RXFP1 receptor modulator and preparation method and medical application thereof

Abstract

The invention provides a compound which is shown in a formula (I) and can be used as an RXFP1 receptor modulator, and a preparation method and medical application thereof, and the compound has good RXFP1 receptor agonist activity and can be used for treating heart failure.

Description

A RXFP1 receptor modulator, its preparation method and medical use Technical Field

[0001] The present invention belongs to the technical field of chemical medicines, and in particular relates to an RXFP1 receptor modulator, a preparation method thereof, and medical uses 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 and B) of 24 and 29 amino acids, respectively, linked by two disulfide bonds, with the A chain further having one intramolecular disulfide bond (see Schwabe & McDonald (1977) Science 197:914-915). RLN2 is produced from its prohormone (prorelaxin) by cleavage of its C peptide.

[0003] Physiologically, RLN2 exhibits multiple functions that regulate cardiovascular, hepatic, neural, pancreatic, pulmonary, and renal adaptations such as vasodilation, antifibrosis, and angiogenesis, although it was originally described as a pregnancy hormone. RLN2 signaling occurs through two distinct classes of G-protein-coupled receptors (GPCRs), the leucine-rich repeat-containing GPCRs LGR7 and LGR8, now known as RXFP1 and RXFP2 receptors, respectively.

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

[0005] Most of the relaxin RLN2 mimetics reported so far are peptides, and very few small-molecule RXFP1 modulators have been reported. For example, patent WO2013165606A1 discloses a small-molecule relaxin modulator, the compound of which can selectively activate the RXFP1 receptor with an EC50 value of approximately 94 nM. Patent WO2022122773A1 discloses 4-(2-fluoro-4-methoxy-5-3-(((1-methylcyclobutyl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid derivatives and similar compounds as RXFP1 modulators for the treatment of heart failure. The compound can also selectively activate the RXFP1 receptor and can be used to treat heart failure, with an EC50 value of approximately 6.3 nM.

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

[0007] Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention provides a RXFP1 receptor modulator.

[0009] The present invention is achieved through the following technical solution: The present invention provides a RXFP1 receptor modulator, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor modulator is shown in general formula (I):

[0010] Where: R 1 is selected from hydrogen, halogen or cyano; R8 is selected from: C1-C6 alkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 haloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl; R6 is selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, halogen, C1-C6 alkoxy; R7 is selected from: H, C1-C6 alkyl; or R7 and R8 together with the atoms to which they are connected form a 3-6 membered ring lactone;

[0011] Said Y1 and Y2 are independently selected from: CH or N;

[0012] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0013] The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the “substituted” substituent is one or more 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, Z is an integer selected from 0, 1, 2 or 3.

[0014] Further, as a preferred technical solution of the present invention, the R8 is selected from: methyl, methoxymethyl (CH3OCH2-), hydroxymethyl (HO-CH2-), cyclopropylmethyl, monofluoromethyl (FCH2-), difluoromethyl (F2CH-) or trifluoromethyl (F3C-);

[0015] Furthermore, as a preferred technical solution of the present invention, the R7 is selected from: H or methyl;

[0016] Furthermore, as a preferred technical solution of the present invention, the R6 is selected from: F, methoxy, monofluoromethoxy (FCH2O-), difluoromethoxy (F2CHO-) or trifluoromethoxy (F3OC-);

[0017] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor modulator, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor modulator is as shown in general formula (I-1) or (I-2):

[0018] Where: R 1 is selected from hydrogen, fluorine or cyano; R4 is selected from H, hydroxyl, C1-C6 alkoxy; R5 is selected from C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl;

[0019] Said Y1 and Y2 are independently selected from: CH or N;

[0020] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0021] The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the “substituted” substituent is one or more 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 10One or more of aryl or 5-10 membered heteroaryl, Z is an integer selected from 0, 1, 2 or 3.

[0022] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor modulator, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that the structure of the RXFP1 receptor modulator is as shown in general formula (IA) or (IB):

[0023] in:

[0024] The R 1 is selected from hydrogen, fluorine or cyano;

[0025] Said X is selected from -O-, -NH-, -N(Me)- or -CH2-;

[0026] The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the “substituted” substituent is one or more 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, Z is an integer selected from 0, 1, 2 or 3.

[0027] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor modulator, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor modulator has a structure shown in (IIA) or (IIB): Among them, R 1 , R4, Y1, Y2, Z and W are defined the same as in the general formula (I-1) or (I-2).

[0028] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor modulator has a structure represented by the general formula (IIC) or (IID): Among them, R 1 , Z and W are defined the same as above.

[0029] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor modulator, or an isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor modulator has a structure represented by formula (IIIA), formula (IIIB), formula (IIIC), formula (IIID), formula (IIIE), formula (IIIF), formula (IIIG), formula (IIIH), formula (IIIIII) or formula (IIIJ): Among them, R 1 , R4, Y1, Y2, Z and W are defined the same as in the general formula (I).

[0030] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor modulator has the structure shown by the general formula (IVA), (IVB), (IVC), and (IVD): Among them, R 1 , Z and W are defined the same as above.

[0031] Furthermore, as a preferred technical solution of the present invention, W is independently selected from: Said R2 and R3 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, 3-8 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0032] The m, n, s and t are independently selected from integers of 0, 1, 2, 3, 4, 5 or 6.

[0033] Furthermore, as a preferred technical solution of the present invention, R7 and R8 together with the atoms to which they are connected form β-propiolactone, γ-butyrolactone or cyclopentanolactone;

[0034] Furthermore, as a preferred technical solution of the present invention, the bicycloalkyl group is selected from a 4-12 membered bicycloalkyl group; preferably a 4-10 membered bicycloalkyl group, and more preferably a 4-8 membered bicycloalkyl group. The bicycloalkyl group is selected from a 4-12 membered spiro bicycloalkyl group or a 4-12 membered fused bicycloalkyl group, preferably a 4-10 membered spiro bicycloalkyl group or a 4-10 membered fused bicycloalkyl group, and more preferably a 4-8 membered spiro bicycloalkyl group or a 4-8 membered fused bicycloalkyl group.

[0035] Further, as a preferred technical solution of the present invention, the C1-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.

[0036] Furthermore, as a preferred technical solution of the present invention, the C 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, the C1-C6 haloalkyl includes fluorine-substituted C1-C6 alkyl; in another embodiment, the C1-C4 haloalkyl includes fluorine-substituted C 1- C4 alkyl; in another embodiment, C1-C3 haloalkyl comprises fluorine-substituted C1-C3 alkyl.

[0037] Furthermore, as a preferred technical solution of the present invention, the C1-C6 alkoxy group is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy group, and further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0038] Furthermore, as a preferred technical solution of the present invention, R1 and R2 are independently selected from: H, C1-C6 alkyl or C1-C6 haloalkyl.

[0039] Furthermore, as a preferred technical solution of the present invention, the W is independently selected from:

[0040] Furthermore, as a preferred technical solution of the present invention, the W is independently selected from: The W is independently selected from:

[0041] Furthermore, as a preferred technical solution of the present invention, W is independently selected from:

[0042] Furthermore, as a preferred technical solution of the present invention, the R5 is independently selected from: methyl, methoxyethyl. Further, as a preferred technical solution of the present invention, the RXFP1 receptor modulator is selected from the following compounds:

[0043] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor modulator is selected from the following compounds:

[0044] Furthermore, the present invention also provides a pharmaceutical composition, characterized in that it comprises an RXFP1 receptor modulator described in Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IB), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (IIID), Formula (IIIE), Formula (IIIF), Formula (IIIG), Formula (IIIH), Formula (IIIIII), Formula (IIIJ), Formula (IVA), Formula (IVB), Formula (IVC) or Formula (IVD), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0045] Furthermore, the present invention also provides an RXFP1 receptor modulator comprising Formula (I), Formula (I-1), Formula (I-2), Formula (IA), Formula (IB), Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIIA), Formula (IIIB), Formula (IIIC), Formula (IIID), Formula (IIIE), Formula (IIIF), Formula (IIIG), Formula (IIIH), Formula (IIIIII), Formula (IIIJ), Formula (IVA), Formula (IVB), Formula (IVC) or Formula (IVD), or an isomer thereof, or a racemate thereof, or a pharmaceutical composition thereof. Use of an acceptable salt of the above-mentioned formula or a pharmaceutical composition comprising formula (I), formula (I-1), formula (I-2), formula (IA), formula (IB), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIIA), formula (IIIB), formula (IIIC), formula (IIID), formula (IIIE), formula (IIIF), formula (IIIG), formula (IIIH), formula (IIIIII), formula (IIIJ), formula (IVA), formula (IVB), formula (IVC) or formula (IVD) in the preparation of a medicament for preventing or treating diseases related to the RXFP1 receptor.

