was administered once, and efficacy indicators were measured. After the measurement, the drug was washed out for 6-7 days before the next dose was administered.

[0365] Renal artery blood flow detection: Animals were fasted overnight the day before the procedure. On the day of the procedure, animals were anesthetized and placed on the operating table. Ultrasound images were taken at appropriate sections, and the TAMEAN blood flow in the renal artery was measured and calculated (blood flow (ml / min) = average flow velocity (cm / s) * vessel area (cm²) * 60 (s)). Renal blood flow was measured at the following time points: before drug administration (0h) and 2h, 4h, and 8h after each administration. The pre-administration renal blood flow value was used as the baseline, and the percentage change in renal blood flow value relative to the baseline was calculated. Additionally, three animals were selected as solvent controls, and renal blood flow was measured at 2h, 4h, and 8h after solvent administration.

[0366] 2. Experimental Results

[0367] As shown in Figure 1, compared with the baseline value before administration, 17BC significantly improved renal artery blood flow at 2, 4 and 8 hours after administration at a dose of 60 mg / kg, and 24BC significantly improved renal artery blood flow at 2, 4 and 8 hours after administration at doses of 30 and 60 mg / kg, suggesting that the compounds have a good effect on improving renal blood flow in vivo.

[0368] Example 17: In vitro liver microsomal stability experiment in different animal species

[0369] Preparation of stock solution and working solution

[0370] The compounds (test samples) of Examples 1-12 and the positive control were dissolved in DMSO to obtain a 10 mM stock solution. The stock solution was diluted with acetonitrile-water (1:1, v / v) to obtain a 100 μM solution, and then further diluted with 0.1 M potassium phosphate buffer solution to obtain a 30 μM working solution.

[0371] Weigh out NADPH powder and dissolve it in 0.1M potassium phosphate buffer solution to obtain a 5 mg / mL solution.

[0372] Liver microsomes of various genera (20 mg / mL) were diluted with 0.1 M potassium phosphate buffer to prepare working solutions of liver microsomes at a concentration of 0.8 mg / mL.

[0373] Liver microsomal stability assay

[0374] Add 25 μL of the test sample or positive control working solution to 475 μL of liver microsome working solution and mix thoroughly. Aliquot the mixture into 30 μL / well (n=2) of a 96-well plate. Add 150 μL of internal standard acetonitrile solution to the 0 min sample to precipitate the protein, then add 15 μL of NADPH solution and incubate at 4°C. For other samples, pre-incubate at 37°C for 10 min, then add 15 μL of NADPH solution to the 20 min and 60 min samples to start the reaction. For samples without NADPH, add 15 μL of potassium phosphate buffer solution and incubate all samples at 37°C. After the reaction time is reached, add 150 μL of internal standard acetonitrile solution to precipitate the protein.

[0375] After vortexing the precipitated sample, centrifuge at 4000 rpm for 5 min. Add 100 μL of purified water to the supernatant and analyze by LC-MS.

[0376] Data Analysis

[0377] The peak area ratio of the analyte to the internal standard was used to calculate the relative percentage content (residual percentage) of the compound after incubation and to fit an exponential function.

[0378] The test results are shown in Table 4.

[0379] Table 4. Stability of the compounds in human liver microsomes

[0380] The experimental results in Table 4 show that the compounds of the present invention have good stability in human and rat liver microsomes, and are significantly superior to the molecules in Example 1 of Patent CN116547270A.

[0381] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims of the present invention.

