RXFP1 receptor agonist and preparation method and medical application thereof

Abstract

The invention belongs to the technical field of chemical drugs, and provides an RXFP1 receptor agonist and a preparation method and medical application thereof, and the compound provided by the invention has good RXFP1 receptor agonist activity and can be used for treating heart failure. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicines, and specifically relates to an RXFP1 receptor agonist and a preparation method and medical use thereof. Background Art

[0002] Relaxin (RLN) is part of the insulin superfamily and includes seven peptides with high structural similarity but low sequence similarity in humans - 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 chain and B chain) of 24 and 29 amino acids, respectively, linked by two disulfide bonds, wherein the A chain further has one intramolecular disulfide bond (see, Schwabe & McDonald (1977) Science 197: 914-915). RLN2 is generated from its prohormone (prorelaxin) by cleaving the C peptide therefrom.

[0003] Physiologically, RLN2 exhibits multiple functions that regulate cardiovascular, hepatic, neural, pancreatic, pulmonary, and renal adaptations such as vasodilation, antifibrotic, and angiogenic effects, although it was originally 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 referred to as RXFP1 and RXFP2 receptors, respectively.

[0004] Activation of RXFP1 by relaxin RLN2 induces: 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) reduction of inflammation by reducing levels of inflammatory cytokines such as TNF-a and TGF-β; and 4) angiogenesis-activating transcription of VEGF. The understanding of the biological effects of relaxin activation of RXFP1 has led to the evaluation of relaxin as a therapeutic agent for patients with acute heart failure (AHF), preeclampsia, and hypertension. In addition, several clinical trials have investigated the therapeutic role of relaxin in the treatment of scleroderma, cervical ripening, fibromyalgia, and orthodontics due to its anti-inflammatory and extracellular matrix remodeling functions.

[0005] Most of the relaxin RLN2 mimetics reported so far are polypeptide substances, and there are very few reports on small molecule RXFP1 modulators. For example, patent WO2013165606A1 discloses a small molecule relaxin modulator, whose compound can selectively activate the RXFP1 receptor, with an EC50 value of about 94nM; 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. Its compounds can also selectively activate the RXFP1 receptor and can be used to treat heart failure, with an EC50 value of about 6.3nM.

[0006] In summary, although small molecule RXFP1 receptor agonists have been reported in the prior art, the activity and selectivity of the above-mentioned small molecule RXFP1 receptor agonists still need to be optimized, and there is currently no related drug on the market. Therefore, there is still a need to provide more small molecule RXFP1 receptor agonists and their preparation methods. Summary of the invention

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

[0008] The present invention is achieved by the following technical scheme: The present invention provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor agonist is shown in general formula (I):

[0009]

[0010] Wherein, the A ring is selected from: The Z is selected from hydrogen or The m is an integer selected from 0, 1, 2 or 3;

[0011] Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0012] The Y is selected from

[0013] The U is selected from

[0014] The V is selected from

[0015] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H;

[0016] Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0;

[0017] The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy;

[0018] The R 1a , R 1b are independently selected from hydrogen, substituted or unsubstituted 7-12 membered heteroaryl, substituted or unsubstituted 7-12 membered benzocarbocyclyl or substituted or unsubstituted 7-12 membered benzoheterocyclyl;

[0019] or R 1a and R1b Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted 7-12-membered heteroaryl group or a substituted or unsubstituted 7-12-membered benzoheterocyclyl group;

[0020] The substituents of the "substituted" are independently selected from H, halogen, -CN, -NH2, -COOH, -SO3H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 One or more of aryl or 5-10 membered heteroaryl.

[0021] Further, as a preferred technical solution of the present invention, the A ring is selected from: The Z is selected from hydrogen or The m is an integer selected from 0, 1, 2 or 3;

[0022] Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0023] The Y is selected from

[0024] The U is selected from

[0025] The V is selected from

[0026] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H;

[0027] Or the R 2 and R3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0;

[0028] The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy.

[0029] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor agonist is as shown in the general formula (IA) or (IB):

[0030]

[0031] in,

[0032] Said T1 and T2 are independently selected from CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; said T is independently selected from C or N; when T is selected from N, R 1 does not exist;

[0033] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0034] The Y is selected from

[0035] The Z is selected from hydrogen or

[0036] The U is selected from

[0037] The V is selected from

[0038] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H;

[0039] Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0;

[0040] The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy.

[0041] Further, as a preferred technical solution of the present invention, the RXFP1 receptor agonist has a structure shown by the general formula (IAA) or (IBA):

[0042] Among them, R 1 , X, T, T1, T2 and W are defined as in the general formula (IA) or (IB).

[0043] Further, as a preferred technical solution of the present invention, the RXFP1 receptor agonist has a structure shown by the general formula (IAB) or (IBB):

[0044] Among them, R 1 , X, T, T1, T2 and W are defined the same as in the general formula (IAA) or (IBA).

[0045] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor agonist of the present invention has a structure shown in general formula (II) or (IIA):

[0046] Wherein, the definitions of X, T1, T2, T3 and W are the same as those in the general formula (I).

[0047] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor agonist has a structure shown in general formula (III) or (IIIA):

[0048]

[0049] Wherein, the definitions of X, T1, T2, T3, W and m are the same as those in the general formula (I).

[0050] Further, as a preferred technical solution of the present invention, the R 1 is selected from hydrogen, fluorine, chlorine or cyano;

[0051] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0052] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C3-C6 cycloalkyl, C4-C7 heterocycloalkyl, C3-C6 cycloalkyloxy, C4-C7 heterocycloalkyloxy, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C7 heterocycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, C4-C7 heterocycloalkyl C1-C3 alkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C4-C7 heterocycloalkyl, C3-C6 halocycloalkyloxy, C4-C7 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H;

[0053] Or the R 2 and R 3Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl or a C4-C7 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0;

[0054] The R 4 Selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 halocycloalkyl, C4-C7 haloheterocycloalkyl, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C7 heterocycloalkyl, C3-C6 cycloalkyloxy, C4-C7 heterocycloalkyloxy, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C4 heterocycloalkyl, C3-C6 cycloalkylC1-C3 alkyl, C4-C7 heterocycloalkylC1-C3 alkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC4-C7 heterocycloalkyl, C3-C6 halocycloalkyloxy and C4-C7 haloheterocycloalkyloxy.

[0055] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor agonist is shown in the general formula (IC):

[0056]

[0057] in:

[0058] Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano;

[0059] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0060] The A ring is selected from: The m is an integer selected from 0, 1, 2 or 3;

[0061] The R 1a , R 1b are independently selected from hydrogen, substituted or unsubstituted 7-12 membered heteroaryl, substituted or unsubstituted 7-12 membered benzocarbocyclyl or substituted or unsubstituted 7-12 membered benzoheterocyclyl;

[0062] or R 1a and R 1bTogether with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted 7-12-membered heteroaryl group or a substituted or unsubstituted 7-12-membered benzoheterocyclyl group;

[0063] The substituents of the "substituted" are independently selected from H, halogen, -CN, -NH2, -COOH, -SO3H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 One or more of aryl or 5-10 membered heteroaryl.

[0064] Further, as a preferred technical solution of the present invention, the structure of the RXFP1 receptor agonist derivative is shown in the general formula (ICA), general formula (ICAA), general formula (ICAB), general formula (ICB), general formula (ICBA), general formula (ICBB) or general formula (ICC), general formula (ICCA), general formula (ICCB):

[0065]

[0066] Among them, X, T1, T2, T3, m, R 1a and R 1b The definition of is the same as that of the general formula (IC).

[0067] Further, as a preferred technical solution of the present invention, the R 1a , R 1b are independently selected from: H, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted 2,3-dihydro-1H-indenyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted thiazolopyridinyl, substituted or unsubstituted thienopyridinyl; or R 1a and R 1b Together with the attached nitrogen atom, it forms: The "substituted" substituents are independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl;

[0068] Preferably, the R 1a , R 1b are independently selected from: H, benzothienyl, trifluoromethylbenzothienyl, halobenzothienyl, cyanobenzothienyl, methylbenzothienyl, benzothiazolyl, benzimidazolyl, thiazo[4,5-b]pyridinyl, thieno[2,3-b]pyridinyl, indolyl, 2,3-dihydro-1H-indenyl, isoindolyl; or R 1a and R 1b Together with the attached nitrogen atom,

[0069] More preferably: the R 1a , R 1b are independently selected from: H,

[0070]

[0071] or R 1a and R 1b Together with the attached nitrogen atom, it forms:

[0072] Further, as a preferred technical solution of the present invention, the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 cycloalkyloxy, C3-C6 heterocycloalkyloxy, C1-C6 alkylC3-C6cycloalkyl, C1-C6 alkylC3-C6heterocycloalkyl, C3-C6cycloalkylC1-C3 alkyl, C3-C6heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C6cycloalkyl, C1-C6 haloalkylC3-C6cycloalkyl, C1-C6 haloalkylC3-C6cycloalkyl, C1-C6 haloalkylC3-C6heterocycloalkyl, C3-C6 halocycloalkyloxy, C3-C6 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H;

[0073] Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C7 cycloalkyl group, a C3-C7 halocycloalkyl group or a C3-C7 heterocycloalkyl group;

[0074] The R 4 Selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 halocycloalkyl, C3-C6 haloheterocycloalkyl, C1-C6 alkyl C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 heterocycloalkyl, C3-C6 cycloalkyloxy, C3-C6 heterocycloalkyloxy, C1-C6 alkyl C3-C6 cycloalkyl, C1-C6 alkyl C3-C6 heterocycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, C3-C6 heterocycloalkyl C1-C3 alkyl, C1-C6 haloalkyl C3-C6 cycloalkyl, C1-C6 haloalkyl C3-C6 cycloalkyl, C1-C6 haloalkyl C3-C6 heterocycloalkyl, C3-C6 halocycloalkyloxy or C3-C6 haloheterocycloalkyloxy;

[0075] And when R 2 and R 3When n is formed together with the carbon atom to which it is connected to form a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0.

[0076] Further, as a preferred technical solution of the present invention, the R 1 is selected from hydrogen, fluorine, chlorine or cyano;

[0077] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0078] The Y is selected from

[0079] Said Z is selected from hydrogen;

[0080] The U is selected from

[0081] The V is selected from

[0082] Further, as a preferred technical solution of the present invention, the R 2 and R 3 are independently selected from H, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; or said R 2 and R 3 Together with the carbon atom to which it is attached, it forms cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0083] The R 4 is selected from H, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy;

[0084] And when R 2 and R 3 When n is formed together with the carbon atom to which it is connected to form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, n is not 0.

[0085] Further, as a preferred technical solution of the present invention, the 7-12 membered heteroaryl is preferably: a 7-10 membered heteroaryl; more preferably: a 7-8 membered heteroaryl; examples of the heteroaryl include but are not limited to: benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purine (e.g., adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, pyrazolopyridinyl, quinolyl, isoquinolyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl, etc.

[0086] Further, as a preferred technical solution of the present invention, the 7-12-membered benzocarbocyclic group is preferably: a 7-10-membered benzocarbocyclic group, a 7-9-membered benzocarbocyclic group or a 7-8-membered benzocarbocyclic group; examples of the benzocarbocyclic group include but are not limited to:

[0087]

[0088] Preferred are: 2,3-dihydro-1H-indenyl;

[0089] Further, as a preferred technical solution of the present invention, the 7-12-membered benzoheterocyclic group is preferably: a 7-10-membered benzoheterocyclic group, a 7-9-membered benzoheterocyclic group or a 7-8-membered benzoheterocyclic group; examples of the benzoheterocyclic group include but are not limited to:

[0090] Further, as a preferred technical solution of the present invention, the RXFP1 receptor agonist is selected from the compounds described in Table 1A or 1B:

[0091] Table 1A

[0092]

[0093]

[0094]

[0095] Table 1B

[0096]

[0097]

[0098]

[0099] .

[0100] Furthermore, the present invention also provides a method for preparing a RXFP1 receptor agonist, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, which can be prepared by conventional methods in the art, or by referring to the method of patent WO2022122773A1 and methods known in the art.

[0101] Furthermore, the present invention also provides a pharmaceutical composition, characterized in that it comprises an RXFP1 receptor agonist described in general formula (I), general formula (IA), general formula (IB), general formula (IC), general formula (IAA), general formula (IBA), general formula (IBA), general formula (IBB), general formula (II), general formula (IIA), general formula (III), general formula (IIIA), general formula (ICA), general formula (ICB), general formula (ICC), general formula (ICAA), general formula (ICAB), general formula (ICBA), general formula (ICBB), general formula (ICCA) or general formula (ICCB), or an isomer thereof, or a racemate thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0102] Furthermore, the present invention also provides an RXFP1 receptor agonist comprising the general formula (I), general formula (IA), general formula (IB), general formula (IC), general formula (IAA), general formula (IBA), general formula (IBA), general formula (IBB), general formula (II), general formula (IIA), general formula (III), general formula (IIIA), general formula (ICA), general formula (ICB), general formula (ICC), general formula (ICAA), general formula (ICAB), general formula (ICBA), general formula (ICBB), general formula (ICCA) or general formula (ICCB), or its isomers, or its racemates or its pharmaceutical preparations. The use of an acceptable salt or a pharmaceutical composition comprising formula (I), formula (IA), formula (IB), formula (IC), formula (IAA), formula (IBA), formula (IBA), formula (IBB), formula (II), formula (IIA), formula (III), formula (IIIA), formula (ICA), formula (ICB), formula (ICC), formula (ICAA), formula (ICAB), formula (ICBA), formula (ICBB), formula (ICCA) or formula (ICCB) in the preparation of a medicament for preventing or treating diseases related to the RXFP1 receptor.