[0046] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor-related disease is selected from: angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary heart disease, acute heart failure, chronic heart failure, hypertension, refractory hypertension, pulmonary hypertension heart failure, chronic kidney disease, acute kidney injury and refractory hypertension.

[0047] Furthermore, as a preferred technical solution of the present invention, the fibrotic disease and related diseases are selected from: for example: lung disease (e.g., idiopathic pulmonary fibrosis), kidney disease (e.g., chronic kidney disease) or liver disease (e.g., non-alcoholic steatohepatitis and portal hypertension).

[0048] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor-related disease is selected from heart failure.

[0049] Furthermore, as a preferred technical solution of the present invention, the compounds of the RXFP1 modulators of the present invention (including salts thereof) can be used alone or in combination with other suitable therapeutic agents; the therapeutic agents include: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulin agents, anti-thrombotic agents, anti-retinopathy drugs, anti-neuropathy drugs, anti-nephropathy drugs, anti-ischemic drugs, anti-hypertensive drugs, anti-obesity drugs, anti-hyperlipidemic drugs, anti-hypertriglyceride drugs, anti-hypercholesterol drugs, anti-restenosis drugs, anti-pancreatic agents, lipid-lowering agents, appetite suppressants, memory enhancers, anti-dementia agents, cognitive enhancers, appetite suppressants, heart failure therapeutic agents, peripheral arterial disease therapeutic agents, SGLT2 inhibitors, malignant tumor therapeutic agents, and anti-inflammatory agents. Additional therapeutic agents may include ACE inhibitors, beta-blockers, diuretics, mineralocorticoid receptor antagonists, ryanodine receptor modulators, SERCA2a activators, renin inhibitors, calcium channel blockers, adenosine A1 receptor agonists, partial adenosine A1 receptors, dopamine beta-hydroxylase inhibitors, angiotensin II receptor antagonists, angiotensin II receptor antagonists with biased agonist effects on selected cell signaling pathways, a combination of angiotensin II receptor antagonists and neprilysin inhibitors, neprilysin inhibitors, soluble guanylate cyclase activators, myosin ATPase activators, rho kinase 1 inhibitors, Rho kinase 2 inhibitors, apelin receptor agonists, nitroxyl donor compounds, calcium-dependent kinase II inhibitors, antifibrotic agents, galectin 3 inhibitors, vasopressin receptor antagonists, FPR2 receptor modulators, natriuretic peptide receptor agonists, transient receptor potential vanilloid-4 channel blockers, anti-arrhythmic drugs, if "funny current" channel blockers, nitrates, digitalis compounds, inotropes and beta-agonists, cell membrane resealing agents such as poloxamer 188, antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG CoA reductase inhibitors), LXR agonists, FXR agonists, probucol, raloxifene, niacin, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants, anion exchange resins, quaternary ammonium amines, cholestyramine, colestipol, low-density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, vitamin B6, vitamin B12, antioxidant vitamins, antidiabetic drugs, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibric acid derivatives, PCSK9 inhibitors, aspirin and P2Y12 inhibitors such as Clopidogrel.Additional therapeutic agents may also include nintedanib, pirfenidone, LPA1 antagonists, LPA1 receptor antagonists, GLP1 analogs, tralokinumab (IL-13, AstraZeneca), vismodegib (hedgehog antagonist, Roche), PRM-151 (pentraxin-2, TGFβ-1, Promedior), SAR-156597 (bispecific Mab IL-4 & IL-13, Sanofi)), simtuzumab ((anti-lysyl oxidase-like 2 (anti-LOXL2) antibody, Gilead), CKD-942, PTL-202 (PDE inh. / pentoxifylline / NAC oral controlled release, Pacific Ther.), omipalisib (oral PI3K / mTOR inhibitor, GSK), IW-001 (oral solution. Bovine type V collagen model, ImmuneWorks), STX-100 (integrin αV / β-6 ant, Stromedix / Bio gen), Actimmune (IFNγ), PC-SOD (midismase; inhaled, LTT Bio-Pharma / CKD Pharm), lebrikizumab (anti-IL-13SC humanized monoclonal antibody, Roche), AQX-1125 (SHIP1 activator, Aquinox), CC-539 (JNK inhibitor, Celgene), FG-3019 (FibroGen), SAR-100842 (Sanofi), and obeticholic acid (OCA or INT-747, Intercept).

[0050] Furthermore, as a preferred technical solution of the present invention, the RXFP1 modulator compound (including its salt) of the present invention is used in combination with an SGLT2 inhibitor (such as dapagliflozin).

[0051] Furthermore, as a preferred technical solution of the present invention, in one embodiment, the SGLT2 inhibitor is gliflozin. In one embodiment, the SGLT2 inhibitor is selected from dapagliflozin, canagliflozin, empagliflozin, erpagliflozin, ipragliflozin, efagliflozin, sergliflozin, sogliflozin, and togliflozin, or a pharmaceutically acceptable salt thereof.

[0052] Furthermore, the present invention also provides a method for preparing an RXFP1 receptor modulator, 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.

[0053] In the chemical structure of the compound of the present invention, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or colleagues include Two configurations;

[0054] 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 contain both configurations;

[0055] The compounds of the present invention and intermediates 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 interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0056] All compounds in the present invention can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0057] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0058] 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 as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0059] The term "alkyl" refers to a branched, unbranched, and cyclic saturated hydrocarbon chain containing the 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; 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.

[0060] The term "haloalkyl" means that the hydrogen atoms 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.

[0061] The term "alkoxy" refers to an alkyl group in which one or more carbon atoms are replaced by oxygen, such as -O-(alkyl), wherein the definition of alkyl is as described above, the number of carbon atoms in the C1-C6 alkoxy group is selected from 1, 2, 3, 4, 5 or 6, and the alkoxy group is preferably a C1-C6 alkoxy group; the C1-C6 alkoxy group is preferably: C1-C2, C1-C3, C1-C4 or C1-C5 alkoxy group, and further, the alkoxy group is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0062] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen; the halogenated alkoxy group is preferably a C1-C6 halogenated alkoxy group, wherein the C 1- The number of carbon atoms in the C6 haloalkoxy group is selected from 1, 2, 3, 4, 5 or 6. 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 C 1- C4 alkoxy; in yet another embodiment, C 1- C3 haloalkyl includes fluorine-substituted C 1- C3 alkoxy.

[0063] 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 groups 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.

[0064] 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 heteroatoms is 1, 2, 3 or 4; the heterocycloalkyl group is selected from a 3-10 membered heterocycloalkyl group; preferably a 3-8 membered heterocycloalkyl group; the number of carbon atoms in the 3-8 membered heterocycloalkyl group is selected from 2, 3, 4, 5, 6 or 7, and the 3-8 membered heterocycloalkyl group is preferably selected from: a 3-7 membered heterocycloalkyl group, a 3-6 membered heterocycloalkyl group, a 3-5 membered heterocycloalkyl group, a 3-4 membered heterocycloalkyl group or a 3 membered heterocycloalkyl group. In one embodiment, the heterocycloalkyl group is specifically selected from cyclopropyloxy, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, morpholinyl, piperazinyl, piperidinyl, N-methylpiperazinyl, N-methylpiperidinyl or N-ethylpiperidinyl.

[0065] The term "bicycloalkyl" refers to a saturated or partially unsaturated bicyclic substituent, wherein the bicycloalkyl group contains 4 to 12 carbon atoms. The bicycloalkyl group is selected from a spirobicycloalkyl group or a fused bicycloalkyl group, excluding bridged rings; the bicycloalkyl group preferably contains 4 to 10 carbon atoms, more preferably 4 to 8 carbon atoms, further preferably 4 to 8 carbon atoms, more preferably 4 to 7 carbon atoms, and most preferably 4 to 6 carbon atoms.

