RXFP1 receptor agonist and preparation method and application thereof

Abstract

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

Description

Technical Field

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

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

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

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

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

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

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

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

[0009]

[0010] in:

[0011] The Y, Z or T are independently selected from CR 1 , CR 9 , CR 10 or N; said R 1 , R 9 or R 10 are independently selected from hydrogen, halogen, cyano or C 1 -C 6 Haloalkyl;

[0012] The X is selected from -O-, -NH-, -N(Me)- or -CH 2 -;

[0013] The ring A is selected from:

[0014]

[0015] The R 5 , R 6 , R 7 or R 8 are independently selected from: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 Aryl or 5-12 membered heteroaryl;

[0016] The R 11 Independently selected from: H, hydroxyl, C 1 -C 6 Alkoxy;

[0017] The R 12 Independently selected from: C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy substituted C 1 -C 6 alkyl;

[0018] The W is selected from The n is an integer selected from 0, 1 or 2; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and R 2 and R 3 Not at the same time H;

[0019] Or the R 2 and R 3 Together with the carbon atom it is attached to, it forms C 3 -C 8 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0020] The R 4 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted 5-12 membered heteroaryl;

[0021] The substituents of the "substituted" are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO 3 H.C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 One or more of aryl or 5-12 membered heteroaryl.

[0022] Furthermore, as a preferred technical solution of the present invention,

[0023] The Y, Z or T are independently selected from CR 1 , CR 9 , CR 10 or N;

[0024] The R 1 , R 9 or R 10 are independently selected from hydrogen, halogen or cyano; X is selected from -O-, -NH-, -N(Me)- or -CH 2 -;

[0025] The ring A is selected from:

[0026]

[0027] The R 5 , R 6 , R 7 or R 8 are independently selected from: H, halogen, C 1 -C6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 Aryl or 5-12 membered heteroaryl;

[0028] The W is selected from The n is an integer selected from 0, 1 or 2; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and R 2 and R 3 Not at the same time H;

[0029] Or the R 2 and R 3 Together with the carbon atom it is attached to, it forms C 3 -C 8 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0030] The R 4 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6 -C 12 Aryl, substituted or unsubstituted 5-12 membered heteroaryl;

[0031] The substituents of the "substituted" are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO 3 H.C 1 -C 6 Alkyl, C 1-C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 One or more of aryl or 5-12 membered heteroaryl.

[0032] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor agonist has a structure shown in the general formula (IIA) or the general formula (IIB):

[0033] Wherein, the definitions of X, Y, Z, T, W and ring A are the same as those in the general formula (I).

[0034] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor agonist has a structure shown in the general formula (IIC) or the general formula (IID):

[0035] Wherein, the definitions of X, Y, Z, T, W and ring A are the same as those in the general formula (I).

[0036] Further, as a preferred technical solution of the present invention, the R 1 , R 9 or R 10 are independently selected from hydrogen, fluorine, chlorine, cyano or C 1 -C 6 alkyl;

[0037] Said X is selected from -O- or -NH-;

[0038] The R 11 Independently selected from: H, hydroxyl, methoxy;

[0039] The R 12 Independently selected from: methyl, methoxyethyl;

[0040] The ring A is selected from:

[0041]

[0042] The R 5 , R 6 , R7 or R 8 are independently selected from: H, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy or C 1 -C 6 Haloalkoxy;

[0043] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, and R 2 and R 3 Not at the same time H;

[0044] Or the R 2 and R 3 Together with the carbon atom it is attached to, it forms C 3 -C 8 Cycloalkyl or 3-8 membered heterocycloalkyl;

[0045] The R 4 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl;

[0046] The substituents of the "substituted" are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO 3 H.C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-C 12 One or more of aryl or 5-12 membered heteroaryl.

[0047] Further, as a preferred technical solution of the present invention, the ring A is selected from:

[0048]

[0049] Furthermore, as a preferred technical solution of the present invention, the present invention also provides a RXFP1 receptor agonist, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, characterized in that the RXFP1 receptor agonist is selected from the structure shown in formula (III) or formula (IV):

[0050]

[0051] Wherein, the definitions of X, Y, Z, T and W are the same as those mentioned above.