[0103] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor-related disease is selected from heart failure.

[0104] In the chemical structure of the compound described in the present invention, the bond or key Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond or key Can be or or include both and Two configurations;

[0105] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or both configurations;

[0106] Compounds and intermediates of the present invention can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.

[0107]

[0108] All compounds in the present invention can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0109] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0110] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood in accordance with the ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0111] The term "alkyl" refers to a branched, unbranched, and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms. 1- C6 alkyl, the C 1- The number of carbon atoms in the C6 alkyl group is selected from 1, 2, 3, 4, 5 or 6. 1-The C6 alkyl group is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 alkyl group; examples of the alkyl group 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, 1-ethylbutyl.

[0112] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms in the alkyl chain are replaced by heteroatoms independently selected from N, O and S; the number of the heteroatoms is preferably 1, 2, 3 or 4; the heteroalkyl group is preferably C 1- C6 heteroalkyl, the C 1- The number of carbon atoms in the C6 heteroalkyl group is selected from 1, 2, 3, 4, 5 or 6. 1- C6 heteroalkyl is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 heteroalkyl; the heteroatoms in the heteroalkyl are selected from one or more of N, O or S, and examples of the heteroalkyl include: CH3O-, HOCH2-, CH3OCH2-, CH3CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, CH3CH2OCH2CH2OCH2-, CH3CH2OCH2CH2OCH2-, CH3CH2OCH2CH2OCH2-, CH3CH2OCH2CH2NHCH2-, CH3CH2OCH2CH2SCH2-, CH3CH2OCH2CH2SCH2CH2-, CH3CH2OCH2CH2NH-CH2CH2-, CH3NH-, H2NCH2-, CH3NHC H2-, CH3CH2NHCH2-, CH3NHCH2CH2-, CH3CH2NHCH2CH2-, CH3CH2NHCH2CH2-, CH3CH2NHCH2CH2OCH2-, CH3CH2NHCH2CH2SCH2-, CH3CH2NHCH2CH2OCH2CH2-, CH3CH2NHCH2-CH2SCH2CH2-, CH3S-, HSCH2-, CH3SCH2-, CH3CH2SCH2-, CH3SCH2CH2-, CH3SCH2CH2-, CH3CH2SCH2CH2-, CH3CH2S-CH2CH2OCH2-, CH3CH2SCH2CH2NHCH2-, CH3CH2SCH2CH2OCH2-, CH3CH2SCH2CH2NHCH2-, CH3CH2SCH2CH2OCH2- or CH3CH2SCH2CH2NHCH2CH2-.

[0113] The term "haloalkyl" means that the hydrogen on the alkyl group may be replaced by one or more halogen atoms, and the haloalkyl group is preferably C 1- C6 alkyl halide, the C 1-The number of carbon atoms in the C6 haloalkyl group is selected from 1, 2, 3, 4, 5 or 6. 1- C6 haloalkyl is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 haloalkyl; examples of the haloalkyl include: -CHF2, -CHCl2, -CF3, -CCl3, -CHFCH2F, -CHClCH2F, -CF2CHF2, -CH2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, etc. In one embodiment, C 1- C6 haloalkyl includes fluorine-substituted C 1- C6 alkyl; in another embodiment, C 1- C4 haloalkyl includes fluorine-substituted C 1- C4 alkyl; in another embodiment, C 1- C3 haloalkyl includes fluorine-substituted C 1- C3 alkyl.

[0114] The term "alkoxy" means that one or more carbon atoms on an alkyl group 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 a C1-C6 alkoxy group; the C1-C6 alkoxy group is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy, and further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0115] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms; the haloalkoxy group is preferably C 1- C6 haloalkoxy, the C 1- The number of carbon atoms in the C6 haloalkoxy group is selected from 1, 2, 3, 4, 5 or 6. 1- C6 haloalkoxy is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 haloalkoxy. Further, the haloalkoxy is specifically selected from -OCHF2, -OCHCl2, -OCF3, -OCCl3, -OCHFCH2F, -OCHClCH2F, -OCF2CHF2, -OCH2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, -OCF2CH3, -OCH2CF2CHF2, etc. In one embodiment, C 1- C6 haloalkoxy contains fluorine substituted C 1- C6 alkoxy; in another embodiment, C 1- C4 haloalkyl includes fluorine-substituted C1- C4 alkoxy; in yet another embodiment, C 1- C3 haloalkyl includes fluorine-substituted C 1- C3 alkoxy.

[0116] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic hydrocarbon ring structure having a specified number of ring atoms, wherein the cycloalkyl is preferably C 3- C8 cycloalkyl, the C 3- C8 cycloalkyl C3, C4, C5, C6, C7 or C8 cycloalkyl group having 3 to 8 carbon ring members, said C 3- The C8 cycloalkyl group is preferably selected from: 3- C7 cycloalkyl, C 3- C6 cycloalkyl, C 3- C5 cycloalkyl or C 3- C4 cycloalkyl, in one embodiment, the cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0117] The term "halogenated cycloalkyl" refers to a cycloalkyl group in which one or more H atoms are replaced by halogen. 3- C8 halocycloalkyl, said C 3- C8 halocycloalkyl C3, C4, C5, C6, C7 or C8 halocycloalkyl group having 3 to 8 carbon ring members, said C 3- C8 halocycloalkyl is preferably selected from: 3- C7 halocycloalkyl, C 3- C6 halocycloalkyl, C 3- C5 halocycloalkyl or C 3- C4 halocycloalkyl, in one embodiment, the halocycloalkyl is specifically selected from:

[0118] The term "cycloalkylalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a cycloalkyl group, wherein the cycloalkylalkyl group is preferably C 3- C8 Cycloalkyl C 1- C3 alkyl, the C 3- C8 Cycloalkyl C 1- The definitions of cycloalkyl and alkyl in C3 alkyl are the same as those described above; 3- C8 Cycloalkyl C 1- The C3 alkyl group is preferably selected from: 3- C7 cycloalkyl-CH2-, C 3- C7 cycloalkyl-CH2CH2-, C 3- C7 cycloalkyl -CH2CH2CH2-, C 3- C7 cycloalkyl -CH(CH3)CH2-, C 3-C6 cycloalkyl-CH2-, C 3- C6 cycloalkyl-CH2CH2-, C 3- C6 cycloalkyl-CH2CH2CH2-, C 3- C6 cycloalkyl -CH(CH3)CH2-, C 3- C5 cycloalkyl-CH2-, C 3- C5 cycloalkyl-CH2CH2-, C 3- C5 cycloalkyl-CH2CH2CH2-, C 3- C5 cycloalkyl -CH(CH3)CH2-, C 3- C4 cycloalkyl-CH2-, C 3- C4 cycloalkyl-CH2CH2-, C 3- C4 cycloalkyl-CH2CH2CH2-, C 3- C4 cycloalkyl-CH(CH3)CH2-; in one embodiment, the C 3- C8 Cycloalkyl C 1- C3 alkyl is specifically selected from cyclopropyl-CH2-, cyclopropyl-CH2CH2-, cyclopropyl-CH2CH2CH2-, cyclopropyl-CH(CH3)CH2-, cyclobutyl-CH2-, cyclobutyl-CH2CH2-, cyclobutyl-CH2CH2CH2-, cyclobutyl-CH(CH3)CH2-, cyclopentyl-CH2-, cyclopentyl-CH2CH2-, cyclopentyl-CH2CH2CH2-, cyclopentyl-CH(CH3)CH2-, cyclohexyl-CH2-, cyclohexyl-CH2CH2-, cyclohexyl-CH2CH2CH2- or cyclohexyl-CH(CH3)CH2-.

[0119] The term "alkylcycloalkyl" refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by an alkyl group. The alkylcycloalkyl group is preferably: C 1- C6 Alkyl C 3- C8 cycloalkyl, the C 1- C6 Alkyl C 3- The definitions of cycloalkyl and alkyl in C8 cycloalkyl are the same as those described above; 1- C6 Alkyl C 3- C8 cycloalkyl is preferably: 1- C3 Alkyl C 3- C7 cycloalkyl, C 1- C3 Alkyl C 3- C6 cycloalkyl, C 1- C3 Alkyl C 3- C5 cycloalkyl, C 1- C3 Alkyl C 3- C4 cycloalkyl; in one embodiment, the C 1- C6 Alkyl C 3-The C8 cycloalkyl group is specifically selected from the group consisting of methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl, propylcyclobutyl, methylcyclopentyl, ethylcyclopentyl, propylcyclopentyl, methylcyclohexyl, ethylcyclohexyl and propylcyclohexyl.

[0120] The term "haloalkylcycloalkyl" refers to one or more hydrogen atoms on a cycloalkyl group being replaced by a haloalkyl group, wherein the haloalkylcycloalkyl group is preferably: C 1- C6 haloalkyl C 3- C8 cycloalkyl, the C 1- C6 haloalkyl C 3- The definitions of cycloalkyl and haloalkyl in C8 cycloalkyl are the same as those described above; 1- C6 haloalkyl C 3- C8 cycloalkyl is preferably: 1- C3 haloalkyl 3- C7 cycloalkyl, C 1- C3 haloalkyl 3- C6 cycloalkyl, C 1- C3 haloalkyl 3- C5 cycloalkyl, C 1- C3 haloalkyl 3- C4 cycloalkyl; in one embodiment, the C 1- C6 haloalkyl C 3- The C8 cycloalkyl group is specifically selected from: trifluoromethylcyclopropyl, trifluoroethylcyclopropyl, trifluoromethylcyclobutyl, trifluoroethylcyclobutyl, trifluoropropylcyclobutyl, trifluoromethylcyclopentyl, trifluoroethylcyclopentyl, trifluoropropylcyclopentyl, trifluoromethylcyclohexyl, trifluoroethylcyclohexyl, trifluoropropylcyclohexyl.

[0121] The term "cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above, and representative examples of cycloalkyloxy include, but are not limited to, monocyclic groups. The cycloalkyloxy is preferably C 3- C8 cycloalkyloxy, the C 3- The number of carbon atoms in the C8 cycloalkyloxy group is selected from 3, 4, 5, 6, 7 or 8. 3- The C8 cycloalkyloxy group is preferably selected from: 3- C7 cycloalkyloxy, C 3- C6 cycloalkyloxy, C 3- C5 cycloalkyloxy or C 3- C4 cycloalkyloxy, in one embodiment, the cycloalkyloxy is selected from: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

[0122] The term "halocycloalkyloxy" refers to -O-halocycloalkyl, wherein the halocycloalkyl is as defined above, and representative examples of halocycloalkyloxy include, but are not limited to, monocyclic groups. The cycloalkyloxy is preferably C 3- C8 halocycloalkyloxy, said C 3- The number of carbon atoms in the C8 halocycloalkyloxy group is selected from 3, 4, 5, 6, 7 or 8. 3- C8 halocycloalkyloxy is preferably selected from: 3- C7 halocycloalkyloxy, C 3- C6 halocycloalkyloxy, C 3- C5 halocycloalkyloxy or C 3- C4 halocycloalkyloxy, in one embodiment, the cycloalkyloxy is selected from:

[0123]

[0124] The term "heterocycloalkyl" 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 the heteroatoms is 1, 2, 3 or 4; the heterocycloalkyl group is preferably C 3- C8 heterocycloalkyl; 3- The number of carbon atoms in the C8 heterocycloalkyl group is selected from 3, 4, 5, 6, 7 or 8. 3- C8 heterocycloalkyl is preferably selected from: 3- C7 heterocycloalkyl, C 3- C6 heterocycloalkyl, C 3- C5 heterocycloalkyl or C 3- C4 heterocycloalkyl, in one embodiment, the heterocycloalkyl is specifically selected from cyclopropyloxy, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperazinyl, piperidinyl, N-methylpiperidinyl or N-ethylpiperidinyl.