[0066] Term " spiral bicycloalkyl " refers to 5 to 20 yuan, the bicyclic group of sharing a carbon atom (claiming spiral atom) between monocycle, it can contain one or more double bonds.Preferably 5 to 12 (for example 5,6,7,8,9,10,11 or 12) yuan, more preferably 5 to 10 yuan (for example 5,6,7,8,9 or 10 yuan), most preferably 5 to 8 yuan (for example 5,6,7 or 8).According to the number of shared spiral atom between ring and ring, spiral bicycloalkyl is divided into single spiral cycloalkyl or polyspiro cycloalkyl (such as double spiral cycloalkyl), preferably single spiral cycloalkyl and double spiral cycloalkyl.More preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan spiral bicycloalkyl. Non-limiting examples of spirobicycloalkyls include, but are not limited to:

[0067] Term " fused bicycloalkyl " refers to 4 to 20 yuan, and each ring in system shares the bicyclic group of a pair of carbon atoms adjacent with other rings in system, and wherein one or more rings can contain one or more double bonds.Preferably 4 to 12 (for example 4, 5, 6, 7, 8, 9, 10, 11 or 12) yuan, more preferably 4 to 10 yuan (for example 4, 5, 6, 7, 8, 9 or 10 yuan), more preferably 4 to 8 (for example 4, 5, 6, 7 or 8) yuan.According to the number forming ring, can be divided into the polycyclic condensed cycloalkyls such as bicyclo, tricycle, tetracycle, be preferably bicyclo or tricycle, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan fused bicycloalkyl. Non-limiting examples of fused bicycloalkyls include, but are not limited to:

[0068] The term "aryl" refers to a 6-14 membered monocyclic or polycyclic aromatic ring assembly in which 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 wherein A and B represent the number of carbon atoms in the ring system. 10Aryl, further preferably: C6-C8 aryl or C6-C7 aryl; in one embodiment, the aryl is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.;

[0069] 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, and most preferably 5, 6 or 7 members. Heteroaryl can 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 a heteroaryl group (including any amino substituents of the ring) will be less than five.

[0070] 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, pyridyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0071] The term "cyclic lactone" refers to a cyclic ester, which refers to a substance containing both a carboxyl group and a hydroxyl group in the same molecule, which are dehydrated and combined. The cyclic lactone is preferably a 3-6 membered cyclic lactone, and more preferably a 4-6 membered cyclic lactone. The cyclic lactone includes but is not limited to: β-propiolactone, γ-butyrolactone or cyclopentanolactone.

[0072] 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 groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0073] 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 resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0074] The term "stereoisomers" refers to compounds that have identical 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.

[0075] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through 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-en-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 indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0076] The term "racemate" refers to an equimolar mixture of two enantiomers, devoid of optical activity.

[0077] 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 S.M. Berge et al., "Describe Pharmaceutically Acceptable Salts in Detail in J. Pharmaceutical Sciences, 66:1-19, 1977." Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates formed by reaction with amino groups, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, 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+(C1-4 alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a nitrogen group. 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 suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates, and aromatic sulfonates.

[0078] 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, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; 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 buffered solution; and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; release agents; coatings; sweeteners; flavoring agents; fragrances; preservatives and antioxidants.

[0079] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0080] 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.

[0081] Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert 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.

[0082] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0083] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). 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, 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 testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, 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.

[0084] For example, the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0085] Furthermore, the compounds of the present invention may have one or more hydrogen atoms replaced by deuterium isotopes ( 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.

[0086] 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 incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0087] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0088] 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.

[0089] The beneficial effects of the present invention over the prior art include but are not limited to:

[0090] Compared with the prior art, the RXFP1 receptor modulator of the present invention has better agonist activity on the RXFP1 receptor and has a lower EC 50 value. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] 1) Figure 1 shows a schematic diagram of the single crystal structure of compound 1F;

[0092] 2) Figure 2 shows a schematic diagram of the single crystal structure of compound 1H;

[0093] 3) Figure 3 shows a schematic diagram of the single crystal structure of compound 1G. DETAILED DESCRIPTION

[0094] The present invention is further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0095] Example 1

[0096] Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0097] The specific synthetic route is as follows:

[0098] Step A: Synthesis of 1-methylspiro[2.2]pentane-1-carbonitrile

[0099] At room temperature, spiro[2.2]pentane-1-carbonitrile (500 mg, 5.4 mmol) was dissolved in tetrahydrofuran (10 mL), the atmosphere was replaced with nitrogen, and the temperature was lowered to -78°C. Lithium diisopropylamide (3.5 mL, 7.0 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise. After stirring for 30 minutes, iodomethane (0.84 g, 5.9 mmol) was added. The mixture was stirred at this temperature for 4 hours until the reaction was essentially complete. The reaction solution was then slowly warmed to room temperature.

[0100] 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 620 mg of 1-methylspiro[2.2]pentane-1-carbonitrile.

[0101] Step B: Synthesis of (1-methylspiro[2.2]pentan-1-yl)methanamine

[0102] At room temperature, 1-methylspiro[2.2]pentane-1-carbonitrile (620 mg, 5.8 mmol) was dissolved in ammonia / methanol solution (10 mL, 7 mol / L). Raney nickel (200 mg) was added, and hydrogen was introduced after replacement. The reaction was allowed to proceed at room temperature for 14 hours. The reaction was monitored by LC-MS until completion.

[0103] The Raney nickel was filtered off, the mixture was washed with methanol (20 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain 150 mg of (1-methylspiro[2.2]pentan-1-yl)methanamine. LC-MS: RT = 0.60 min, [M+H] + =112.16.

[0104] Step C: Synthesis of naphth-2-ylmethyl (1S,4S)-4-(1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0105] 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 (1-methylspiro[2.2]pentan-1-yl)methanamine (150 mg, 1.34 mmol) were dissolved in dichloromethane (10 ml). N,N-diisopropylethylamine (322 mg, 2.5 mmol) was added, and the temperature was lowered to 0°C. Propylphosphonic anhydride (954 mg, 1.5 mmol, 50% by mass solution in ethyl acetate) was added, and 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.

[0106] The reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (10 ml x 2). The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). This afforded 150 mg of naphth-2-ylmethyl (1S,4S)-4-(1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 2.45 min, [M+H] + =695.21.

[0107] Step D: Synthesis of (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0108] At room temperature, naphthalen-2-ylmethyl (1S,4S)-4-(1R,2R,3S,4S)-3-((1-methylspiro[2.2]pent-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-5-en-2-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (150 mg, 0.22 mmol) was dissolved in ethanol (10 ml). Wet palladium on carbon (10 mg, 10% palladium / 55% water) was added, and hydrogen was introduced into the mixture after replacement. The reaction was carried out at room temperature for 15 hours and monitored by LC-MS until the reaction was complete.

[0109] The palladium / carbon was filtered off, the mixture was washed with ethanol (10 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 9.5 mg of the product (1S,4s)-4-(5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.11 min, [M+H] + =557.2.

[0110] Examples 1A and 1B

[0111] Compound 1A or 1B: (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(3-((R)-1-methylspiro[2.2]pentan-1-yl)propanoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid; Compound 1B or 1A: (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-(3-((S)-1-methylspiro[2.2]pentan-1-yl)propanoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0112] The product of Example 1 was subjected to chiral SFC separation (Daicel Chiralpak AD, 50*250 mm, mobile phase: 35% IPA (0.1% NH4OH) and fluid CO2) to give Compound 1A (RT=2.151 min) and Compound 1B (RT=2.263 min).

[0113] NMR data of compound 1A: 1HNMR(500MHz,DMSO-d6)δ12.25(s,1H),8.85(d,J=8.1Hz,1H),7.87(s,1H),7.65(d,J=9.9Hz,1H), 7.08(d,J=12.7Hz,1H),4.19-4.05(m,2H),3.86(s,3H),2.99(d,J=5.7Hz,2H),2.60(d,J=8.4Hz,1 H),2.25-2.19(m,1H),2.09-2.01(m,3H),1.97(d,J=9.9Hz,1H),1.86(d,J=12.7Hz,2H),1.54-1.4 9(m,1H),1.48-1.35(m,3H),1.30-1.08(m,8H),0.88(s,3H),0.78-0.69(m,2H),0.58-0.46(m,4H).

[0114] NMR data of compound 1B: 1 HNMR(500MHz,DMSO-d6)δ12.24(s,1H),8.84(d,J=8.2Hz,1H),7.87(s,1H),7.65(d,J=9.9Hz,1H),7.09(d,J=12.8Hz,1H), 4.18-4.08(m,2H),3.87(s,3H),3.08(dd,J=13.5,6.3Hz,1H),2.87(dd,J=13.5,5.1Hz,1H),2.60(d,J=8.6Hz,1H),2.24-2 .19(m,1H),2.10-2.01(m,3H),1.97(d,J=9.9Hz,1H),1.86(d,J=12.4Hz,2H),1.59-1.48(m,1H),1.46-1.37(m,3H),1.31- 1.12(m,5H),1.10(s,3H),0.85(s,3H),0.83-0.79(m,1H),0.64(d,J=4.4Hz,1H),0.61-0.50(m,3H),0.38(d,J=4.0Hz,1H).

[0115] Examples 1C and 1D

[0116] The synthetic route is as follows:

[0117] Step A: Synthesis of (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

[0118] At room temperature, nadic anhydride (1.64 g, 10.0 mmol) was dissolved in anhydrous ether (100 ml), N-[(8α,9S)-6'-methoxyquinin-9-yl]-3,5-bis(trifluoromethyl)benzenesulfenamide (0.6 g, 1.0 mmol) was added, and methanol (3.2 g, 100.0 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 6 hours until the reaction was almost complete.