Claims

An RXFP1 receptor agonist analogue, or an isomer, racemate thereof or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the RXFP1 receptor agonist analog is shown as general formula (I): in: Each of R2, R3, or R4 is independently selected from: H, -CN, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic alkyl; X or Y is each independently selected from: -0-, -S-, -NH-, -N(R8)- or -C(R9)(R 10 )-; R8, R9or R 10 are each independently selected from the group consisting of H, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl, Ci-C6-haloalkoxy; The R5 is independently selected from: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy; The R6 is independently selected from: H, halogen, substituted or unsubstituted C1-C6 alkyl; Alternatively, R5 and R6, together with the carbon atom they are attached to, may be cyclized into substituted or unsubstituted C3-C8 cycloalkyl groups or substituted or unsubstituted 3-10 heterocyclic alkyl groups. said R7is independently selected from: -COOH, -SO3H, -CON(R 11 )(R 12 ), substituted or unsubstituted 5-12 membered heteroaryl, C6-C 10 aryl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; said R 11 or R 12 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6alkyl; Alternatively, R6 and R7, together with the carbon atom they are attached to, may be cyclized into substituted or unsubstituted C3-C8 cycloalkyl groups or substituted or unsubstituted 3-10 heterocyclic alkyl groups. R1 is independently selected from: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, and substituted or unsubstituted C3-C8 cycloalkyl; W is independently selected from: The n is selected from integers of 0, 1, or 2; the R 13 R 14 or R 15 Each is independently selected from: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic alkyl, substituted or unsubstituted C6-C 12 Aryl, substituted or unsubstituted 5-12 heteroaryl groups; said R 16 or R 17 are each independently selected from the group consisting of H, Ci-C6-alkyl, Ci-C6-haloalkyl; or said R 13 and R 14 together with the carbon atom to which they are attached cyclize to substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C5-C7cycloalkenyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; or said R 12 spirocycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; or said R 13 , R 14 and R 15 form together with the carbon atom to which they are attached a substituted or unsubstituted C5-C 12 bridged cycloalkyl group; Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl; The substituents referred to as "substitution" are all independently selected from: -OH, oxo, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups. The RXFP1 receptor agonist analogue according to claim 1, or an isomer, racemate thereof or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analogues have structures represented by general formula (IIA), general formula (IIB), general formula (IIC), or general formula (IID): The definitions of R1-R7, X, Y and W are the same as in claim 1. The RXFP1 receptor agonist analogue according to claim 2, or an isomer, racemate thereof or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analog is selected from the group consisting of structures represented by Formula (IIAA), (IIAB), (IIBA), (IICA), (IICB), (IIDA), or (IIDB): The definitions of R1-R7, X, Y and W are the same as in claim 2. The RXFP1 receptor agonist analogue according to any one of claims 1 to 3, or an isomer, racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analog is selected from the group consisting of: structures shown in formula (IIIA) or (IIIB): Wherein, X is selected from -O- or -NH-; The Y is independently selected from -NH-; R1, R2, and R3 are independently selected from one of the following combinations a)-c): a) R1 is selected from: substituted or unsubstituted C1-C3 alkyl groups, and R2 is independently selected from: halogens or -CN; R3 is independently selected from: substituted or unsubstituted C1-C3 alkyl groups, halogens or -CN; b) R1 is selected from: -CHF2, R2 is selected from H, halogen, and R3 is independently selected from: halogen or C1-C3 haloalkyl; c) R1 is selected from: substituted or unsubstituted C1-C3 alkyl groups, R2 is selected from H, halogens, and R3 is independently selected from: -CHF2; said R7is independently selected from: -COOH or W is independently selected from: The n is selected from integers of 0, 1, or 2; the R 13 R 14 Or R 15 Each of the following is independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl; R 16 Or R 17 Each is independently selected from: H, C1-C6 alkyl, and C1-C6 haloalkyl; Or the R 13 and R 14 Together with the carbon atom attached thereto, it cyclizes into a substituted or unsubstituted C3-C8 cycloalkyl group, or a substituted or unsubstituted C5-C group. 12 Spirocycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl; The substituents referred to as "substitution" are all independently selected from: -OH, oxo, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 heterocyclic alkyl, C6-C 12 One or more of aryl or 5-12 heteroaryl groups. The RXFP1 receptor agonist analogue according to claim 4, or an isomer, racemate thereof or a pharmaceutically acceptable salt thereof, characterized in that, R1, R2, and R3 are independently selected from one of the following combinations a)-c): a) R1 is selected from: C1-C3 alkyl or C1-C3 haloalkyl, and R2 or R3 is independently selected from: halogen; b) R1 is selected from: -CHF2, R2 is selected from H, halogen, and R3 is independently selected from: halogen or C1-C3 haloalkyl; c) R1 is selected from C1-C3 alkyl or C1-C3 haloalkyl, R2 is selected from H or halogen, and R3 is independently selected from -CHF2. The RXFP1 receptor agonist analogue according to any one of claims 1 to 5, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, X is selected from -O- or -NH-; Y is independently selected from -NH-; Each