[0125] The term "halogenated heterocycloalkyl" refers to a heterocycloalkyl in which one or more hydrogen atoms are replaced by halogen; the number of the heteroatoms is 1, 2, 3 or 4; the halogenated heterocycloalkyl is preferably C 3- C8 halogenated heterocycloalkyl; 3- The number of carbon atoms in the C8 haloheterocycloalkyl group is selected from 3, 4, 5, 6, 7 or 8. 3- C8 haloheterocycloalkyl is preferably selected from: 3- C7 haloheterocycloalkyl, C 3- C6 haloheterocycloalkyl, C 3- C5 haloheterocycloalkyl or C 3- C4 haloheterocycloalkyl, in one embodiment, the heterocycloalkyl is specifically selected from:

[0126]

[0127] The term "heterocycloalkylalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a heterocycloalkyl group, wherein the heterocycloalkylalkyl group is preferably C 3- C8 Heterocycloalkyl 1- C3 alkyl, the C 3- C8 Heterocycloalkyl 1- The definitions of cycloalkyl and alkyl in C3 alkyl are the same as those described above; 3- C8 Heterocycloalkyl 1- C3 alkyl 3- The number of carbon atoms in the C8 heterocycloalkyl group is selected from 3, 4, 5, 6, 7 or 8. 1- The number of carbon atoms in the C3 alkyl group is selected from 1, 2 or 3; 3- C8 Heterocycloalkyl 1- The C3 alkyl group is preferably selected from: 3- C7 heterocycloalkyl-CH2-, C 3- C7 heterocycloalkyl -CH2CH2-, C 3- C7 heterocycloalkyl -CH2CH2CH2-, C 3- C7 heterocycloalkyl -CH(CH3)CH2-, C 3- C6 heterocycloalkyl-CH2-, C 3- C6 heterocycloalkyl-CH2CH2-, C 3- C6 heterocycloalkyl-CH2CH2CH2-, C 3- C6 heterocycloalkyl -CH(CH3)CH2-, C 3- C5 heterocycloalkyl-CH2-, C 3- C5 heterocycloalkyl-CH2CH2-, C 3- C5 heterocycloalkyl-CH2CH2CH2-, C 3- C5 heterocycloalkyl -CH(CH3)CH2-, C 3- C4 heterocycloalkyl-CH2-, C 3- C4 heterocycloalkyl-CH2CH2-, C 3- C4 heterocycloalkyl-CH2CH2CH2-, C 3- C4 heterocycloalkyl -CH(CH3)CH2-, the C 3- C8 Heterocycloalkyl 1-C3 alkyl is specifically selected from cyclopropyloxy-CH2-, cyclopropyloxy-CH2CH2-, cyclopropyloxy-CH2CH2CH2-, cyclopropyloxy-CH(CH3)CH2-, oxetanyl-CH2-, oxetanyl-CH2CH2-, oxetanyl-CH2CH2CH2-, oxetanyl-CH(CH3)CH2-, pyrrolidinyl-CH2-, pyrrolidinyl-CH2CH2-, pyrrolidinyl-CH2CH2CH2-, pyrrolidinyl-CH(C H3)CH2-, piperidinyl-CH2-, morpholinyl-CH2-, morpholinyl-CH2CH2-, morpholinyl-CH2CH2CH2-, morpholinyl-CH(CH3)CH2-, piperidinyl-CH2-, piperidinyl-CH2CH2-, piperidinyl-CH2CH2CH2-, piperidinyl-CH(CH3)CH2-, piperazinyl-CH2-, piperazinyl-CH2CH2-, piperazinyl-CH2CH2CH2- or piperazinyl-CH(CH3)CH2-.

[0128] The term "alkylheterocycloalkyl" refers to one or more hydrogen atoms on a heterocycloalkyl group being replaced by an alkyl group, wherein the alkylheterocycloalkyl group is preferably: C 1- C6 Alkyl C 3- C8 heterocycloalkyl, the C 1- C6 Alkyl C 3- The definitions of cycloalkyl and alkyl in C8 heterocycloalkyl are the same as those described above; 1- C6 Alkyl C 3- C8 heterocycloalkyl is preferably: 1- C3 Alkyl C 3- C7 heterocycloalkyl, C 1- C3 Alkyl C 3- C6 heterocycloalkyl, C 1- C3 Alkyl C 3- C5 heterocycloalkyl, C 1- C3 Alkyl C 3- C4 heterocycloalkyl; in one embodiment, the C 1- C6 Alkyl C 3- The C8 heterocycloalkyl group is specifically selected from: methylcyclopropyloxy, dimethylcyclopropyloxy, ethylcyclopropyloxy, methylcyclobutyloxy, ethylcyclobutyloxy, propylcyclobutyloxy, methylpyrrolidinyl, ethylpyrrolidinyl, propylpyrrolidinyl, methyltetrahydrofuranyl, ethyltetrahydrofuranyl, propyltetrahydrofuranyl, methylpiperidinyl, ethylpiperidinyl, methylpiperazinyl, ethylpiperazinyl, methylmorpholinyl, ethylmorpholinyl, N-methylpiperazinyl, N-methylmorpholinyl.

[0129] The term "haloalkylheterocycloalkyl" refers to one or more hydrogen atoms on the heterocycloalkyl group being replaced by a haloalkyl group, wherein the haloalkylheterocycloalkyl group is preferably: C 1- C6 haloalkyl C3- C8 heterocycloalkyl, the C 1- C6 haloalkyl C 3- The definitions of cycloalkyl and alkyl in C8 heterocycloalkyl are the same as those described above; 1- C6 haloalkyl C 3- C8 heterocycloalkyl is preferably: 1- C3 haloalkyl 3- C7 heterocycloalkyl, C 1- C3 haloalkyl 3- C6 heterocycloalkyl, C 1- C3 haloalkyl 3- C5 heterocycloalkyl, C 1- C3 haloalkyl 3- C4 heterocycloalkyl; in one embodiment, the C 1- C6 haloalkyl C 3- The C8 heterocycloalkyl group is specifically selected from: trifluoromethylcyclopropyloxy, difluoromethylcyclopropyloxy, trifluoroethylcyclopropyloxy, trifluoromethylcyclobutyloxy, trifluoroethylcyclobutyloxy, trifluoropropylcyclobutyloxy, trifluoromethylpyrrolidinyl, trifluoroethylpyrrolidinyl, trifluoropropylpyrrolidinyl, trifluoromethyltetrahydrofuranyl, trifluoroethyltetrahydrofuranyl, trifluoropropyltetrahydrofuranyl, trifluoromethylpiperidinyl, trifluoroethylpiperidinyl, trifluoromethylpiperazinyl, trifluoroethylpiperazinyl, trifluoromethylmorpholinyl, trifluoroethylmorpholinyl, N-trifluoromethylpiperazinyl, N-trifluoromethylmorpholinyl.

[0130] The term "heterocycloalkyloxy" refers to -O-heterocycloalkyl, wherein heterocycloalkyl is as defined above, and representative examples of heterocycloalkyloxy include, but are not limited to, monocyclic groups. The heterocycloalkyloxy is preferably C 3- C8 heterocycloalkyloxy, the C 3- The number of carbon atoms in the C8 heterocycloalkyloxy group is selected from 3, 4, 5, 6, 7 or 8. 3- C8 heterocycloalkyloxy is preferably selected from: 3- C7 heterocycloalkyloxy, C 3- C6 heterocycloalkyloxy, C 3- C5 heterocycloalkyloxy or C 3- C4 heterocycloalkyloxy, in one embodiment, the heterocycloalkyl is specifically selected from: cyclopropyloxy-O-, oxabutanyl-O-, pyrrolidinyl-O-, tetrahydrofuranyl-O-, tetrahydrothienyl-O-, morpholinyl-O-, piperazinyl-O-, piperidinyl-O-, N-methylpiperidinyl-O- or N-ethylpiperidinyl-O-.

[0131] The term "halogenated heterocycloalkyloxy" refers to -O-halogenated heterocycloalkyl, wherein the halogenated heterocycloalkyl is as defined above, and representative examples of halogenated heterocycloalkyloxy include, but are not limited to, monocyclic groups. The halogenated heterocycloalkyloxy is preferably C 3- C8 haloheterocycloalkyloxy, said C 3- The number of carbon atoms in the C8 haloheterocycloalkyloxy group is selected from 3, 4, 5, 6, 7 or 8. 3- C8 haloheterocycloalkyloxy is preferably selected from: 3- C7 haloheterocycloalkyloxy, C 3- C6 haloheterocycloalkyloxy, C 3- C5 haloheterocycloalkyloxy or C 3- C4 haloheterocycloalkyloxy, in one embodiment, the haloheterocycloalkyloxy is specifically selected from:

[0132]

[0133] The term "aryl" refers to a 6-14 membered monocyclic or polycyclic aromatic ring assembly, wherein all the ring atoms are carbon atoms. Generally, aryl is a 6-membered monocyclic, 10-12 membered bicyclic or 14-membered fused tricyclic aromatic ring system. As used herein, C A Aryl and C A-B Aryl represents an aromatic group in which A and B represent the number of carbon atoms in the ring system. 10 Aryl, further preferably: C6-C8 aryl or C6-C7 aryl; in one embodiment, the aryl is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.;

[0134] The term "benzocarbocyclyl" refers to a non-aromatic bicyclic group having 7 to 12 carbon atoms formed by the fusion of a benzene ring and another carbocyclic ring sharing two carbon atoms; wherein the carbocyclic ring may be a 5-8-membered saturated or partially unsaturated carbocyclic ring, for example: cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexene; examples of the benzocarbocyclyl group include, but are not limited to:

[0135]

[0136] The term "benzoheterocyclic group" means that a benzene ring and another heterocyclic ring share two carbon atoms and are fused together to form a non-aromatic bicyclic group having 7-12 carbon atoms, wherein the heterocyclic ring contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the heterocyclic ring can be a 5-8 membered saturated or partially unsaturated heterocyclic ring containing 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur, such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.; the examples of the benzoheterocyclic group include but are not limited to:

[0137]

[0138] 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. Heteroaryl is preferably 5 to 10 members, more preferably 5 to 8 members, most preferably 5, 6 or 7 members. Heteroaryl may be, for example, a five-membered or six-membered monocyclic ring or a fused bicyclic structure formed by fused five-membered 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 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring may 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 the heteroaryl group (including any amino substituents of the ring) will be less than five.

[0139] Examples of five-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of six-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryls containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl. Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g., adenine, guanine), indazolyl, 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, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl. Particular heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0140] The term "halogen" is selected from F, Cl, Br or I;

[0141] When "cycloalkyl" or "heterocycloalkyl" is expressed together with another group such as "cycloalkyloxy", "heterocycloalkyloxy", the cycloalkyl or heterocycloalkyl part shall have the same meaning as described in the above definition of "cycloalkyl" or "heterocycloalkyl".

[0142] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0143] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, 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 pure desired enantiomer. 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 diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0144] The term "stereoisomers" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc.;

[0145] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0146] The term "racemate" refers to an equimolar mixture of two enantiomers, devoid of optical activity.

[0147] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.

[0148] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetable and mineral, cream base, lotion base, ointment base, etc. Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum protein, such as human serum protein; buffer substances such as phosphate; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; 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, ethylcellulose 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; glycol compounds 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 saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0149] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0150] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0151] Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0152] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0153] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, stabilize metabolism, and improve the in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom with the same atomic number (proton number) and a different mass number (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy inspection of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amount nor have radioactivity, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0154] For example, the compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, 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, whether radioactive or not, are included within the scope of the present invention.

[0155] Furthermore, the compounds of the present invention may have one or more hydrogen atoms deuterated with isotopes of deuterium ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0156] The preparation method of the isotopic derivative generally includes: a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium introduction than reduction with deuterated silane (e.g., triethyldeuterated monosilane) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate in the presence of an acid (e.g., methanesulfonic acid).

[0157] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount 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 age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0158] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0159] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0160] Compared with the prior art, the RXFP1 receptor agonist of the present invention has a lower EC 50 value. DETAILED DESCRIPTION

[0161] The present invention is further described in detail below in conjunction with embodiments, but the content of the invention is not limited to the embodiments.

[0162] Example 1

[0163] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0164] The specific synthetic route is as follows:

[0165]

[0166] Step A: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4R)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0167] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (200 mg, 0.33 mmol) (the compound was obtained from patent PCT / EP2021 / 084673) and dicyclopropylmethylamine (40 mg, 0.36 mmol) were dissolved in dichloromethane (2 ml), N,N-diisopropylethylamine (170 mg, 1.32 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (315 mg, 0.5 mmol, 50% mass fraction ethyl acetate solution) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and LC-MS was monitored until the reaction was complete.

[0168] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 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). 180 mg of naphthalene-2-ylmethyl (1S, 4s)-4-(5-(((1R, 2R, 3S, 4S)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.36 min, [M+H] + =695.41.

[0169] Step B: Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0170] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (200 mg, 0.29 mmol) was dissolved in ethanol (4 ml), wet palladium / carbon (20 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was carried out at room temperature for 16 hours. The reaction was monitored by LC-MS until the reaction was completed.

[0171] The 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 / 2), to obtain 87 mg of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((dicyclopropylmethyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid.

[0172] LC-MS: RT = 2.07 min, [M + H] + =557.09. NMR data: 1 H NMR(400MHz,Chloroform-d6)δ8.61(d,J=9.6Hz,1H),8.22(d,J=8.0Hz,1H),6.70(d,J= 10.9Hz,1H),5.85(d,J=21.3Hz,1H),4.53-4.32(m,2H),4.02(s,3H),3.43(dd,J=14.2,5 .8Hz,1H),3.34-3.08(m,3H),3.08-2.95(m,1H),2.52-2.48(m,2H),2.26-2.22(m,2H),2 .11-2.07(m,2H),1.89-1.68(m,4H),1.68-1.46(m,5H),1.45-1.15(m,8H),1.00(s,3H).

[0173] Example 2

[0174] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((2-cyclopropylbutyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0175] Compound 2a or 2b: (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(((S)-2-cyclopropylbutyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0176] Compound 2b or 2a: (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(((R)-2-cyclopropylbutyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0177] The specific synthetic route is as follows:

[0178]

[0179] Step A: Synthesis of 2-cyclopropylbutyronitrile

[0180] At room temperature, cyclopropylacetonitrile (500 mg, 6.2 mmol) was dissolved in tetrahydrofuran (10 ml), nitrogen was replaced, the temperature was lowered to -78 degrees Celsius, and lithium diisopropylamide (6.2 ml, 12.4 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise. After stirring for 30 minutes, iodoethane (1 g, 6.8 mmol) was added. The reaction was stirred for 4 hours at the temperature until the reaction was basically complete, and the reaction solution was slowly warmed to room temperature.