[0119] A 1 mol dilute hydrochloric acid aqueous solution (60 ml) was added, extracted with ethyl acetate (200 ml × 2 times), the organic phases were combined, washed with saturated brine (100 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 1.3 g of (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

[0120] This synthesis method refers to A Highly Reactive and Enantioselective Bifunctional Organocatalyst for the Methanolytic Desymmetrization of Cyclic Anhydrides: Prevention of Catalyst Aggregation, Angew.Chem.Int.Ed.2008,47,7872–7875

[0121] Step B: Synthesis of (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0122] At room temperature, (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1.3 g, 6.6 mmol) was added to toluene (50 ml), and N,N-diisopropylethylamine (1.0 g, 7.9 mmol) was slowly added. The mixture was cooled to 0-5 degrees with ice water, and diphenylphosphoryl azide (1.8 g, 6.6 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and the reaction was allowed to react overnight. The reaction was basically complete as monitored by TLC.

[0123] The product was washed with saturated citric acid aqueous solution (20 ml × 2 times), 1 mol per liter sodium hydroxide aqueous solution (20 ml × 2 times), saturated brine (20 ml × 1 time), dried over anhydrous sodium sulfate, filtered to obtain a toluene solution, and heated to 90 degrees for 3 hours until the reaction was substantially complete.

[0124] The temperature was slowly lowered to room temperature, the solvent was replaced with 1,4-dioxane (50 mL), 2 mL of concentrated hydrochloric acid was added, and the reaction was allowed to proceed at room temperature overnight.

[0125] The pH was adjusted to 8-9 by adding concentrated aqueous ammonia, and the mixture was concentrated. The crude product was purified by column chromatography (eluent: methanol / dichloromethane = 2 / 8) to obtain 0.6 g of (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester. LC-MS: RT = 0.4 min, [M+H] + =168.2.

[0126] Step C: Synthesis of (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 methyl ester

[0127] At room temperature, 4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (1.3 g, 2.8 mmol) and (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (0.6 g, 3.6 mmol) were dissolved in dichloromethane (20 ml). N,N-diisopropylethylamine (1.4 g, 11.2 mmol) was added and the temperature was lowered to 0°C. Propylphosphonic anhydride (3.6 g, 5.6 mmol, 50% by mass in ethyl acetate) was added, and the temperature was slowly raised to room temperature. The reaction was stirred for 3 hours and monitored by LC-MS until the reaction was complete.

[0128] The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml x 2). The organic phases were combined, washed with saturated brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 1.2 g of (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 methyl ester was obtained. LC-MS: RT = 2.21 min, [M+H] + =616.03.

[0129] Step D: Synthesis of (1S,2R,3S,4R)-3-(4-fluoro-2-methoxy-5-((1S,4R)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

[0130] Methyl (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-carboxylate (1.2 g, 1.9 mmol) was dissolved in tetrahydrofuran (20 ml) at room temperature, and an aqueous solution (20 ml) of lithium hydroxide (144 mg, 6 mmol) was added. The mixture was stirred at room temperature for 15 hours and monitored by LC-MS until the reaction was complete.

[0131] Most of the tetrahydrofuran was concentrated, and the pH was adjusted to 4-5 with 1 mol / L dilute hydrochloric acid. A white solid precipitated, which was filtered and dried under vacuum at 50°C to yield 0.9 g of (1S,2R,3S,4R)-3-(4-fluoro-2-methoxy-5-((1S,4R)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid. LC-MS: RT = 1.81 min, [M+H] + =602.2.

[0132] Step E: Synthesis of naphth-2-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0133] At room temperature, (1S,2R,3S,4R)-3-(4-fluoro-2-methoxy-5-((1s,4R)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (300 mg, 0.5 mmol) and (1-methylspiro[2.2]pentan-1-yl)methanamine (150 mg, 1.34 mmol) were dissolved in dichloromethane (10 ml). N,N-diisopropylethylamine (322 mg, 2.5 mmol) was added, and the temperature was lowered to 0°C. Propylphosphonic anhydride (954 mg, 1.5 mmol, 50% by weight solution in ethyl acetate) was added, and 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.

[0134] The reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (10 ml x 2). The combined organic phases were washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). This afforded 200 mg of naphth-2-ylmethyl (1R,4S)-4-(2-fluoro-4-methoxy-5-((1R,2S,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 2.42 min, [M+H] + =695.22.

[0135] Step F: Synthesis of (1R,4s)-4-(2-fluoro-4-methoxy-5-((1S,2S,3R,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0136] Naphthalen-2-ylmethyl (1R,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (200 mg, 0.29 mmol) was dissolved in ethanol (10 ml) at room temperature, and wet palladium / carbon (20 mg, 10% palladium / 55% water) was added. The mixture was replaced with hydrogen and allowed to react at room temperature for 15 hours. The reaction was monitored by LC-MS until completion.

[0137] The palladium / carbon was filtered off, the mixture was washed with ethanol (10 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 60 mg of the product (1R,4s)-4-(2-fluoro-4-methoxy-5-((1S,2S,3R,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.11 min, [M+H] + =557.2. The product was separated by chiral SFC (Chiralpak AD-350×4.6 mm, mobile phase: IPA (0.05% DEA) to give compound 1C (RT=1.876 min) and compound 1D (RT=1.941 min).

[0138] Compound (RT = 1.876min) 1C NMR data: 1HNMR (400MHz, DMSO-d6) δ9.86(d,J=7.1Hz,1H),7.98(t,J=5.8Hz,1H),7.66(d,J=9.9Hz,1H),7.12(d,J=12 .7Hz,1H),4.16(dt,J=9.9,5.5Hz,2H),3.93(s,3H),3.07(d,J=5.8Hz,2H),2.89(dd,J=11.0,4.3Hz,1H),2. 42(d,J=17.4Hz,2H),2.08(d,J=13.3Hz,2H),1.87(s,2H),1.56(dd,J=26.2,8.8Hz,2H),1.50-1.34(m,3H) ,1.32-1.20(m,5H),1.11(s,3H),1.00(s,3H),0.90-0.87(m,1H),0.77(d,J=4.0Hz,1H),0.66-0.54(m,4H).

[0139] 1D NMR data of compound (RT=1.941min) 1 H NMR (400MHz, DMSO-d6) δ9.74(d,J=7.1Hz,1H),7.88(t,J=5.8Hz,1H),7.57(d,J=9.9Hz,1H),7.03(d,J=12.7Hz,1H),4.21(ddd,J=11 .0,6.9,3.9Hz,1H),4.08(dt,J=9.9,5.5Hz,1H),3.84(s,3H),3.09(dd,J=13.5,6.2Hz,1H),2.88(dd,J=13.5,5.3Hz,1H),2.80(dd,J =11.0,4.3Hz,1H),2.34(d,J=18.2Hz,2H),1.99(d,J=13.1Hz,2H),1.80(t,J=8.5Hz,2H),1.48(dd,J=27.9,8.8Hz,2H),1.40-1.27( m,4H),1.20(d,J=10.0Hz,4H),1.03(s,3H),0.91(s,3H),0.76(td,J=7.2,6.6,3.7Hz,1H),0.72(d,J=4.0Hz,1H),0.58-0.46(m,4H).

[0140] Examples 1E and 1F, 1G and 1H

[0141] The synthetic route is as follows:

[0142] Step A: Synthesis of (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid

[0143] At room temperature, dissolve nadic anhydride (1.64 g, 10.0 mmol) in anhydrous ether (100 ml), add hydroquinidine (anthraquinone-1,4-diyl) diether (0.85 g, 1.0 mmol), cool to -30 degrees, and slowly add methanol (3.2 g, 100.0 mmol) dropwise. Stir at this temperature for 48 hours until the reaction is almost complete.

[0144] A 1 mol dilute hydrochloric acid aqueous solution (60 ml) was added, and the mixture was extracted with ethyl acetate (200 ml × 2 times). The organic phases were combined, washed with saturated brine (100 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4) to obtain 1.6 g of (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid.

[0145] This synthesis method is referenced in A Highly Enantioselective Catalytic Desymmetrization of Cyclic Anhydrides with Modified Cinchona Alkaloids, J. Am. Chem. Soc. 2000, 122, 9542-9543

[0146] Step B: Synthesis of (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester

[0147] At room temperature, (1S,2R,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (20 g, 100 mmol) was added to toluene (500 ml), and N,N-diisopropylethylamine (15.5 g, 120 mmol) was slowly added. The mixture was cooled to 0-5 degrees with ice water, and diphenylphosphoryl azide (27.5 g, 100 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and the reaction was allowed to react overnight. The reaction was basically complete as monitored by TLC.