of the R1s is independently selected from: -CH2F, -CHF2, -CF3, -CH3, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; R2 or R3 is independently selected from: F, Cl, -CN, -CH2F, -CHF2, -CF3, -CH3; said W is independently selected from: C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, or said Y-W is independently selected from: The m, p, q, r, s, t, u, v, z1, z2, or z3 are each independently selected from integers of 0, 1, 2, or 3; The R 15 All are independently selected from: H, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl; wherein R 18 It is independently selected from: C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic alkyl. The RXFP1 receptor agonist analogue according to any one of claims 1 to 6, or an isomer, racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analog is selected from the group consisting of: a structure represented by Formula (IV), Formula (IVA), or Formula (IVB): Wherein, R1 is independently selected from: C1-C3 alkyl or C1-C3 haloalkyl; The R2 is independently selected from: halogen or -CN; The R3 is independently selected from: C1-C3 haloalkyl or halogen; said R7is independently selected from: -COOH or W is independently selected from: said n is selected from an integer of 0 or 1 ; said R 13 , R 14 or R 15 are each independently selected from: H or substituted or unsubstituted C1-C3 alkyl; said R 16 or R 17 are each independently selected from: H or substituted or unsubstituted C1-C3 alkyl; or said R 13 and R 14 together with the carbon atom to which they are attached cyclize to substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C5-C 12 spirocycloalkyl; or said R 13 and R 14 and R 15 together with the carbon atom to which they are attached cyclize to substituted or unsubstituted C5-C 12 bridged cycloalkyl; The Y is independently selected from: -NH-; Alternatively, Y and W together form a substituted or unsubstituted 5-12 membered spirocycloalkyl, or a substituted or unsubstituted 5-12 membered bridged heterocycloalkyl; The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups. The RXFP1 receptor agonist analogue according to any one of claims 1 to 6, or an isomer, racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analog is selected from the group consisting of: a structure represented by Formula (VA) or Formula (VB): Wherein, R1 is independently selected from: methyl or CH3OCH2CH2-; W is independently selected from: R 13 , R 14 , or R 15 are each independently selected from: H, or substituted or unsubstituted C1-C3alkyl; R 16 , or R 17 are each independently selected from: H, C1-C3alkyl, C1-C3haloalkyl; or said R 13 and R 14 together with the carbon atom to which they are attached cyclize to substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C5-C 10 spirocycloalkyl; or said R 13 , R 14 and R 15 form together with the carbon atom to which they are attached a substituted or unsubstituted C5-C 10 bridged cycloalkyl group; The substituents referred to in the "substitution" are all independently selected from: halogens or C1-C3 alkyl groups. The RXFP1 receptor agonist analogue according to any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The RXFP1 receptor agonist analogues are selected from the compounds shown in Table 1A or Table 1B. The RXFP1 receptor agonist analogue according to any one of claims 1 to 9, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, One or more hydrogen atoms on the RXFP1 receptor agonist analogue are coated with the isotope deuterium ( 2 H) substitution, preferably, the RXFP1 receptor agonist analogue is selected from the structures shown in Table 1C. The RXFP1 receptor agonist analogue according to any one of claims 1 to 10, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salt of the RXFP1 receptor agonist analogue is a salt that forms with a base. Further, the pharmaceutically acceptable salt is preferably selected from at least one of: lithium, sodium, potassium, calcium, magnesium, aluminum, iron, zinc, or ammonium salts; or the pharmaceutically acceptable salt is independently selected from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, 2-ethylaminoethanol, pyridine, methylpyridine, ethanolamine, diethanolamine, ammonium, tetramethylamine, etc. At least one of the following: ammonium salt, tetraethylammonium salt, triethanolamine salt, piperidine salt, piperazine salt, morpholine salt, lysine salt, arginine salt, L-arginine salt, histidine salt, L-histidine salt, meglumine salt, dimethylglucosamine salt, ethylglucosamine salt, dicyclohexylamine salt, 1,6-hexanediamine salt, glucosamine salt, sarcosine salt, serine salt, trihydroxymethylaminomethane salt, aminopropylene glycol salt, 1-amino-2,3,4-butanetriol salt, L-lysine salt, ornithine salt, or choline salt. The RXFP1 receptor agonist analogue according to claim 11, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that, The molar ratio of the RXFP1 receptor agonist analog to the base is 1 to 3:1; preferably 3:1, 2:1 or 1:

1. A pharmaceutically acceptable salt of an RXFP1 receptor agonist analogue according to any one of claims 1-12, characterized in that, The pharmaceutically acceptable salts of the RXFP1 receptor agonist analogues are selected from the structures shown in Table 1D. A pharmaceutical composition, characterized in that, It comprises the RXFP1 receptor agonist analogue as described in any one of claims 1-13, or an isomer thereof, a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers. Use of the RXFP1 receptor agonist analogue, or isomer thereof, racemate thereof, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-13, or the pharmaceutical composition of claim 14, in the preparation of a drug for the prevention or treatment of RXFP1 receptor-related diseases; preferably, the RXFP1 receptor-related diseases are selected from heart failure.

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