[0181] Saturated aqueous ammonium chloride solution (15 ml) was added, extracted with ethyl acetate (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 / 10) to give 510 mg of 2-cyclopropylbutyronitrile.

[0182] Step B: Synthesis of 2-cyclopropylbutan-1-amine

[0183] At room temperature, 2-cyclopropylbutyronitrile (431 mg, 4.0 mmol) was dissolved in ammonia / methanol solution (10 ml, 7 mol / L), Raney nickel (200 mg) was added, and hydrogen was introduced and replaced. The reaction was carried out at room temperature for 14 hours and monitored by LC-MS until the reaction was complete.

[0184] The Raney nickel was filtered off, the mixture was washed with methanol (20 ml), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain 350 mg of 2-cyclopropylbutan-1-amine. LC-MS: RT = 1.74 min, [M+H] + =114.0.

[0185] Step C: Synthesis of naphth-2-ylmethyl (1S,4S)-4-(1R,2R,3S,4S)-3-((2-cyclopropylbutyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0186] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (150 mg, 0.25 mmol) and 2-cyclopropylbutan-1-amine (57 mg, 0.50 mmol) were dissolved in dichloromethane (2 ml), N,N-diisopropylethylamine (129 mg, 1.00 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (318 mg, 0.5 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0187] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2 / 3). 120 mg of naphthalene-2-ylmethyl (1S, 4S)-4-(1R, 2R, 3S, 4S)-3-((2-cyclopropylbutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.78 min, [M+H] + =679.4.

[0188] Step D: Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((2-cyclopropylbutyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0189] At room temperature, naphthalen-2-ylmethyl (1S,4S)-4-(1R,2R,3S,4S)-3-((2-cyclopropylbutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (120 mg, 0.17 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0190] The palladium / carbon was filtered off, ethanol (10 ml) was used for elution, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). The product was separated by chiral HPLC (Agilentprep C18, mobile phase: 0.1% formic acid aqueous solution and acetonitrile) to obtain 12 mg of single-configuration compound 2a or 2b (RT = 17.714 min) and 11 mg of single-configuration compound 2b or 2a (RT = 18.859 min). [M+H] + =559.4.

[0191] NMR data of compound 2a or 2b: 1 HNMR (400MHz, DMSO-d6) δ12.38(s,1H),8.79(d,J=8.4Hz,1H),7.93(t,J=5.9Hz,1H),7.67(d,J=10.0Hz,1H),7.1 2(d,J=12.8Hz,1H),4.14(t,J=8.7Hz,2H),3.86(s,3H),3.28-3.21(m,1H),2.79(ddd,J=13.1,7.8,5.2Hz,1H),2. 56(d,J=8.6Hz,2H),2.23(d,J=3.6Hz,1H),2.13-1.95(m,4H),1.87(d,J=12.2Hz,2H),1.59-1.35(m,4H),1.34-1 .04(m,9H),0.66(t,J=7.4Hz,3H),0.52-0.22(m,4H),-0.03(dd,J=8.4,4.2Hz,1H),-0.14(dt,J=6.6,3.9Hz,1H).

[0192] NMR data of compound 2b or 2a: 1HNMR (400MHz, DMSO-d6) δ12.38(s,1H),8.84(d,J=8.2Hz,1H),7.92(t,J=5.9Hz,1H),7.67(d,J=9.9Hz,1H),7.12(d,J=12.7Hz, 1H),4.20-4.07(m,2H),3.89(s,3H),3.10(dt,J=13.2,6.6Hz,1H),2.98(dt,J=13.2,5.6Hz,1H),2.56(d,J=8.6Hz,2H),2.23(d, J=3.6Hz,1H),2.14-1.95(m,4H),1.88(d,J=12.5Hz,2H),1.62-1.35(m,4H),1.31-1.09(m,9H),0.75(t,J=7.5Hz,3H),0.49(dq, J=12.6,6.9,6.3Hz,1H),0.44-0.33(m,1H),0.26(qq,J=8.9,3.8Hz,2H),0.00--0.08(m,1H),-0.16(dq,J=9.1,3.2,2.0Hz,1H).

[0193] Example 3

[0194] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((2-cyclopropyl-3-methylbutyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0195]

[0196] Compound 3 was prepared by referring to the method of compound 2. LC-MS: RT = 2.41 min, [M+H] + =573.4. NMR data: 1HNMR(400MHz,DMSO-d6)δ12.33(s,1H),8.84-8.81(m,1H),7.95-7.89(m,1H),7.69-7.66(m,1H), 7.15-7.12(m,1H),4.20-4.08(m,2H),3.88-3.86(m,3H),3.29-3.13(m,1H),2.99-2.82(m,1H),2. 56-2.54(m,2H),2.23-2.22(m,1H),2.07-1.97(m,4H),1.87-1.87(m,2H),1.68-1.34(m,5H),1.3 3-1.05(m,8H),0.82-0.72(m,4H),0.63(d,J=6.8Hz,1H),0.50-0.21(m,4H),-0.01--0.21(m,2H).

[0197] Example 4

[0198] Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0199] The specific synthetic route is as follows:

[0200]

[0201] Step A: Synthesis of (2-methoxyethylene-1,1-diyl)dicyclopropane

[0202] Dissolve (methoxymethyl)triphenylphosphonium chloride (4.68 g, 13.65 mmol) in tetrahydrofuran (50 ml) at room temperature, cool to 5-10°C, slowly add potassium tert-butoxide (1.5 g, 13.65 mmol), stir for half an hour, add dicyclopropyl ketone (1.0 g, 9.1 mmol) dropwise, and after the addition is complete, slowly warm to room temperature and stir for 2 hours. Monitor by LC-MS until the reaction is complete.

[0203] Water (50 ml) was added to quench the reaction, and ethyl acetate was extracted (100 ml × 2 times). The organic phases were combined, washed with sodium bicarbonate aqueous solution (50 ml × 1 time), washed with saturated brine (50 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 obtain 486 mg of (2-methoxyethylene-1,1-diyl)dicyclopropane. LCMS: RT = 2.11 min, [M+H] + =139.19.

[0204] Step B: Synthesis of 2,2-dicyclopropylacetaldehyde

[0205] Dissolve (2-methoxyethylene-1,1-diyl)dicyclopropane (486 mg, 3.5 mmol) in tetrahydrofuran (5 ml), add 0.5 ml of 5M hydrochloric acid solution, react at room temperature for 5 hours, and monitor the reaction by LC-MS until the reaction is complete.

[0206] The reaction solution was extracted with ethyl acetate (5 ml x 3 times), the organic phases were combined, washed with saturated sodium chloride solution (10 ml x 2 times), dried over anhydrous sodium sulfate, and concentrated to obtain 285 mg of 2,2-dicyclopropylacetaldehyde. LCMS: RT = 2.07 min, [M+H] + =125.17.

[0207] Step C: Synthesis of 2,2-dicyclopropylacetaldehyde oxime

[0208] At room temperature, 2,2-dicyclopropylacetaldehyde (285 mg, 2.3 mmol) was dissolved in pyridine (5 ml), hydroxylamine hydrochloride (241 mg, 3.5 mmol) was added, and the mixture was heated to 100°C for 4 hours. The reaction was monitored by LC-MS until completion.

[0209] The mixture was cooled to room temperature, concentrated under reduced pressure to remove pyridine, diluted with ethyl acetate (10 ml), washed with dilute hydrochloric acid solution (10 ml x 1 time, concentration 1 mol / L), washed with saturated brine (10 ml x 1 time), dried over anhydrous sodium sulfate, and concentrated to obtain 53 mg of 2,2-dicyclopropylacetaldehyde oxime. LCMS: RT = 1.81 min, [M+H] + =140.18.

[0210] Step D: Synthesis of 2,2-dicyclopropylethane-1-amine

[0211] 2,2-Dicyclopropylacetaldehyde oxime (1.19 g, 8.56 mmol) was dissolved in tetrahydrofuran (10 ml), lithium aluminum tetrahydride was slowly added at room temperature, heated to 65°C and refluxed, reacted for 2 hours, and monitored by LC-MS until the reaction was complete.

[0212] Cool to room temperature, add sodium hydroxide solution (15 ml, concentration 1 mol / L) dropwise to quench until no gas escapes, filter, add ethyl acetate (15 ml × 3 times) to extract, combine the organic phases, wash with saturated sodium chloride solution (20 ml × 2 times), dry over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain 74 mg of 2,2-dicyclopropylethane-1-amine. LCMS: RT = 1.63 min, [M+H] + =126.14.

[0213] Step E: Synthesis of naphth-1-ylmethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0214] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (200 mg, 0.33 mmol) and 2,2-dicyclopropylethane-1-amine (45 mg, 0.36 mmol) were dissolved in dichloromethane (2 ml), N,N-diisopropylethylamine (170 mg, 1.32 mmol) was added, the temperature was lowered to 0 degrees Celsius, propylphosphonic anhydride (420 mg, 0.66 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0215] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 126 mg of naphthalene-1-ylmethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.37 min, [M+H] + =709.41.

[0216] Step F: Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0217] At room temperature, naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (126 mg, 0.18 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0218] The palladium / carbon was filtered off, and 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 = 2 / 3). 18.6 mg of (1S, 4s)-4-(5-(((1S, 2R, 3S, 4R)-3-((2,2-dicyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.20 min, [M+H] + =571.39. NMR data: 1 HNMR (400MHz, DMSO-d6) δ12.17(s,1H),8.83(d,J=8.2Hz,1H),8.00(t,J=5.9Hz,1H),7.67(d,J=9.9Hz,1H),7.12 (d,J=12.7Hz,1H),4.23-4.07(m,2H),3.87(s,3H),3.30-3.22(m,2H),2.97(ddd,J=12.8,7.2,5.3Hz,1H),2.58( d,J=8.5Hz,1H),2.24(d,J=3.6Hz,1H),2.14-1.95(m,4H),1.88(dd,J=12.5,4.8Hz,2H),1.61-1.35(m,4H),1.35 -1.05(m,9H),0.53-0.45(m,2H),0.27-0.24(m,2H),0.20-0.15(m,2H),0.00--0.06(m,2H),-0.12--0.19(m,1H).

[0219] Example 5

[0220] (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0221] Compound 5a or 5b: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0222] Compound 5b or 5a: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0223] The specific synthetic route is as follows:

[0224]

[0225] Step A: Synthesis of 2-cyclobutyl-2-cyclopropylacetonitrile

[0226] At room temperature, cyclopropylacetonitrile (527 mg, 6.5 mmol) was dissolved in tetrahydrofuran (6.5 ml), nitrogen was replaced, the temperature was lowered to -78 degrees Celsius, and lithium diisopropylamide (3.9 ml, 7.8 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise. After stirring for 30 minutes, cyclobutyl bromide (1.1 ml, 13 mmol) was added, the temperature was slowly raised to room temperature, and the reaction was stirred for 20 hours until the reaction was basically complete.

[0227] Saturated aqueous ammonium chloride solution (15 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10) to give 514 mg of 2-cyclobutyl-2-cyclopropylacetonitrile.

[0228] Step B: Synthesis of 2-cyclobutyl-2-cyclopropylethylamine

[0229] At room temperature, 2-cyclobutyl-2-cyclopropylacetonitrile (514 mg, 3.8 mmol) was dissolved in ammonia-methanol (10 ml, 7.0 mol / L) solution, Raney nickel (514 mg) was added, hydrogen was replaced and introduced, and the reaction was stirred at room temperature overnight until the reaction was complete.

[0230] The Raney nickel was filtered off, washed with methanol (20 ml), and the filtrate was concentrated to obtain 500 mg of 2-cyclobutyl-2-cyclopropylethylamine, which was used directly in the next reaction without purification. LC-MS: RT = 1.84 min, [M+H] + =140.2.

[0231] Step C: Synthesis of naphth-1-ylmethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0232] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (124 mg, 0.21 mmol) and 2-cyclobutyl-2-cyclopropylethylamine (58.5 mg, 0.42 mmol) were dissolved in dichloromethane (10 ml). N,N-diisopropylethylamine (0.11 ml, 0.63 mmol) was added. The temperature was cooled to zero degrees Celsius. Propylphosphonic anhydride (167 mg, 0.32 mmol, 50% by mass solution in ethyl acetate) was added. The temperature was slowly raised to room temperature. The reaction was stirred for 1 hour and monitored by LC-MS until the reaction was complete.

[0233] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml × 3 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 = 2 / 3). 133 mg of naphthalene-1-ylmethyl (1S, 4s)-4-(5-(((1S, 2R, 3S, 4R)-3-((2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.79 min, [M+H] + =723.4.

[0234] Step D: Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0235] At room temperature, naphthalen-1-ylmethyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclobutyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (133 mg, 0.18 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (50 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0236] The palladium / carbon was filtered off, ethanol (10 ml) was used for elution, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 2 / 3). The product was separated by chiral HPLC (Waters xbridge prep C18, mobile phase: 0.1% aqueous ammonia solution and acetonitrile) to obtain 21 mg of single-configuration compound 5a or 5b (RT = 1.616 min), [M+H] + =585.2; 38.1 mg of single-configuration compound 5b or 5a (RT=2.745 min) (yield: 36.2%). [M+H] + =585.2.