[0148] The mixture was washed with saturated citric acid aqueous solution (200 ml × 2 times), 1 mol sodium hydroxide aqueous solution (200 ml × 2 times), saturated brine (200 ml × 1 time), dried over anhydrous sodium sulfate, filtered to obtain a toluene solution, benzyl alcohol (21.6 g, 200 mmol) was added, and the mixture was heated to 90 degrees for 3 hours to react until the reaction was almost complete.

[0149] The mixture was slowly cooled to room temperature and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 18 g of methyl (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate. LC-MS: RT = 1.82 min, [M+H] + =302.1.

[0150] Step C: Synthesis of (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0151] Methyl (1R,2S,3R,4S)-3-((benzyloxycarbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate (18 g, 60 mmol) was dissolved in methanol (300 ml) at room temperature. Wet palladium on carbon (1.8 g, 10% palladium / 55% water) was added, and hydrogen was introduced into the mixture. The mixture was allowed to react at room temperature for 15 hours until the reaction was complete.

[0152] The palladium / carbon was filtered off, the mixture was rinsed with methanol (50 ml), the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: methanol / dichloromethane = 1 / 9) to give 9.1 g of oily product (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester. LC-MS: RT = 0.4 min, [M+H] + =170.15.

[0153] Step D: Synthesis of (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0154] At room temperature, 4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (5 g, 10.7 mmol) and (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (2.7 g, 16.0 mmol) were dissolved in dichloromethane (100 ml). N,N-diisopropylethylamine (6.9 g, 53.5 mmol) was added, and the temperature was lowered to 0 degrees Celsius. Propylphosphonic anhydride (13.6 g, 21.4 mmol, 50% by mass in ethyl acetate) was added, and 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.

[0155] The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml x 2). The organic phases were combined, washed with saturated brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 5.0 g of (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester were obtained. LC-MS: RT = 2.25 min, [M+H] + =618.03.

[0156] Step E: Synthesis of (1S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4R)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid

[0157] Methyl (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylate (5.0 g, 8.1 mmol) was dissolved in tetrahydrofuran (100 ml) at room temperature, and an aqueous solution (200 ml) of lithium hydroxide (1.16 g, 48.6 mmol) was added. The mixture was stirred at room temperature for 15 hours and monitored by LC-MS until the reaction was complete.

[0158] Most of the tetrahydrofuran was concentrated, and the pH was adjusted to 4-5 with 1 mol / L dilute hydrochloric acid aqueous solution. A large amount of white solid precipitated, which was filtered and dried in vacuo at 50 degrees to obtain 3.9 g of (1S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1s,4R)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid. The product was subjected to chiral separation by SFC (Chiralpak AS-350×4.6 mm, mobile phase: EtOH (0.05% DEA) and fluid CO2) to give the compound (RT=4.283 min) (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid, LC-MS: RT=3.95 min, [M+H] += 604.2. and compound (RT = 5.5 min) (1S, 2R, 3R, 4R)-3-(4-fluoro-2-methoxy-5-((1S, 4S)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid. LC-MS: RT = 4.20 min, [M+H] + =604.2.

[0159] Step F: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0160] At room temperature, (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1s,4S)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (3.9 g, 6.5 mmol) and (1-methylspiro[2.2]pentan-1-yl)methanamine (1.44 g, 13 mmol) were dissolved in dichloromethane (50 ml). N,N-diisopropylethylamine (4.2 g, 32.5 mmol) was added, and the temperature was lowered to 0°C. Propylphosphonic anhydride (8.3 g, 13 mmol, 50% by mass in ethyl acetate) was added, and the temperature was slowly raised to room temperature. The reaction was stirred for 2 hours and monitored by LC-MS until the reaction was complete.

[0161] The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml x 2). The organic phases were combined, washed with saturated brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 4.0 g of naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.43 min, [M+H] + =697.19.

[0162] Step G: Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0163] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (4 g, 5.7 mmol) was dissolved in ethanol (80 ml). Wet palladium on carbon (0.4 g, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 3 hours and monitored by LC-MS until the reaction was complete.

[0164] The palladium / carbon was filtered off, the mixture was washed with ethanol (30 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 2.3 g of the product (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptane-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.10 min, [M+H] + =557.2. The product was separated by chiral SFC (Chiralpak AD-350×4.6 mm, mobile phase: IPA (0.05% DEA) and fluid CO2) to give compound 1E (RT=2.169 min) and compound 1F (RT=2.632 min).

[0165] Compound (RT = 2.169 min) 1E NMR data: 1HNMR(400MHz, DMSO-d6) δ 9.75 (d, J = 7.0 Hz, 1H), 7.87 (t, J = 5.8 Hz, 1H), 7.55 (d, J = 10.0 Hz, 1H), 7.01 (d, J = 12.7 Hz, 1H), 4.18 (ddd, J = 11.1, 7.0, 3.9 Hz, 1H), 4.06 (dq, J = 10.1, 5.5, 4.8 Hz, 1H), 3.82 (s, 3H), 2.96 (d, J = 5.7 Hz, 2H), 2.78 (dd, J = 11.1, 4.3 Hz, 1H), 2.34 (s, 1H), 2.29 (s, 1H), 1.96 (d, J = 13.1 Hz, 2H), 1.84 - 1.74 (m, 2H), 1.45 (dd, J = 25.6, 8.8 Hz, 2H), 1.37 - 1.24 (m, 4H), 1.18 (td, J = 12.6, 10.2, 6.5 Hz, 4H), 1.02 (s, 3H), 0.89 (s, 3H), 0.78 (dq, J = 10.3, 5.2 Hz, 1H), 0.67 (d, J = 3.9 Hz, 1H), 0.60 - 0.40 (m, 4H).

[0166] 1H NMR data of compound (RT = 2.632 min): 1 HNMR(400MHz, DMSO-d6) δ 9.82 (d, J = 7.1 Hz, 1H), 7.96 (t, J = 5.9 Hz, 1H), 7.65 (d, J = 9.9 Hz, 1H), 7.12 (d, J = 12.8 Hz, 1H), 4.29 (ddd, J = 11.2, 7.1, 3.9 Hz, 1H), 4.17 (tt, J = 9.6, 4.2 Hz, 1H), 3.93 (s, 3H), 3.17 (dd, J = 13.5, 6.2 Hz, 1H), 2.97 (dd, J = 13.5, 5.4 Hz, 1H), 2.88 (dd, J = 11.1, 4.2 Hz, 1H), 2.45 (d, J = 3.5 Hz, 1H), 2.40 (s, 1H), 2.07 (dd, J = 13.1, 4.4 Hz, 2H), 1.90 (dt, J = 13.3, 3.9 Hz, 2H), 1.56 (dd, J = 26.6, 8.8 Hz, 2H), 1.41 (ddd, J = 23.2, 11.2, 8.4 Hz, 4H), 1.32 - 1.26 (m, 4H), 1.12 (s, 3H), 0.99 (s, 3H), 0.88 - 0.83 (m, 1H), 0.80 (d, J = 4.0 Hz, 1H), 0.65 - 0.56 (m, 4H).

[0167] Step H: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0168] At room temperature, (1S,2R,3R,4R)-3-(4-fluoro-2-methoxy-5-((1s,4S)-4-methyl-4-((naphthalen-2-ylmethoxycarbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]heptane-2-carboxylic acid (2 g, 3.3 mmol) and (1-methylspiro[2.2]pentan-1-yl)methanamine (0.73 g, 6.6 mmol) were dissolved in dichloromethane (50 ml). N,N-diisopropylethylamine (2.1 g, 16.6 mmol) was added, and the temperature was lowered to 0°C. Propylphosphonic anhydride (4.2 g, 6.6 mmol, 50% by mass in ethyl acetate) was added, and the temperature was slowly raised to room temperature. The reaction was stirred for 2 hours and monitored by LC-MS until the reaction was complete.

[0169] The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (100 ml x 2). The organic phases were combined, washed with saturated brine (200 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 2.0 g of naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2R,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.43 min, [M+H] + =697.19.

[0170] Step I: Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0171] At room temperature, 2-naphthylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (2 g, 2.9 mmol) was dissolved in ethanol (80 ml). Wet palladium on carbon (0.2 g, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 3 hours and monitored by LC-MS until the reaction was complete.

[0172] The palladium / carbon was filtered off, the mixture was washed with ethanol (30 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 1.3 g of the product (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3R,4S)-3-(((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.10 min, [M+H] + =557.2. The product was separated by chiral SFC (Chiralpak AS-350×4.6 mm, mobile phase: EtOH (0.05% DEA) and fluid CO 2 ) to give compound 1G (RT=2.012 min) and compound 1H (RT=2.183 min).