[0237] NMR data of compound 5a or 5b: 1 HNMR (400MHz, DMSO-d6) δ12.42(br,1H),8.83(d,J=8.3Hz,1H),7.88(dt,J=13.2,5.9Hz,1H),7.68(dd,J =9.9,5.3Hz,1H),7.15(dd,J=12.8,5.4Hz,1H),4.20-4.08(m,2H),3.88(d,J=14.5Hz,3H),3.12(tt,J=12 .6,5.9Hz,1H),2.77(dt,J=12.8,6.2Hz,1H),2.56-2.51(m,1H),2.22(s,1H),2.14-1.98(m,5H),1.89-1 .83(m,3H),1.76-1.12(m,14H),1.11(s,3H),0.55-0.49(m,1H),0.38-0.08(m,3H),-0.02--0.28(m,2H).

[0238] NMR data of compound 5b or 5a: 1HNMR(400MHz,DMSO-d6)δ12.29(br,1H),8.83(d,J=8.3Hz,1H),7.88(dt,J=13.1,5.9Hz,1 H),7.68(dd,J=9.9,5.3Hz,1H),7.14(dd,J=12.7,5.4Hz,1H),4.12-4.07(m,2H),3.88(d, J=14.5Hz,3H),3.17-3.07(m,1H),2.80-2.74(m,1H),2.58-2.54(m,1H),2.22(s,1H),2.1 9-1.95(m,5H),1.92-1.13(m,16H),1.10(s,3H),0.73-0.07(m,5H),-0.03--0.29(m,2H).

[0239] Example 6

[0240] Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2-cyclohexyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0241]

[0242] Compound 6a or 6b: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-2-cyclohexyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0243] Compound 6b or 6a: Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-2-cyclohexyl-2-cyclopropylethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0244]

[0245] Compound 6 / 6a / 6b was prepared according to the method of Example 5. The obtained product was separated by chiral HPLC (Agilentprep C18, mobile phase: 0.1% formic acid aqueous solution and acetonitrile) to obtain 14.2 mg of single-configuration compound 6a or 6b (RT=16.230 min), [M+H] +=613.4; 18.7 mg of single-configuration compound 6b or 6a (RT=17.319 min). [M+H] + =613.4.

[0246] NMR data of compound 6a or 6b: 1 HNMR (400MHz, DMSO-d6) δ12.32(br,1H),8.87(d,J=8.1Hz,1H),7.85(t,J=5.8Hz,1H),7.66(d,J=9.9Hz ,1H),7.11(d,J=12.7Hz,1H),4.15-4.08(m,2H),3.88(s,3H),3.21-3.15(m,1H),3.01-2.95(m,1H),2. 56(d,J=8.6Hz,1H),2.22-2.21(m,1H),2.08-1.98(m,4H),1.89-1.85(m,2H),1.59-1.41(m,9H),1.28- 0.95(m,14H),0.45-0.40(m,2H),0.33-0.23(m,2H),-0.02--0.07(m,1H),-0.16(dd,J=9.4,4.9Hz,1H).

[0247] Example 7

[0248] Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((2,3-dicyclopropylpropyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0249]

[0250] Compound 7 was prepared by referring to the method of compound 2. LCMS: RT = 2.438 min, [M+H] + =585.4. NMR data: 1HNMR(400MHz,DMSO-d6)δ12.32(s,1H),8.88-8.83(m,1H),7.96-7.91(m,1H),7.69-7.66(m,1H),7.14-7.11(m, 1H),4.16-4.07(m,2H),3.89-3.86(m,3H),3.34-3.15(m,1H),3.06-2.84(m,1H),2.63-2.54(m,1H),2.23-2.22( m,1H),2.13-1.95(m,4H),1.94-1.81(m,2H),1.60-1.34(m,4H),1.34-0.97(m,10H),0.71-0.55(m,2H),0.49-0 .38(m,1H),0.32-0.25(m,3H),0.14-0.08(m,1H),0.03-0.02(m,1H),-0.05--0.22(m,2H),-0.24--0.30(m,1H).

[0251] Example 8

[0252] Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyclobutyl-2-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0253]

[0254] Compound 8 was prepared by referring to the method of compound 2. LCMS: RT = 2.20 min, [M+H] + =599.28. NMR data: 1HNMR(400MHz, DMSO-d6)δ12.30(s,1H),8.88(t,J=8.4Hz,1H),7.94(dt,J=20.2,5.9Hz,1H),7.68(d,J=10.0Hz,1H), 7.13(dd,J=12.7,3.3Hz,1H),4.16-4.09(m,2H),3.89-3.87(m,3H),3.31-3.21(m,1H),3.13-2.90(m,1H),2.76-2.6 7(m,1H),2.59-2.50(m,1H),2.41-2.30(m,1H),2.23(s,1H),2.13-1.96(m,4H),1.94-1.80(m,3H),1.74-1.49(m,4H ),1.44-1.33(m,4H),1.32-1.06(m,10H),0.49(s,1H),0.42-0.19(m,3H),-0.01--0.08(m,1H),-0.13--0.18(m,1H).

[0255] Example 9

[0256] Synthesis of (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((3-cyclohexyl-2-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0257]

[0258] Compound 9a or 9b: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((S)-3-cyclohexyl-2-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0259] Compound 9b or 9a: (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-(((R)-3-cyclohexyl-2-cyclopropylpropyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0260]

[0261] Compound 9 / 9a / 9b was prepared according to the method of Example 5. The obtained product was separated by chiral HPLC (Polaris5C18-A, mobile phase: 0.1% aqueous ammonia solution and acetonitrile) to obtain 2.7 mg of single-configuration compound 9a or 9b (RT = 16.234 min), [M+H] + =627.28; 2.8 mg of single-configuration compound 9b or 9a (RT=18.847 min). [M+H] + =627.28.

[0262] Example 10

[0263] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(([1,1'-bis(cyclobutane)]-1-ylmethyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0264]

[0265] Compound 10 was prepared by referring to the method of compound 5. LC-MS: RT = 2.43 min, [MH] + =583.4. NMR data: 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.89(d,J=8.2Hz,1H),7.88(t,J=6.1Hz,1H),7.67(d,J=9.9 Hz,1H),7.11(d,J=12.7Hz,1H),4.13(q,J=8.2,5.8Hz,2H),3.88(s,3H),3.10(dd,J=13.4,6.7Hz,1 H),2.90(dd,J=13.3,5.4Hz,1H),2.62(d,J=8.5Hz,1H),2.30-2.16(m,2H),2.14-1.97(m,4H),1.8 7(dt,J=12.9,4.6Hz,2H),1.67(dp,J=10.8,6.4,5.3Hz,7H),1.61-1.35(m,9H),1.34-1.05(m,8H).

[0266] Embodiment 11

[0267] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-cyclopentylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0268]

[0269] Compound 11 was prepared by referring to the method of compound 2. LC-MS: RT = 2.25 min, [M+H] + =599.37. NMR data: 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.91(d,J=8.3Hz,1H),7.91(t,J=5.9Hz,1H),7.66 (d,J=9.9Hz,1H),7.11(d,J=12.7Hz,1H),4.13(t,J=8.3Hz,2H),3.88(d,J=1.1Hz,3H),3 .24(dd,J=13.4,6.9Hz,1H),3.00(dd,J=13.4,5.1Hz,1H),2.65(d,J=8.6Hz,1H),2.23(s ,1H),2.13-1.97(m,4H),1.87(d,J=12.2Hz,2H),1.81-1.36(m,15H),1.36–1.00(m,12H).

[0270] Example 12

[0271] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-cyclohexylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0272]

[0273] Compound 12 was prepared by referring to the method of compound 2. LC-MS: RT = 2.58 min, [M+H] + =613.4. NMR data: 1HNMR (400MHz, DMSO-d6) δ12.29(s,1H),8.95(d,J=8.1Hz,1H),7.89(t,J=6.1Hz,1H),7.66( d,J=9.9Hz,1H),7.10(d,J=12.8Hz,1H),4.13(q,J=8.6,8.0Hz,2H),3.88(s,3H),3.23(dd,J =13.6,6.8Hz,1H),3.02(dd,J=13.6,5.2Hz,1H),2.66(d,J=8.6Hz,1H),2.23(d,J=3.5Hz,1H ),2.13-1.97(m,4H),1.87(dd,J=13.1,6.3Hz,2H),1.67-1.40(m,14H),1.31-0.80(m,15H).

[0274] Example 13

[0275] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-(cyclopropylmethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0276]

[0277] Compound 13 was prepared by referring to the method of compound 2. LC-MS: RT = 2.19 min, [M+H] + =585.35. NMR data: 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.90(d,J=8.2Hz,1H),7.82(t,J=5.7Hz,1H),7.67(d,J=9.9Hz,1H),7.10( d,J=12.8Hz,1H),4.13(dd,J=18.3,10.9Hz,2H),3.88(s,3H),3.27(dd,J=13.4,6.3Hz,1H),3.12(dd,J=13.4,5.3 Hz,1H),2.67(d,J=8.5Hz,1H),2.23(s,1H),2.03(dd,J=23.5,10.5Hz,4H),1.88(d,J=9.4Hz,2H),1.76-1.58(m,6 H),1.57-1.34(m,4H),1.32-1.05(m,10H),0.54(dd,J=12.8,5.2Hz,1H),0.36-0.16(m,2H),-0.03--0.16(m,2H).

[0278] Embodiment 14

[0279] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-(cyclobutylmethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0280]

[0281] Compound 14 was prepared by referring to the method of compound 5. LC-MS: RT = 2.54 min, [M+H] + =599.40. NMR data: 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.92(d,J=8.2Hz,1H),7.81(t,J=5.7H z,1H),7.67(d,J=9.9Hz,1H),7.12(d,J=12.8Hz,1H),4.12(m,2H),3.89(s,3 H),3.13(m,1H),2.96(m,1H),2.67(d,J=8.4Hz,1H),2.22(q,J=8.0Hz,2H),2 .11-1.95(m,4H),1.95-1.72(m,4H),1.71-1.33(m,16H),1.31-1.08(m,8H).

[0282] Embodiment 15

[0283] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-(cyclopentylmethyl)cyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0284]

[0285] Compound 15 was prepared by referring to the method of compound 2. LC-MS: RT = 2.52 min, [M+H] + =613.4. NMR data: 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.95(d,J=8.1Hz,1H),7.89(t,J=6.1Hz, 1H),7.66(d,J=9.9Hz,1H),7.10(d,J=12.8Hz,1H),4.13(q,J=8.6,8.0Hz,2H), 3.88(s,3H),3.23(m,1H),3.02(m,1H),2.66(d,J=8.6Hz,1H),2.23(d,J=3.6Hz ,1H),2.14-1.98(m,4H),1.87(m,2H),1.75-1.36(m,15H),1.35-0.76(m,14H).

[0286] Example 16

[0287] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-(cyclopentylmethyl)cyclopropyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0288]

[0289] Compound 16 was prepared by referring to the method of compound 2. LC-MS: RT = 2.78 min, [M+H] + =599.4. NMR data: 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.91(d,J=8.1Hz,1H),7.91(t,J=5.4Hz,1H),7.67(d,J=9.9Hz,1H ),7.12(d,J=12.8Hz,1H),4.12(dd,J=18.2,10.5Hz,2H),3.89(s,3H),3.19(dd,J=13.5,6.4Hz,1H),2.75 (dd,J=13.6,4.5Hz,1H),2.63(d,J=8.6Hz,1H),2.21(s,1H),2.02(dd,J=31.2,6.6Hz,4H),1.93-1.83(m, 2H),1.81-1.70(m,1H),1.57-1.07(m,20H),0.99-0.78(m,2H),0.36-0.23(m,2H),0.12(q,J=9.9Hz,2H).

[0290] Embodiment 17

[0291] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-cyclobutylcyclopentyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0292]

[0293] Compound 17 was prepared by referring to the method of compound 5. LC-MS: RT = 2.25 min, [M+H] + =599.27. NMR data: 1 H NMR(400MHz,Chloroform-d)δ8.64(d,J=8.8Hz,1H),7.89(d,J=9.6Hz,1H),6.72(d,J=12.1Hz,1H ),5.70(t,J=6.1Hz,1H),4.42(t,J=8.6Hz,1H),4.19(tt,J=9.9,4.4Hz,1H),3.94(s,3H),3.02(d d,J=13.4,6.3Hz,1H),2.84(dd,J=13.4,5.8Hz,1H),2.52(d,J=3.6Hz,1H),2.46(d,J=8.5Hz,1H) ,2.42–2.22(m,4H),2.12–1.96(m,3H),1.84–1.57(m,9H),1.56–1.06(m,16H),0.95–0.76(m,1H).

[0294] Embodiment 18

[0295] Synthesis of (1S,4s)-4-((5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid

[0296] The specific synthetic route is as follows:

[0297]

[0298] Step A: Synthesis of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid

[0299] At 25°C, 5-bromo-2-methoxypyridine-3-carboxylic acid (5 g, 21.55 mmol), cuprous iodide (615.60 mg, 3.23 mmol), 1,10-phenanthroline (1.16 g, 6.46 mmol), cesium carbonate (17.55 g, 53.87 mmol) and benzyl alcohol (23.30 g, 215.49 mmol, 22.32 ml) were added to toluene (100 ml), and then the mixture was stirred at 110°C under nitrogen atmosphere for 10 hours. The reaction was basically complete as monitored by LC-MS.

[0300] The reaction mixture was cooled to 25 degrees Celsius. The mixture was filtered through a pad of silica gel powder to remove insoluble matter, and the filtrate was concentrated to obtain an oily crude product. The crude product was purified by reverse phase HPLC (0.1% formic acid) to obtain 900 mg of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid.

[0301] Step B: Synthesis of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester

[0302] At room temperature, 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid (750 mg, 2.89 mmol) was added to methanol (20 ml), sulfuric acid (2.90 mg, 28.93 μmol, 1.57 μl, 98% purity) was added, and the reaction solution was heated at 70 degrees Celsius for 0.5 hours. TLC monitoring was performed until the reaction was complete.

[0303] The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice water (10 ml) and extracted with ethyl acetate (20 ml × 2 times). The combined organic phase was washed with saturated sodium carbonate solution (15 ml × 2 times), saturated brine (15 ml × 2 times), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.83 g of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester.

[0304] Step C: Synthesis of 5-hydroxy-2-methoxypyridine-3-carboxylic acid methyl ester

[0305] At room temperature, 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester (830 mg, 3.04 mmol) was dissolved in methanol (1 ml), wet palladium / carbon (83 mg, 10% palladium / 55% water) was added, hydrogen was introduced and replaced, and stirred at room temperature for 1 hour. TLC was monitored until the reaction was complete.

[0306] The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 0.5 g of methyl 5-hydroxy-2-methoxypyridine-3-carboxylate. The product was used directly in the next step without further purification. LC-MS: RT = 0.351 min, [M+H] + =184.0.

[0307] Step D: Synthesis of methyl 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxynicotinate

[0308] At room temperature, naphthalene-1-ylmethyl (1r, 4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate (487.08 mg, 1.63 mmol) was dissolved in THF (5 ml), 5-hydroxy-2-methoxypyridine-3-carboxylic acid methyl ester (0.23 g, 1.26 mmol) and triphenylphosphine (658.72 mg, 2.51 mmol) were added in sequence, and di-tert-butyl azodicarboxylate (578.29 mg, 2.51 mmol) was slowly added, and the reaction solution was stirred at 25 degrees Celsius under a nitrogen atmosphere for 1 hour. TLC monitoring was performed until the reaction was complete.

[0309] The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-8 / 1) to obtain 1.4 g of methyl 2-methoxy-5-((1s, 4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxynicotinate.

[0310] Step E: Synthesis of 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalene-1-methoxy)carbonyl)cyclohexyl)oxy)nicotinic acid

[0311] At room temperature, 2-methoxy-5-((1s, 4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxynicotinic acid methyl ester (1.1 g, 2.37 mmol) was dissolved in tetrahydrofuran (10 ml) and water (10 ml), followed by the addition of lithium hydroxide monohydrate (129.46 mg, 3.09 mmol). The reaction solution was stirred at 25 degrees Celsius for 1 hour. LC-MS was used to monitor the reaction until it was complete.

[0312] The reaction solution was concentrated to remove most of the THF, diluted with water (20 ml), adjusted to pH 3 with 1 mol dilute hydrochloric acid, and then extracted with ethyl acetate (50 ml x 2 times). The combined organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 1.1 g of 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalene-1-methoxy)carbonyl)cyclohexyl)oxy)nicotinic acid was obtained.

[0313] Step F: Synthesis of naphthalene-1-methyl (1S, 4s)-4-((5-(((1S, 2R, 3S, 4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate

[0314] At room temperature, 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalene-1-methoxy)carbonyl)cyclohexyl)oxy)nicotinic acid (100 mg, 222.47 μmol) was dissolved in N,N-dimethylformamide (1 ml), (1R,2S,3R,4S)-3-amino-N-[(1-cyclopropylcyclobutyl)methyl]norborneol-2-carboxamide (58.37 mg, 222.47 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126.89 mg, 333.71 μmol), and diisopropylethylamine (143.76 mg, 1.11 mmol, 193.75 μl) were added, and the mixture was stirred at 25 degrees Celsius for 0.5 hours. The reaction was monitored by LC-MS until completion.

[0315] The reaction solution was concentrated to remove the solvent, and the crude product was purified by reverse phase HPLC (chromatographic column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 80%-100% B, time over 7 min), and freeze-dried to obtain 70 mg of naphthalene-1-methyl (1S, 4s)-4-((5-(((1S, 2R, 3S, 4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT=0.792 min, [M+H] + =694.5.

[0316] Step G: Synthesis of (1S,4s)-4-((5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid

[0317] Naphthalene-1-methyl (1S,4s)-4-((5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate (70 mg, 100.88 μmol) was dissolved in ethyl acetate (10 ml) at room temperature, wet palladium / carbon (7 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the mixture was stirred at room temperature for 0.5 hour. The reaction was monitored by LC-MS until completion.

[0318] The palladium / carbon was filtered off, and the mixture was washed with ethyl acetate (20 ml). The filtrate was concentrated and the crude product was purified by reverse phase HPLC (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 22%-52% B, time over 9 minutes). After preparative lyophilization, 35.87 mg of (1S, 4s)-4-((5-(((1S, 2R, 3S, 4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-6-methoxypyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 0.574 min, [M+H] + =554.3.

[0319] Compound 18 NMR data: 1H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.02-7.97 (m, 2H), 7.83 (d, J = 3.2 Hz, 1H), 4.30-4.22 (m, 1H), 4.13 (t, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.30-3.27 (m, 2H), 3.06-3.02 (m, 1H), 2 .69-2.64(m,1H),2.25(bs,1H),2.10-2.00(m,4H),1.93-1.85(m,2H),1.63-1.37(m,8H),1.34-1.2 2(m,4H),1.20-1.14(m,2H),1.11(s,3H),0.69-0.65(m,1H),0.17-0.14(m,2H),0.06-0.04(m,2H).

[0320] Embodiment 19

[0321] Synthesis of (1S,4s)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-(((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0322] The specific synthetic route is as follows:

[0323]

[0324] Step A: Synthesis of 5-bromo-4-chloro-2-methoxybenzoic acid

[0325] At 25°C, 4-chloro-2-methoxybenzoic acid (5 g, 26.80 mmol) was dissolved in glacial acetic acid (25 mL) and water (25 mL), followed by the addition of liquid bromine (4.50 g, 28.14 mmol, 1.45 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction was monitored by LC-MS until completion.

[0326] The reaction solution was poured into water (50 ml) and stirred for 30 minutes. After filtration, the filter cake was rinsed with water (50 ml × 3 times). The filtrate was concentrated to dryness to obtain 8.0 g of a yellow solid. At 0 degrees Celsius, the filtrate was quenched with a saturated sodium sulfite solution (100 ml) and a saturated sodium hydroxide solution (20 ml), filtered, and the filter cake solid was slurried and stirred with methyl tert-butyl ether (20 ml) for 30 minutes, and 5.7 g of 5-bromo-4-chloro-2-methoxybenzoic acid was obtained by filtration.

[0327] Step B: Synthesis of methyl 5-bromo-4-chloro-2-methoxybenzoate

[0328] At room temperature, sulfuric acid (214.87 mg, 2.15 mmol, 116.78 μL, 98% purity) was added to a solution of 5-bromo-4-chloro-2-methoxybenzoic acid (5.7 g, 21.47 mmol) in methanol (60 mL), and the mixture was heated at 80°C for 5 hours. The reaction was monitored by LC-MS until completion.

[0329] The reaction solution was cooled to room temperature, poured into ice water (100 ml), extracted with ethyl acetate (200 ml × 2 times), and the combined organic phase was washed with saturated sodium carbonate solution (150 ml × 2 times), saturated brine (150 ml × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5.2 g of methyl 5-bromo-4-chloro-2-methoxybenzoate.

[0330] Step C: Synthesis of methyl 4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzoate

[0331] At room temperature, methyl 5-bromo-4-chloro-2-methoxybenzoate (4.7 g, 16.81 mmol) was dissolved in dioxane (100 ml), and bis(triphenylphosphine)palladium (II) (6.40 g, 25.22 mmol), dichlorobis(triphenylphosphine)palladium (II) (354.07 mg, 504.45 μmol), and KOAc (4.95 g, 50.44 mmol) were added. The nitrogen atmosphere was replaced three times, and then the reaction solution was stirred at 110 degrees Celsius under a nitrogen atmosphere for 10 hours. LC-MS monitoring was performed until the reaction was complete.

[0332] The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was reduced to obtain 10.0 g of crude methyl 4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronic acid-2-yl)benzoate. The product was used directly in the next step without further purification. LC-MS: RT = 0.593 min, [M+H] + =327.1.

[0333] Step D: Synthesis of methyl 4-chloro-5-hydroxy-2-methoxybenzoate

[0334] At room temperature, methyl 4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzoate (5 g, 15.31 mmol) was dissolved in tetrahydrofuran (50 ml), cooled to 0 °C, and hydrogen peroxide (17.36 g, 153.10 mmol, 14.71 ml, 30% purity) was slowly added. The mixture was stirred at room temperature for 2 hours and monitored by LC-MS until the reaction was complete.

[0335] The reaction solution was quenched by adding 500 ml of saturated sodium sulfite solution. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml × 2 times). The combined organic phase was washed with saturated brine (150 ml × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain 2.1 g of methyl 4-chloro-5-hydroxy-2-methoxybenzoate. LC-MS: RT = 0.427 min, [M+H] + =217.0.

[0336] Step E: Synthesis of methyl 4-chloro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate

[0337] At room temperature, naphthalen-1-ylmethyl (1r, 4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate (544.49 mg, 2.51 mmol) was dissolved in toluene (5 ml), methyl 4-chloro-5-hydroxy-2-methoxybenzoate (0.5 g, 1.68 mmol), tributylphosphine (508.55 mg, 2.51 mmol, 620.18 μl) were added, ADDP (634.22 mg, 2.51 mmol) was slowly added, and stirred at 80 °C under nitrogen atmosphere for 2 hours, and the reaction was monitored by LC-MS until completion.

[0338] The reaction solution was cooled to room temperature. The solvent was removed by concentration. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1–0 / 1) to obtain 6.0 g of a yellow solid. At 25 degrees Celsius, 6.0 g of the yellow solid was slurried and stirred with a mixed solvent (20 ml) of petroleum ether / ethyl acetate = 10 / 1 for 2 hours, and filtered to obtain 1.7 g of methyl 4-chloro-2-methoxy-5-((1s, 4s)-4-methyl-4-((naphthalene-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate.

[0339] Step F: Synthesis of 4-chloro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid

[0340] Methyl 4-chloro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoate (1.7 g, 3.42 mmol) was dissolved in tetrahydrofuran (20 ml) and water (20 ml) at room temperature, and then lithium hydroxide monohydrate (186.59 mg, 4.45 mmol) was added, and the reaction solution was stirred at 25 degrees Celsius for 2 hours. LC-MS was used to monitor the reaction until it was complete.

[0341] The reaction solution was concentrated to remove most of the tetrahydrofuran. The residue was diluted with water (20 ml), the pH was adjusted to 3 with 1 mol dilute hydrochloric acid, and extracted with ethyl acetate (50 ml x 2 times). The combined organic layer was washed with 50 ml of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. 1.3 g of 4-chloro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid was obtained.

[0342] Step G: Synthesis of naphth-1-ylmethyl (1S,4s)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0343] To 4-chloro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (150 mg, 310.59 μmol) was dissolved in N,N-dimethylformamide (5 ml) at room temperature, (1R,2S,3R,4S)-3-amino-N-[(1-cyclopropylcyclobutyl)methyl]norborneol-2-carboxamide (81.50 mg, 310.59 μmol) was added, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (153.52 mg, 403.77 μmol) and diisopropylethylamine (100.35 mg, 776.48 μmol, 135.24 μl) were added, and the mixture was stirred at 25°C for 0.5 h. The reaction was monitored by LC-MS until completion.

[0344] The reaction solution was concentrated to remove the solvent, and the crude product was purified by reverse phase HPLC (chromatographic column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; gradient: 80%-100% B, time over 7 min), and preparative lyophilization to obtain 160 mg of naphthalen-1-ylmethyl (1S,4s)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate, LC-MS: RT=0.816 min, [M+H] + =727.4.

[0345] Step H: Synthesis of (1S,4S)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0346] Naphthalen-1-ylmethyl (1S,4s)-4-(2-chloro-5-(((1S,2R,3S,4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (120 mg, 164.99 μmol) was dissolved in ethyl acetate (10 ml) at room temperature, wet palladium / carbon (12 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was stirred at room temperature for 0.5 hour. LC-MS was monitored until the reaction was completed.

[0347] The palladium / carbon was filtered off, and the mixture was washed with ethyl acetate (20 ml). The filtrate was concentrated and the crude product was purified by reverse phase HPLC (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 30%-60% B, time over 9 minutes). After preparative lyophilization, 58.96 mg of (1S, 4s)-4-(2-chloro-5-(((1S, 2R, 3S, 4R)-3-((1-cyclopropylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 0.623 min, [M+H] + =587.4.

[0348] Compound 19 NMR data: 1H NMR (400MHz, DMSO-d6) δ12.30 (br s, 1H), 8.94 (d, J = 8.0Hz, 1H), 7.98 (t, J = 6.4Hz, 1H), 7.62 (s, 1H), 7.22 (s, 1H), 4.25-4.19 (m, 1H), 4.11 (t, J = 8.0Hz, 1H), 3.88 (s, 3H), 3.27-3.21 (m, 1H), 3.10-3.06 (m, 1H), 2.67-2.64 (m, 1H), 2.24 (br s,1H),2.09–1.99(m,4H),1.89-1.86(m,2H),1.61-1.43(m,8H),1.34-1.22(m,5H),1. 19-1.13(m,2H),1.11(s,3H),0.71-0.65(m,1H),0.19-0.14(m,2H),0.08-0.04(m,2H).