[0173] Compound 1G (RT = 2.012 min) NMR data: 1HNMR (400MHz, DMSO-d6) δ8.12(d,J=7.1Hz,1H),7.85(t,J=5.7Hz,1H),7.52(d,J=9.8Hz,1H),7.18(d,J=12.9Hz,1H),4.39(dt,J=7.9,4.5Hz,1H), 4.19(td,J=9.7,4.7Hz,1H),3.90(s,3H),3.12(dd,J=13.5,5.8Hz,1H),3 .02(dd,J=13.5,5.6Hz,1H),2.41(d,J=4.3Hz,1H),2.31(d,J=3.9Hz,1H), 2.09(d,J=13.5Hz,2H),2.05-1.97(m,2H),1.95-1.83(m,2H),1.67(d,J= 9.7Hz,1H),1.58(td,J=8.9,4.8Hz,2H),1.45(t,J=11.3Hz,4H),1.36(dd ,J=11.6,2.8Hz,2H),1.11(s,3H),1.04(s,3H),0.87(dd,J=6.6,4.1Hz,1 H),0.80(d,J=4.0Hz,1H),0.69–0.65(m,2H),0.60(dd,J=8.3,4.3Hz,2H).

[0174] Compound 1H (RT = 2.183 min) NMR data: 1HNMR (400MHz, DMSO-d6) δ8.12(d,J=7.1Hz,1H),7.83(t,J=5.7Hz,1H),7.51(d,J=9.7Hz,1H),7.17(d,J=12.9Hz,1H),4.37(q,J=4.9Hz,1H),4.24-4 .12(m,1H),3.90(s,3H),3.22-3.18(m,1H),2.94(dd,J=13.4,5.2Hz,1H) ,2.41(d,J=4.2Hz,1H),2.30(d,J=3.9Hz,1H),2.09(d,J=13.2Hz,2H),2.0 2(d, J=5.4 Hz, 2H),1.93-1.83(m, 2H),1.69(d, J=9.7 Hz, 1H),1.59(tt, J=9.2,4.9 Hz, 2H),1.52-1.37(m, 4H),1.33(d, J=13.2 Hz, 2H),1.10(s, 3H),1.03(s, 3H),0.90(q, J=6.2 Hz, 1H),0.80(d, J=3.9 Hz, 1H),0.66(d, J=5.8 Hz, 2H),0.59(dd, J=11.9,4.3 Hz, 2H). The single crystal structure of compound 1F is shown in Figure 1. The specific crystal parameters are as follows:

[0175] The single crystal structure of compound 1H is shown in Figure 2, and the specific crystal parameters are as follows:

[0176] The single crystal structure of compound 1G is shown in Figure 3, and the specific crystal parameters are as follows:

[0177] Example 2

[0178] Compound 5 was prepared according to the method of Example 1. LC-MS: [M+H]+=543.17 RT=2.07 min.

[0179] Examples 5A and 5B

[0180] Compounds 5A and 5B were separated by reverse phase preparative separation (Pursuit XRS 5 C18, 21.2*100 mm, mobile phase: NH4OH (0.05%) and acetonitrile) according to the method of Examples 1A and 1B to give Compound 5A (RT=5.664 min) and Compound 5B (RT=9.317 min).

[0181] Example 3

[0182] Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid

[0183] The specific synthetic route is as follows:

[0184] Step A: Synthesis of naphth-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4s)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylate

[0185] At room temperature, (1S,2S,3R,4R)-3-(4-fluoro-2-methoxy-5-((1S,4S)-4-(methoxymethyl)-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (200 mg, 0.32 mmol) (the compound was obtained from patent PCT / EP2021 / 084673) and (1 -Methylspiro[2.2]pentan-1-yl)methanamine (150 mg, 1.34 mmol) was dissolved in dichloromethane (10 ml), N,N-diisopropylethylamine (170 mg, 1.32 mmol) was added, the temperature was lowered to 0 degrees Celsius, propylphosphonic anhydride (315 mg, 0.5 mmol, 50% mass fraction of 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.

[0186] The reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (10 ml x 2). The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). This afforded 100 mg of an oily substance: naphth-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4s)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylate. LC-MS: RT = 2.26 min, [M+H] + =725.2.

[0187] Step B: Synthesis of (1S,4S)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid

[0188] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2R,3S,4s)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylate (100 mg, 0.14 mmol) was dissolved in ethanol (4 ml). Wet palladium on carbon (20 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 16 hours and monitored by LC-MS until the reaction was complete.

[0189] The palladium / carbon was filtered off, the mixture was washed with ethanol (10 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2). 17 mg of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1S,2R,3S,4R)-3-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)bicyclo[2.2.1]hept-2-yl)carbamoyl)phenoxy)-1-(methoxymethyl)cyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.11 min, [M+H] + =587.05.

[0190] Example 4

[0191] Synthesis of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0192] The specific synthetic route is as follows:

[0193] Step A: Synthesis of naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate

[0194] At room temperature, (1S,2R)-2-(4-fluoro-2-methoxy-5-((1S,4S)-4-methyl-4-((naphthalen-2-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)cyclobutane-1-carboxylic acid (80 mg, 0.14 mmol) (the compound was obtained from patent PCT / EP2021 / 084673) and (1-methylspiro[2.2]pentan-1-yl)methanamine (50 mg, 0.45 mmol) were dissolved in dichloromethane (10 ml), and N,N-diisopropylethylamine (57 mg, 0.44 mmol) was added. The temperature was lowered to 0°C, and propylphosphonic anhydride (126 mg, 0.2 mmol, 50% by mass solution in ethyl acetate) was added. The temperature was slowly raised to room temperature, and the reaction was stirred for 1 hour. The reaction was monitored by LC-MS until completion.

[0195] The reaction mixture was diluted with water (10 ml) and extracted with dichloromethane (10 ml x 2). The organic phases were combined, washed with saturated brine (20 ml x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). This afforded 90 mg of an oily substance: naphth-2-ylmethyl (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 2.3 min, [M+H] + =657.3.

[0196] Step B: Synthesis of (1S,4S)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid

[0197] At room temperature, naphthalen-2-ylmethyl (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylate (90 mg, 0.14 mmol) was dissolved in ethanol (4 ml), and wet palladium / carbon (20 mg, 10% palladium / 55% water) was added. The mixture was replaced with hydrogen and allowed to react at room temperature for 16 hours. The reaction was monitored by LC-MS until completion.

[0198] The palladium / carbon was filtered off, the mixture was washed with ethanol (10 ml), and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 2). 20 mg of (1S,4s)-4-(2-fluoro-4-methoxy-5-((1R,2S)-2-((1-methylspiro[2.2]pentan-1-yl)methyl)carbamoyl)cyclobutyl)carbamoyl)phenoxy)-1-methylcyclohexane-1-carboxylic acid was obtained. LC-MS: RT = 2.02 min, [M+H] + =517.04.

[0199] Example 5-35

[0200] Compounds 2 / 2A / 2B, 4, and 6 / 6A / 6B-35 were prepared according to the method of Example 1. The structures and characterization data of compounds 2 / 2A / 2B-4 and 6 / 6A / 6B-35 are as follows:

[0201] Compound 2 was separated by chiral SFC (Chiralpak AD-350×4.6 mm, mobile phase: IPA (0.05% DEA) and fluid CO2) to give compound 2A (RT=1.872 min) and compound 2B (RT=2.029 min). NMR data of compound 2B: 1 H NMR (400MHz, DMSO-d6) δ9.01(d,J=8.2Hz,1H),7.94(t,J=5.7Hz,1H),7.66(s,1H),7.55(s,1H),4.42(t,J=9.3Hz,1H) ,4.12(t,J=8.3Hz,1H),3.92(s,3H),3.10(dd,J=13.5,6.1Hz,1H),2.93(dd,J=13.5,5.2Hz,1H),2.65(d,J=8.4Hz,1H) ,2.25-2.24(m,1H),2.08-2.07(m,3H),2.04-1.97(m,2H),1.94-1.91(m,2H),1.50-1.48(m,4H),1.26(bs,4H),1.14(s ,3H),0.89(s,3H),0.87-0.80(m,1H),0.68(d,J=4.0Hz,1H),0.59(dq,J=21.5,5.1,4.6Hz,3H),0.43(d,J=4.0Hz,1H).

[0202] NMR data of compound 4: 1HNMR(400MHz,DMSO-d6)δ12.29-11.82(m,1H)8.62(d,J=8.24Hz,1H)7.74(br t,J=6.00Hz,1H)7.41(d,J=9.88Hz,1H)6.87(d,J=12.76Hz,1H)3.96-3.82(m,2H)3.64(s,3H)3.00(br dd,J=13.36,6.72Hz,1H)2.78(dd,J=13.24,5.12Hz,1H)2.40(d,J=8.52Hz,1H)2.00(br s,1H)1.88-1.73(m,4H)1.72-1.52(m,4H)1.36-1.13(m,6H)1.07-0.90(m,5H)0.87(s,3H)0.79(s,3H)0.16-0.09(m,4H)

[0203] Compound 11 was separated by chiral SFC (Chiralpak IE-350×4.6 mm, mobile phase: IPA (0.05% DEA) and fluid CO2) to give compound 11A (RT=1.61 min) and compound 11B (RT=2.00 min). NMR data of compound 11A: 1 H NMR (400MHz, CDCl 3)δ=8.74-8.36(m,1H),8.01-7.76(m,1H),6.81-6.59(m,1H),5.81-5.57(m,1H),4.48-4.38 (m,1H),4.27-4.08(m,1H),4.00-3.84(m,3H),3.03-2.90(m,1H),2.83-2.70(m,1H),2.55-2 .50(m,1H),2.49-2.43(m,1H),2.36-2.21(m,3H),2.15-1.97(m,3H),1.75-1.41(m,10H),1. 39-1.28(m,5H),1.27-1.25(m,3H),0.71-0.58(m,3H),0.44-0.31(m,3H),0.22-0.14(m,1H)

[0204] NMR data of compound 11B: 1H NMR (400MHz, DMSO-d6) δ = 9.00-8.80 (m, 1H), 7.82-7.73 (m, 1H), 7.69-7.63 (m, 1H), 7.13-7.06 (m, 1H), 4. 22-3.98(m,2H),3.92-3.81(m,3H),2.94-2.83(m,1H),2.81-2.72(m,1H),2.70-2.62(m,1H),2.26-2.17( m,1H),2.11-1.95(m,4H),1.93-1.80(m,2H),1.75-1.62(m,2H),1.61-1.49(m,3H),1.49-1.35(m,4H),1. 31-1.13(m,6H),1.10(s,3H),0.54-0.46(m,3H),0.43-0.30(m,2H),0.28-0.21(m,1H),0.13-0.03(m,1H)

[0205] NMR data of compound 20: 1 HNMR (400MHz, DMSO-d6) δ12.38-12.04(m,1H),8.87(dd,J=8.2,3.2Hz,1H),7.90(td,J=5.7,2.3Hz,1H),7.67(dd,J= 9.9,1.8Hz,1H),7.12(dd,J=12.8,3.6Hz,1H),4.13(q,J=7.5,7.0Hz,2H),3.89(d,J=2.3Hz,3H),3.55-3.50(m,2H)3. 15-3.07(m,2H),3.01(d,J=5.6Hz,1H),2.62(d,J=8.5Hz,1H),2.24(d,J=3.6Hz,1H),2.09-2.01(m,4H),1.90(dt,J= 12.6,3.9Hz,2H),1.51-1.38(m,4H),1.33-1.24(m,4H),0.89(d,J=9.1Hz,3H),0.85-0.73(m,2H),0.62-0.51(m,4H).

[0206] NMR data of compound 24: 1H NMR(400MHz, DMSO-d6)δ8.37(t,J=7.4Hz,1H),8.00(q,J=5.4Hz,1H),7.49-7.37(m,2H),4.34-4.23 (m,1H),4.11(t,J=8.1Hz,1H),3.07-2.98(m,2H),2.66(d,J=8.3Hz,1H),2.24(s,1H),2.11(dd,J=19 .9,8.6Hz,4H),1.97-1.86(m,3H),1.50(dddd,J=24.7,12.8,9.0,4.0Hz,4H),1.24(dd,J=19.0,9.8 Hz,4H),1.12(s,3H),0.93(d,J=5.2Hz,3H),0.83-0.71(m,2H),0.59(ddd,J=19.5,10.3,4.3Hz,4H).

[0207] NMR data of compound 25: 1 H NMR (400MHz, DMSO-d6) δ8.74(dd,J=8.1,4.8Hz,1H),7.95(t,J=5.7Hz,1H),7.62(dd,J=9.7,3.4Hz,1H),7.21(dd ,J=12.0,3.4Hz,1H),5.98(dt,J=10.4,3.2Hz,1H),5.93-5.80(m,1H),4.24(tt,J=9.7,4.1Hz,1H),4.09(t,J=8. 1Hz,1H),3.07-2.92(m,3H),2.63(d,J=8.4Hz,1H),2.22(d,J=3.5Hz,1H),2.11-1.97(m,4H),1.94-1.85(m,2H), 1.57-1.38(m,4H),1.32-1.17(m,4H),1.11(s,3H),0.91(d,J=5.6Hz,3H),0.84-0.67(m,2H),0.63-0.43(m,4H).

[0208] NMR data of compound 26: 1H NMR(400MHz, DMSO-d6)δ8.37(t,J=7.4Hz,1H),8.00(q,J=5.4Hz,1H),7.50-7.36( m,2H),4.34-4.24(m,1H),4.11(t,J=8.1Hz,1H),3.07-2.97(m,3H),2.66(d,J=8. 3Hz,1H),2.24(s,1H),2.14-2.03(m,4H),1.94-1.88(m,2H),1.52-1.40(m,4H),1 .30-1.21(m,4H),1.12(s,3H),0.94-0.93(m,3H),0.8-0.78(m,1H),0.60-0.52(m, 4H),0.47-0.46(dd,J=11.9,4.1Hz,1H).

[0209] NMR data of compound 28: 1 HNMR(400MHz,DMSO-d6)δ8.88(dd,J=8.2,2.6Hz,1H),7.91(dt,J=7.3,3.6Hz,1H),7.69(dd,J=10.0 ,1.7Hz,1H),7.13(dd,J=12.7,3.6Hz,1H),4.42(d,J=47.3Hz,2H),4.15(dq,J=22.1,7.4,6.3Hz,2H) ,3.89(d,J=2.4Hz,3H),3.16-2.86(m,2H),2.62(d,J=8.5Hz,1H),2.24(d,J=3.6Hz,1H),2.11-1.88 (m,6H),1.61-1.33(m,6H),1.20(dt,J=21.9,10.5Hz,3H),0.89(d,J=8.8Hz,3H),0.85-0.36(m,6H).

[0210] NMR data of compound 30: 1HNMR(400MHz,DMSO-d6)δ8.86(d,J=8.1Hz,1H),7.89(t,J=5.6Hz,1H),7.69(dd,J=9.9,1.7Hz,1H),7.11 (dd,J=12.7,3.5Hz,1H),4.22(tt,J=10.6,4.3Hz,1H),4.10(td,J=8.3,4.5Hz,1H),3.87(d,J=2.4Hz,3H) ,3.14-2.85(m,2H),2.61(d,J=8.5Hz,1H),2.32-2.17(m,3H),2.12-1.89(m,4H),1.68(td,J=13.5,3.6H z,2H),1.57-1.28(m,4H),1.18(td,J=18.6,17.1,10.2Hz,3H),0.88(d,J=8.1Hz,3H),0.84-0.35(m,6H).

[0211] Example 36 In vitro activity test of human RXFP1 receptor modulators

[0212] This experiment uses a CHO-K1 cell line stably transfected with the human RXFP1 receptor. The activity of the compound is evaluated by detecting the cAMP produced after stimulating the RXFP1 receptor coupled to the Gs protein.

[0213] Main reagents: cAMP detection kit (Cisbio), 1 M HEPES (Invitrogen), HBSS (Invitrogen), BSA (Sigma), IBMX (Sigma).

[0214] Test process:

[0215] (1) Compound preparation: The test compound was dissolved in DMSO and diluted into 10 concentration gradients at a 4-fold dilution factor. 250 nL of each concentration was transferred to the test plate (OptiPlate-384 well plate) using Echo.

[0216] (2) Assay buffer: 1X stimulation buffer, 500 μM IBMX, deionized water;

[0217] (3) Cell preparation: Thaw the frozen cells (RXFP1 cAMP cells), wash them twice with HBSS, and then resuspend them in stimulation buffer;

[0218] (4) 10 μL of cell suspension containing 10,000 cells was added to each well of the test plate, centrifuged at 1000 rpm for 5 seconds, and then incubated at 37°C for 60 minutes;

[0219] (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;

[0220] (6) Read the plate using an EnVision microplate reader.

[0221] 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.

[0222] %Effect=100×(Sample RawValue-Low ControlAverage) / (High ControlAverage-Low ControlAverage)

[0223] Table 1 Human RXFP1 receptor agonist activity test data

[0224] According to the data in Table 1, it can be seen that the compounds of the present invention have good agonist activity on RXFP1 receptor.