[0349] Examples 20-30

[0350] Compounds 20-30 were prepared according to the method of Example 2, 5, 18 or 19. The structures and characterization data of compounds 20-30 are as follows:

[0351]

[0352]

[0353] Example 31A

[0354] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(benzothiophen-2-ylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0355] The specific synthetic route is as follows:

[0356]

[0357] Step A: Synthesis of benzothiophene-2-amine

[0358] The hydrogen bromide / acetic acid solution was cooled to 0-5 degrees Celsius with ice water, tert-butyl benzothiophen-2-ylcarbamate (1 g, 4 mmol) was slowly added, the temperature was slowly raised to room temperature, and the reaction was stirred for 2 hours. The reaction was monitored by LC-MS until completion.

[0359] Most of the hydrogen bromide / acetic acid was concentrated, 30 ml of ethyl acetate was added to dilute, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 ml × 3 times), the organic phases were combined, washed with saturated brine (50 ml × 1 time), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to obtain 340 mg of benzothiophene-2-amine. LC-MS: RT = 1.87 min, [M+H] + =150.10.

[0360] Step B: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(benzo[b]thiophen-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0361] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (200 mg, 0.33 mmol) and benzothiophene-2-amine (74 mg, 0.50 mmol) were dissolved in dichloromethane (2 ml), N,N-diisopropylethylamine (213 mg, 1.65 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (420 mg, 0.66 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0362] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 180 mg of naphthalene-2-ylmethyl (1S, 4s)-4-(5-(((1R, 2R, 3S, 4S)-3-(benzo[b]thiophen-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.45 min, [M+H] + =733.33.

[0363] Step C: Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(benzothiophen-2-ylcarbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0364] Naphthalen-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(benzo[b]thiophen-2-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (170 mg, 0.23 mmol) was dissolved in ethanol (10 ml) at room temperature, wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was carried out at room temperature for 15 hours. LC-MS monitoring was performed until the reaction was completed.

[0365] The palladium / carbon was filtered off, and 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). 33 mg of (1S, 4s)-4-(5-((1S, 2R, 3S, 4R)-3-(benzothiophen-2-ylcarbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.398 min, [MH] - =593.2.

[0366] Example 32A

[0367] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(benzothiophen-3-ylcarbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0368] The specific synthetic route is as follows:

[0369]

[0370] Step A: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(benzo[b]thiophen-3-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0371] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (200 mg, 0.33 mmol) and benzothiophene-2-amine (74 mg, 0.50 mmol) were dissolved in dichloromethane (3 ml), N,N-diisopropylethylamine (213 mg, 1.65 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (420 mg, 0.66 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0372] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 140 mg of naphthalene-2-ylmethyl (1S, 4s)-4-(5-(((1R, 2R, 3S, 4S)-3-(benzo[b]thiophen-3-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.39 min, [M+H] + =733.27.

[0373] Step B: Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-(benzothiophen-3-ylcarbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0374] Naphthalen-2-ylmethyl (1S,4s)-4-(5-(((1R,2R,3S,4S)-3-(benzo[b]thiophen-3-ylcarbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (140 mg, 0.19 mmol) was dissolved in ethanol (10 ml) at room temperature, wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was carried out at room temperature for 15 hours. LC-MS monitoring was performed until the reaction was completed.

[0375] The palladium / carbon was filtered off, and 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). 30 mg of (1S, 4s)-4-(5-((1S, 2R, 3S, 4R)-3-(benzothiophen-3-ylcarbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.15 min, [M+H] + =595.23.

[0376] Example 33A

[0377] Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0378] The specific synthetic route is as follows:

[0379]

[0380] Step A: Synthesis of benzyl (7-(trifluoromethyl)benzothiophen-2-yl) carbamate

[0381] At room temperature, 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in toluene (30 ml), N,N-diisopropylethylamine (1.03 g, 8.0 mmol) was added, the temperature was lowered to 0 degrees Celsius, diphenylphosphoryl azide (1.16 g, 4.2 mmol) was slowly added, the temperature was slowly raised to room temperature for reaction overnight, the reaction was completed after TLC monitoring, saturated citric acid water (30 ml × 2 times) was added to wash, saturated brine (30 ml × 1 time) was added, the mixture was dried over anhydrous sodium sulfate, filtered, benzyl alcohol (0.865 g, 8.0 mmol) was added, the temperature was raised to 90 degrees Celsius for reaction for 2 hours, and the reaction was completed after LC-MS monitoring.

[0382] The reaction solution was concentrated and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 10). 1.2 g of oily benzyl (7-(trifluoromethyl)benzothiophen-2-yl) carbamate was obtained. LC-MS: RT = 2.19 min, [MH] - =350.01.

[0383] Step B: Synthesis of 7-(trifluoromethyl)benzothiophene-2-amine

[0384] The hydrogen bromide / acetic acid solution was cooled to 0-5 degrees Celsius with ice water, benzyl (7-(trifluoromethyl)benzothiophen-2-yl) carbamate (1.2 g, 3.4 mmol) was slowly added, the temperature was slowly raised to room temperature, and the reaction was stirred for 2 hours. The reaction was monitored by LC-MS until completion.

[0385] Most of the hydrogen bromide / acetic acid was concentrated, 50 ml of ethyl acetate was added to dilute, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 ml × 3 times), the organic phases were combined, washed with saturated brine (80 ml × 1 time), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to obtain 0.7 g of 7-(trifluoromethyl)benzothiophene-2-amine. LC-MS: RT = 2.02 min, [M+H] + =217.98.

[0386] Step C: Synthesis of naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0387] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (300 mg, 0.5 mmol) and 7-(trifluoromethyl)benzothiophene-2-amine (175 mg, 1.0 mmol) were dissolved in dichloromethane (5 ml), N,N-diisopropylethylamine (193 mg, 1.5 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (1.6 g, 2.5 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0388] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 200 mg of naphthalene-2-ylmethyl (1S, 4s)-4-(2-fluoro-4-methoxy-5-((1R, 2R, 3S, 4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.53 min, [MH]- = 801.02.

[0389] Step D: Synthesis of (1S,4S)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0390] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (200 mg, 0.25 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (30 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0391] The palladium / carbon was filtered off, and 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). 83 mg of (1S, 4s)-4-(2-fluoro-4-methoxy-5-((1S, 2R, 3S, 4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.21 min, [MH]- = 661.03.

[0392] Example 33B

[0393] Synthesis of (1R,4s)-4-(2-fluoro-4-methoxy-5-((1S,2S,3R,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0394] The specific synthetic route is as follows:

[0395]

[0396] Step A: Synthesis of naphth-2-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S,3R4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0397] At room temperature, (1S,2R,3S,4R)-3-(4-fluoro-2-methoxy-5-((1s,4R)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (150 mg, 0.25 mmol) and 7-(trifluoromethyl)benzothiophene-2-amine (88 mg, 0.5 mmol) were dissolved in dichloromethane (5 ml), N,N-diisopropylethylamine (96 mg, 0.75 mmol) was added, the temperature was lowered to 0 degrees Celsius, propylphosphonic anhydride (0.8 g, 1.25 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0398] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 94 mg of naphthalene-2-ylmethyl (1R, 4s)-4-(2-fluoro-4-methoxy-5-((1R, 2S, 3R4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate were obtained. LC-MS: RT = 0.746 min, [M+H] + =803.3.

[0399] Step D: Synthesis of (1R,4s)-4-(2-fluoro-4-methoxy-5-((1S,2S,3R,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0400] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (94 mg, 0.12 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (20 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0401] The palladium / carbon was filtered off, and 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). 50 mg of (1R, 4s)-4-(2-fluoro-4-methoxy-5-((1S, 2S, 3R, 4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 0.516 min, [MH] - =661.2.

[0402] Example 34A

[0403] Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0404] The specific synthetic route is as follows:

[0405]

[0406] Step A: Synthesis of tert-butyl (6-(trifluoromethyl)benzothiophen-2-yl)carbamate

[0407] At room temperature, 6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (2.0 g, 8.12 mmol) was dissolved in tert-butanol (20 ml), triethylamine (1.64 g, 16.2 mmol, 2.26 ml) and diphenylphosphoryl azide (2.68 g, 9.75 mmol, 2.1 ml) were added, and the mixture was heated to 90 °C and stirred overnight. The reaction was completed by monitoring by TLC.

[0408] The reaction solution was concentrated, diluted with ethyl acetate, washed with 1 mol sodium hydroxide (30 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4.4 g of tert-butyl (6-(trifluoromethyl)benzothiophen-2-yl)carbamate. LC-MS: RT = 0.611 min, [M+H-56] + = 262.0.

[0409] Step B: Synthesis of 6-(trifluoromethyl)benzothiophene-2-amine

[0410] The hydrogen chloride / dioxane solution was cooled to 0-5 degrees Celsius with ice water, tert-butyl (6-(trifluoromethyl)benzothiophen-2-yl)carbamate (4.4 g, 13.8 mmol) was slowly added, the temperature was slowly raised to room temperature, the reaction was stirred for 2 hours, and the reaction was monitored by LC-MS until completion.

[0411] Most of the hydrogen chloride / dioxane was concentrated, 50 ml of ethyl acetate was added to dilute, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (50 ml × 3 times), the organic phases were combined, washed with saturated brine (80 ml × 1 time), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to obtain 1 gram of 6-(trifluoromethyl)benzothiophene-2-amine. LC-MS: RT = 0.532 min, [M+H] + =218.1.

[0412] Step C: Synthesis of naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0413] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (107 mg, 0.2 mmol) and 6-(trifluoromethyl)benzothiophen-2-amine (200 mg, 0.3 mmol) were dissolved in N,N-dimethylformamide (2 ml). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (188 mg, 0.496 mmol) and N,N-diisopropylethylamine (85.6 mg, 0.662 mmol, 0.115 ml) were added. The mixture was reacted at 60 °C for 12 hours and monitored by LC-MS until the reaction was almost complete.

[0414] The reaction solution was diluted with water (10 ml), extracted with ethyl acetate (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 100 mg of naphthalene-2-ylmethyl (1S, 4s)-4-(2-fluoro-4-methoxy-5-((1R, 2R, 3S, 4S)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 0.729 min, [M+H] + =801.3.

[0415] Step D: Synthesis of (1S,4S)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0416] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (100 mg, 0.124 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (30 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was completed.

[0417] The palladium / carbon was filtered off, and 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). 13.8 mg of (1S, 4s)-4-(2-fluoro-4-methoxy-5-((1S, 2R, 3S, 4R)-3-((6-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 0.623 min, [M+H] + =663.2.

[0418] Example 35A

[0419] Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((5-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0420]

[0421] Compound 35A was prepared by the method of Reference Example 34A. LC-MS: RT = 0.621 min, [M+H] + =663.2.

[0422] Example 36A

[0423] Synthesis of (1S,4s)-4-((6-methoxy-5-(((1S,2R,3S,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid

[0424] The specific synthetic route is as follows:

[0425]

[0426] Step A: Synthesis of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid

[0427] At room temperature, 5-bromo-2-methoxypyridine-3-carboxylic acid (5 g, 21.55 mmol) was dissolved in toluene (100 ml), and cuprous iodide (615.60 mg, 3.23 mmol), 1,10-phenanthroline (1.16 g, 6.46 mmol), cesium carbonate (17.55 g, 53.87 mmol) and benzyl alcohol (23.30 g, 215.49 mmol, 22.32 ml) were added. The atmosphere was replaced and nitrogen was introduced. The reaction was heated to 110 °C and stirred overnight. The reaction was basically complete as monitored by TLC.

[0428] The reaction solution was cooled to room temperature, filtered through a pad of silica gel powder to remove insoluble matter, and the reaction solution was concentrated. The crude product was purified by reverse phase HPLC (0.1% formic acid) to give 900 mg of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid.

[0429] Step B: Synthesis of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester

[0430] At room temperature, 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid (750 mg, 2.89 mmol) was dissolved in methanol (20 mL), and 1 drop of concentrated sulfuric acid was added. The reaction was heated to 70 °C for 0.5 h and monitored by TLC until the reaction was complete.

[0431] The reaction solution was cooled to room temperature, poured into ice water (10 ml), and extracted with ethyl acetate (20 ml × 3 times). The combined organic phase was washed with saturated sodium carbonate solution (15 ml × 1 time), saturated brine (15 ml × 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.83 g of 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester.

[0432] Step C: Synthesis of 5-hydroxy-2-methoxypyridine-3-carboxylic acid methyl ester

[0433] At room temperature, 5-benzyloxy-2-methoxy-pyridine-3-carboxylic acid methyl ester (830 mg, 3.04 mmol) was dissolved in methanol (1 ml), wet palladium / carbon (83 mg, 10% palladium / 55% water) was added, and hydrogen (50 Psi) was introduced after replacement. The reaction was carried out at room temperature for 1 hour and monitored by TLC until the reaction was completed.

[0434] The palladium / carbon was filtered off, washed with methanol (10 ml), and the filtrate was concentrated to obtain 0.5 g of methyl 5-hydroxy-2-methoxypyridine-3-carboxylate. The product was used directly in the next step without further purification. LC-MS: RT = 0.351 min, [M+H] + =184.0.

[0435] Step D: Synthesis of methyl 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxynicotinate

[0436] At room temperature, naphthalen-1-ylmethyl (1r, 4r)-4-hydroxy-1-methylcyclohexane-1-carboxylate was dissolved in tetrahydrofuran (5 ml), 5-hydroxy-2-methoxypyridine-3-carboxylic acid methyl ester (0.23 g, 1.26 mmol), triphenylphosphine (658.72 mg, 2.51 mmol) were added, and di-tert-butyl azodicarboxylate (578.29 mg, 2.51 mmol) was slowly added. The reaction was stirred at room temperature for 1 hour and monitored by TLC until the reaction was complete.

[0437] The reaction solution was concentrated and the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-8 / 1) to obtain 1.4 g of methyl 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxynicotinate.

[0438] Step E: Synthesis of 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)nicotinic acid

[0439] At room temperature, methyl 2-methoxy-5-[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyloxy]pyridine-3-carboxylate (1.1 g, 2.37 mmol) was dissolved in tetrahydrofuran (10 ml) and water (10 ml), followed by the addition of lithium hydroxide monohydrate (129.46 mg, 3.09 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was completed by LC-MS monitoring.

[0440] Concentrate to remove most of the tetrahydrofuran, dilute with water (20 ml), adjust the pH to 3 with 1 mol dilute hydrochloric acid, extract with ethyl acetate (50 ml x 2 times). The combined organic layer is washed with brine (50 ml x 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.1 g of 2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)nicotinic acid.

[0441] Step F: Synthesis of naphth-2-ylmethyl (1S,4s)-4-((6-methoxy-5-(((1R,2R,3S,4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate

[0442] At room temperature, (1R,2S,3R,4S)-3-(5-(((1s,4S)-4-carboxy-4-methylcyclohexyl)oxy)-4-fluoro-2-methoxybenzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (200 mg, 0.34 mmol) and 7-(trifluoromethyl)benzothiophene-2-amine (74 mg, 0.4 mmol) were dissolved in dichloromethane (5 ml), N,N-diisopropylethylamine (129 mg, 1 mmol) was added, the temperature was cooled to zero degrees Celsius, propylphosphonic anhydride (0.95 g, 1.5 mmol, 50% by mass solution in ethyl acetate) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0443] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3). 130 mg of naphthalene-2-ylmethyl (1S, 4s)-4-((6-methoxy-5-(((1R, 2R, 3S, 4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate was obtained.

[0444] Step G: Synthesis of (1S,4s)-4-((6-methoxy-5-(((1S,2R,3S,4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid

[0445] Naphthalen-2-ylmethyl (1S,4s)-4-((6-methoxy-5-(((1R,2R,3S,4S)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylate (50 mg, 0.063 mmol) was dissolved in ethanol (10 ml) at room temperature, wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was carried out at room temperature for 15 hours. LC-MS monitoring was performed until the reaction was completed.

[0446] The palladium / carbon was filtered off, and 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). 18 mg of (1S, 4s)-4-((6-methoxy-5-(((1S, 2R, 3S, 4R)-3-((7-(trifluoromethyl)benzo[b]thiophen-2-yl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)pyridin-3-yl)oxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 0.616 min, [M+H] + =646.2.

[0447] Examples 36B-76D

[0448] Compounds 36B-76D were prepared according to the method of Example 31A, 33A, 33B or 36A. The structures and characterization data (mass spectra and liquid phase retention times) of the compounds 36B-76D are as follows:

[0449]

[0450]

[0451]

[0452] Experiment 77 Human RXFP1 receptor agonist in vitro activity test

[0453] In this experiment, a CHO-K1 cell line stably transfected with human RXFP1 receptor was used to evaluate the activity of the compound by detecting the cAMP produced after stimulating the RXFP1 receptor coupled to Gs protein.

[0454] Main reagents: cAMP detection kit (Cisbio), 1M HEPES (Invitrogen), HBSS (Invitrogen), BSA (Sigma), IBMX (Sigma).

[0455] Test process:

[0456] (1) Compound preparation: The test compound was dissolved in DMSO and diluted 4-fold to 10 concentration gradients. 250 nL of each concentration was transferred to the test plate (OptiPlate-384-well plate) using Echo;

[0457] (2) Assay buffer: 1X stimulation buffer, 500 μM IBMX, deionized water;

[0458] (3) Cell preparation: After thawing, the frozen cells (RXFP1 cAMP cells) were washed twice with HBSS and then resuspended in stimulation buffer;

[0459] (4) Add 10 μL of cell suspension containing 10,000 cells to each well of the test plate, centrifuge at 1,000 rpm for 5 seconds, and then incubate at 37°C for 60 minutes;

[0460] (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;

[0461] (6) Read the plate using EnVision microplate reader.

[0462] Data analysis: The response value of each concentration was calculated using the following formula, and then the curve was fitted using Graphpad software to obtain the EC 50 value.

[0463] %Effect=100×(Sample Raw Value-Low Control Average) / (High ControlAverage-Low Control Average)

[0464] Table 1 Human RXFP1 receptor agonist activity test data

[0465]

[0466]

[0467] According to the data in Table 1, it can be seen that the compounds of the present invention have good agonist activity on the RXFP1 receptor. Specifically, when n=1 and W contains 2 or more C3-C8 cycloalkyl groups, the agonist activity of the compounds on RXFP1 is better. In addition, the applicant has also found that when R 1a , R 1b When selected from substituted or unsubstituted 7-12 membered heteroaryl groups, the agonist activity of the compounds on RXFP1 is also significantly better than that of R 1a , R 1b A compound selected from a 6-membered heteroaryl, a substituted or unsubstituted 7-12-membered benzoheterocyclyl or a substituted or unsubstituted 7-12-membered benzocarbocyclyl.

[0468] 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. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A RXFP1 receptor agonist, or an isomer, racemate or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor agonist is shown in general formula (I): Wherein, the A ring is selected from: The Z is selected from hydrogen or The m is an integer selected from 0, 1, 2 or 3; Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; X is selected from -O-, -NH-, -N(Me)- or -CH2-; The Y is selected from The U is selected from The V is selected from The W is selected from The n is an integer selected from 0 or 1; The R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 are not H at the same time; or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0; The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy; The R 1a , R 1b are independently selected from hydrogen, substituted or unsubstituted 7-12 membered heteroaryl, substituted or unsubstituted 7-12 membered benzocarbocyclyl or substituted or unsubstituted 7-12 membered benzoheterocyclyl; or R 1a and R 1b Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted 7-12-membered heteroaryl group or a substituted or unsubstituted 7-12-membered benzoheterocyclyl group; The "substituted" substituents are independently selected from H, halogen, -CN, -NH2, -COOH, -SO3H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 One or more of aryl or 5-10 membered heteroaryl.

2. The RXFP1 receptor agonist according to claim 1, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The A ring is selected from: The Z is selected from hydrogen or The m is an integer selected from 0, 1, 2 or 3; Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; X is selected from -O-, -NH-, -N(Me)- or -CH2-; Said Y and U are the same as those in claim 1; The V is selected from The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0; The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8 cycloalkyl, C1-C6 alkylC3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy.

3. A RXFP1 receptor agonist, or an isomer, racemate or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor agonist is shown in general formula (IA) or (IB): Wherein, said T1 and T2 are independently selected from CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; said T is independently selected from C or N; when T is selected from N, R 1 does not exist; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The Y is selected from The Z is selected from hydrogen or The U is selected from The V is selected from The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C2-C6 alkyl, C2-C6 heteroalkyl, C2-C6 haloheteroalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkylC3-C8cycloalkyl, C1-C6 alkylC3-C8heterocycloalkyl, C3-C8cycloalkylC1-C3 alkyl, C3-C8heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8cycloalkyl, C1-C6 haloalkylC3-C8heterocycloalkyl, C3-C8 halocycloalkyloxy, C3-C8 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl, a C3-C8 halocycloalkyl or a C3-C8 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0; The R 4 Selected from C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 halocycloalkyl, C3-C8 haloheterocycloalkyl, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkyloxy, C3-C8 heterocycloalkyloxy, C1-C6 alkyl C3-C8 cycloalkyl, C1-C6 alkyl C3-C8 heterocycloalkyl, C3-C8 cycloalkylC1-C3 alkyl, C3-C8 heterocycloalkylC1-C3 alkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 cycloalkyl, C1-C6 haloalkylC3-C8 heterocycloalkyl, C3-C8 halocycloalkyloxy or C3-C8 haloheterocycloalkyloxy; Preferably, the RXFP1 receptor agonist has a structure represented by the general formula (IAA) or (IBA): Further preferably, the RXFP1 receptor agonist has a structure represented by the general formula (IAB) or (IBB):

4. The RXFP1 receptor agonist according to any one of claims 1 to 2, or its isomer, racemate or pharmaceutically acceptable salt, characterized in that: The RXFP1 receptor agonist has a structure shown in general formula (II) or (IIA): Wherein, the definitions of X, T1, T2, T3 and W are the same as those in claim 2. Alternatively, the RXFP1 receptor agonist has a structure represented by general formula (III) or (IIIA): Wherein, the definitions of X, T1, T2, T3, W and m are the same as those in claim 2.

5. The RXFP1 receptor agonist according to any one of claims 1 to 4, or its isomer, racemate or pharmaceutically acceptable salt, characterized in that: The R 1 is selected from hydrogen, fluorine, chlorine or cyano; said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, C3-C6 cycloalkyl, C4-C7 heterocycloalkyl, C3-C6 cycloalkyloxy, C4-C7 heterocycloalkyloxy, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C7 heterocycloalkyl, C3-C6 cycloalkyl C1-C3 alkyl, C4-C7 heterocycloalkyl C1-C3 alkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C3-C6 cycloalkyl, C1-C3 haloalkyl C4-C7 heterocycloalkyl, C3-C6 halocycloalkyloxy, C4-C7 haloheterocycloalkyloxy, And R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C6 cycloalkyl, a C3-C6 halocycloalkyl or a C4-C7 heterocycloalkyl; and when R 2 and R 3 When the carbon atom to which it is attached forms a C3-C6 cycloalkyl group, a C3-C6 halocycloalkyl group or a C4-C7 heterocycloalkyl group, n is not 0; The R 4 Selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C3-C6 halocycloalkyl, C4-C7 haloheterocycloalkyl, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C7 heterocycloalkyl, C3-C6 cycloalkyloxy, C4-C7 heterocycloalkyloxy, C1-C4 alkyl C3-C6 cycloalkyl, C1-C4 alkyl C4-C4 heterocycloalkyl, C3-C6 cycloalkylC1-C3 alkyl, C4-C7 heterocycloalkylC1-C3 alkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC3-C6 cycloalkyl, C1-C3 haloalkylC4-C7 heterocycloalkyl, C3-C6 halocycloalkyloxy and C4-C7 haloheterocycloalkyloxy.

6. An RXFP1 receptor agonist according to claim 1, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor agonist is shown in the general formula (IC): in: Said T1, T2 or T3 are independently selected from CR 1 , CR5, CR6 or N; said R 1 , R5 or R6 are independently selected from hydrogen, halogen or cyano; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The A ring is selected from: The m is an integer selected from 0, 1, 2 or 3; The R 1a , R 1b are independently selected from hydrogen, substituted or unsubstituted 7-12 membered heteroaryl, substituted or unsubstituted 7-12 membered benzocarbocyclyl or substituted or unsubstituted 7-12 membered benzoheterocyclyl; or R 1a and R 1b Together with the nitrogen atom to which it is attached, it forms a substituted or unsubstituted 7-12-membered heteroaryl group or a substituted or unsubstituted 7-12-membered benzoheterocyclyl group; The "substituted" substituents are independently selected from H, halogen, -CN, -NH2, -COOH, -SO3H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 One or more of aryl or 5-10 membered heteroaryl.

7. The RXFP1 receptor agonist derivative according to claim 6, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor agonist derivative is shown in the general formula (ICA), general formula (ICAA), general formula (ICAB), general formula (ICB), general formula (ICBA), general formula (ICBB) or general formula (ICC), general formula (ICCA), general formula (ICCB): Among them, X, T1, T2, T3, m, R 1a and R 1b The definition is the same as that of claim 6.

8. The RXFP1 receptor agonist derivative according to any one of claims 6 to 7, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The R 1a , R 1b are independently selected from: H, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted indolyl, substituted or unsubstituted 2,3-dihydro-1H-indenyl, substituted or unsubstituted isoindolinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted thiazolopyridinyl, substituted or unsubstituted thienopyridinyl; or R 1a and R 1b Together with the attached nitrogen atom, it forms: The "substituted" substituents are independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl; Preferably, the R 1a , R 1b are independently selected from: H, benzothienyl, trifluoromethylbenzothienyl, halobenzothienyl, cyanobenzothienyl, methylbenzothienyl, benzothiazolyl, benzimidazolyl, thiazo[4,5-b]pyridinyl, thieno[2,3-b]pyridinyl, indolyl, 2,3-dihydro-1H-indenyl, isoindolyl; or R 1a and R 1b Together with the attached nitrogen atom, More preferably: the R 1a , R 1b are independently selected from: H, or R 1a and R 1b Together with the attached nitrogen atom, it forms:

9. The RXFP1 receptor agonist according to any one of claims 1 to 8, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor agonist is selected from the compounds described in Table 1A or Table 1B.

10. A pharmaceutical composition, characterized in that The invention comprises the RXFP1 receptor agonist according to any one of claims 1 to 9, or its isomer, racemate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

11. Use of the RXFP1 receptor agonist according to any one of claims 1 to 9, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for preventing or treating a disease associated with the RXFP1 receptor; preferably, the RXFP1 receptor associated disease is selected from heart failure.

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