[0225] Example 37

[0226] Pharmacokinetic study of the compound in beagle dogs

[0227] (1) Experimental materials

[0228] Beagle dogs: male, 8-13 kg, purchased from Beijing Masi Biotechnology Co., Ltd.

[0229] Reagents: physiological saline, EDTA-2K, acetonitrile, methanol, formic acid, and propranolol (internal standard) are all commercially available.

[0230] Instrument: AB SCIEX QTRAP 5500+

[0231] (2) Experimental methods

[0232] Compounds were weighed and dissolved in DMSO-PEG-400-normal saline (5:60:35, v / v / v). After intravenous or oral administration to beagle dogs, 200 μL of venous blood was collected at 15, 30, 1, 2, 4, 6, 8, and 24 hours (5 minutes additionally for the IV group) in EDTA-K2 anticoagulant EP tubes. The blood was centrifuged at 12,000 rpm for 2 minutes, and plasma was frozen at -80°C for analysis. A precisely weighed amount of test compound was dissolved in DMSO to 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions. 10 μL of each standard solution was accurately pipetted and added to 90 μL of blank plasma. Vortex mixing was performed to prepare plasma samples equivalent to plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. Duplicate samples were analyzed at each concentration to construct a standard curve. 30 μL of plasma (5, 15, and 30 minutes after intravenous administration, diluted 5-fold) was collected and 150 μL of an acetonitrile solution of internal standard propranolol (50 ng / mL) was added. After vortex mixing, 100 μL of purified water was added and vortex mixing was repeated. The supernatant was centrifuged at 4000 rpm for 5 minutes and analyzed by LC-MS. LC-MS detection conditions were as follows:

[0233] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0234] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0235] (3) Data processing

[0236] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The results are shown in Table 2.

[0237] Table 2. Beagle PK data

[0238] The experimental results in Table 2 show that the series of compounds of the present invention have good pharmacokinetic characteristics in beagle dogs, and their exposure, half-life and absolute bioavailability are better than those of the positive control compound in Example 1 of CN116547270A.

[0239] Example 38

[0240] In vitro stability test of compounds in human hepatocytes

[0241] 38.1 Preparation of Stock and Working Solutions

[0242] The compound and positive drug were dissolved in DMSO to obtain a 10 mM stock solution, and the stock solution was diluted with acetonitrile-water (1:1, v / v) to obtain a 100 μM solution.

[0243] 38.2 Hepatocyte Stability Assay

[0244] The compounds were respectively mixed with human hepatocytes (0.5×10 6 Two parallel incubations were performed in an incubation medium (Williams' Medium E and 1×GlutaMAX) containing 10 cells / mL and an incubation medium without cells. The final drug concentration in the incubation system was 1 μM, and the total incubation time was 120 minutes. During the incubation process, samples were taken at time points of 0.0, 15, 30, 60, 90, and 120 minutes, and the reaction was terminated by adding an acetonitrile solution containing an internal standard (0.5 μM tolbutamide). Verapamil (1 μM) was used as a positive control drug for the incubation system. UPLC-MS / MS was used to analyze the test samples and calculate the remaining percentage, in vitro intrinsic clearance, and half-life.

[0245] 38.3 Data Analysis

[0246] The peak area ratio of the analyte to the internal standard is used to calculate the relative percentage content (residual rate %) of the compound after incubation and perform exponential function fitting. The calculation formula is as follows:

[0247] t 1 / 2 =0.693 / k, k=rate constant(-slope value);

[0248] Scaled-up CL int =kV / N×scaling factor, V=incubation volume (0.2mL); N=number of hepatocytes per well (0.1×10 6 cells).

[0249] CL invivo =(Q*F u / R B *Scale-up C lint ) / (Q+F u / R B *Scale-up C lint ) If F u =1&R B =1 then CL = (Q * Scale-up C lint ) / (Q+Scale-up C lint )

[0250] ER (extraction rate) = CLinvivo / Hepatic blood flow

[0251] Physiological parameter

[0252] Classification criteria: slow metabolism (ER < 0.3), medium metabolism (0.3 < ER < 0.7), fast metabolism (ER > 0.7).

[0253] The test results are shown in Table 3.

[0254] Table 3. Stability of the compound in human hepatocytes

[0255] The experimental results show that the stability of the compound of the present invention in human hepatocytes is better than that of the compound in Example 1 of CN116547270A.

[0256] 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 by the above embodiments. For those of ordinary skill in the art, improvements or changes can be made according to the above description, and all such improvements and changes should fall within the protection scope of the appended claims of the present invention.

Claims

1. A RXFP1 receptor modulator, or an isomer, racemate or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor modulator is shown in general formula (I): Where: R 1 is selected from hydrogen, halogen or cyano; R8 is selected from: C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with C3-C8 cycloalkyl; R6 is selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, halogen, C1-C6 alkoxy; R7 is selected from: H, C1-C6 alkyl; or R7 and R8 together with the atoms connected to them form a 3-6 membered ring lactone; Said Y1 and Y2 are independently selected from: CH or N; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the "substituted" substituent is one or more, 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 The aryl group or one or more of the 5-10 membered heteroaryl groups, Z is selected from an integer of 0, 1, 2 or 3.

2. The RXFP1 receptor modulator according to claim 1, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor modulator is shown in general formula (I-1) or (I-2): Where: R 1 is selected from hydrogen, fluorine or cyano; said R4 is selected from: H, hydroxyl, C1-C6 alkoxy; said R5 is selected from: C1-C6 alkyl, C1-C6 alkoxy substituted C1-C6 alkyl; Said Y1 and Y2 are independently selected from: CH or N; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the "substituted" substituent is one or more, 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 The aryl group or one or more of the 5-10 membered heteroaryl groups, Z is selected from an integer of 0, 1, 2 or 3.

3. The RXFP1 receptor modulator according to claim 2, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor modulator is shown in general formula (IA) or (IB): Among them, the R 1 is selected from hydrogen, fluorine or cyano; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The W is selected from substituted or unsubstituted 4-12 membered bicycloalkyl; the "substituted" substituent is one or more, 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 The aryl group or one or more of the 5-10 membered heteroaryl groups, Z is selected from an integer of 0, 1, 2 or 3.

4. The RXFP1 receptor modulator according to claim 2, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor modulator has a structure shown in general formula (IIA) or (IIB): Among them, R 1 , R4, Y1, Y2, Z and W are defined the same as in claim 2.

5. The RXFP1 receptor modulator according to claim 3, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor modulator has a structure shown in the general formula (IIC) or (IID): Among them, R 1 The definitions of , Z and W are the same as those in claim 3.

6. The RXFP1 receptor modulator according to claim 2 or 4, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor modulator has a structure represented by formula (IIIA), formula (IIIB), formula (IIIC), formula (IIID), formula (IIIE), formula (IIIF), formula (IIIG), formula (IIIH), formula (IIII) or formula (IIIJ): Among them, R 1 , R4, Y1, Y2, Z and W are defined the same as in claim 2.

7. The RXFP1 receptor modulator according to claim 3 or 5, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor modulator has the structure shown in the general formula (IVA), (IVB), (IVC), and (IVD): Among them, R 1 The definitions of , Z and W are the same as those in claim 3.

8. The RXFP1 receptor modulator according to any one of claims 1 to 7, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: Said W is independently selected from: The R2 and R3 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, 3-8 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; The m, n, s and t are independently selected from integers of 0, 1, 2, 3, 4, 5 or 6.

9. The RXFP1 receptor modulator according to any one of claims 1 to 8, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The R2 and R3 are independently selected from: H, C1-C6 alkyl or C1-C6 haloalkyl.

10. The RXFP1 receptor modulator according to any one of claims 1 to 9, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: Said W is independently selected from:

11. The RXFP1 receptor modulator according to any one of claims 1 to 10, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: Said W is independently selected from:

12. The RXFP1 receptor modulator according to any one of claims 1 to 11, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The RXFP1 receptor modulator is selected from:

13. The RXFP1 receptor modulator according to any one of claims 1 to 12, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor modulator is selected from:

14. A pharmaceutical composition, characterized in that The invention comprises the RXFP1 receptor modulator according to any one of claims 1 to 13, or its isomer, racemate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

15. Use of the RXFP1 receptor modulator according to any one of claims 1 to 13, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing or treating diseases associated with the RXFP1 receptor.

16. The use according to claim 15, characterized in that The RXFP1 receptor-related disease is selected from angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary heart disease, acute heart failure, chronic heart failure, hypertension, refractory hypertension, pulmonary hypertension heart failure, chronic kidney disease, acute kidney injury and refractory hypertension.

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