[0052] Further, as a preferred technical solution of the present invention, the R 1 , R 9 or R 10 are independently selected from hydrogen, chlorine or fluorine;

[0053] X is selected from -O- or -NH-;

[0054] The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, and R 2 and R 3 Not at the same time H;

[0055] Or the R 2 and R 3 Together with the carbon atom it is attached to, it forms C 3 -C 8 Cycloalkyl;

[0056] The R 4 is selected from substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl;

[0057] The "substituted" substituents are independently selected from -OH, -NH2, -CN, -COOH, -SO 3 H.C 1-C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, halogen, C 3 -C 8 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 12 One or more of aryl or 5-12 membered heteroaryl.

[0058] Further, as a preferred technical solution of the present invention, R 1 , R 9 or R 10 are independently selected from hydrogen, chlorine or fluorine; said X is selected from -O- or -NH-;

[0059] The R 2 and R 3 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl; said R 4 is selected from methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

[0060] Further, as a preferred technical solution of the present invention, W is selected from:

[0061]

[0062] Further, as a preferred technical solution of the present invention, the R 2 and R 3 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl;

[0063] Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0064] The R 4Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and the like.

[0065] Further, as a preferred technical solution of the present invention, R 5 , R 6 , R 7 or R 8 are independently selected from: H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, trifluoromethyloxy, trifluoroethyloxy, isobutoxy, tert-butoxy, sec-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

[0066] Further, as a preferred technical solution of the present invention, the RXFP1 receptor agonist is selected from:

[0067]

[0068]

[0069]

[0070]

[0071] Further, as a preferred technical solution of the present invention, the RXFP1 receptor agonist is selected from:

[0072]

[0073]

[0074]

[0075]

[0076] Furthermore, the present invention also provides a deuterated compound of the RXFP1 receptor agonist of the present invention, or its isomer, racemate or pharmaceutically acceptable salt.

[0077] Furthermore, as a preferred technical solution of the present invention, it is characterized in that the deuterated compound is selected from the following structures:

[0078]

[0079]

[0080] Furthermore, the present invention also provides a method for preparing a RXFP1 receptor agonist, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, which can be prepared by conventional methods in the art, or by referring to the method of patent WO2022122773A1 and methods known in the art.

[0081] Furthermore, the present invention also provides a pharmaceutical composition, characterized in that it comprises the RXFP1 receptor agonist described in formula (I), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (III) or formula (IV) of the present invention, or its isomer, or its racemate or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

[0082] Furthermore, the present invention also provides a use of a RXFP1 receptor agonist of formula (I), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (III) or formula (IV) of the present invention, or an isomer thereof, or a racemic form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (III) or formula (IV) of the present invention in the preparation of a drug for preventing or treating a disease associated with the RXFP1 receptor.

[0083] Furthermore, as a preferred technical solution of the present invention, the RXFP1 receptor-related disease is selected from heart failure.

[0084] In the chemical structure of the compound described in the present invention, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be Or colleagues include Two configurations;

[0085] In the chemical structure of the compound described in the present invention, the bond Indicates that the bond can be a single bond or double bond

[0086] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or both configurations;

[0087] Compounds and intermediates of the present invention can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.

[0088]

[0089] All compounds in the present invention can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0090] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0091] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood in accordance with the ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0092] The term "alkyl" refers to a branched, unbranched, and cyclic saturated hydrocarbon chain containing a specified number of carbon atoms. 1- C 6 Alkyl, the C 1- C 6 The number of carbon atoms in the alkyl group is selected from 1, 2, 3, 4, 5 or 6, and the C 1- C 6 Alkyl is preferably: C 1 -C 2 , C 1 -C 3 , C 1 -C 4 or C 1 -C 5Alkyl; 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.

[0093] The term "haloalkyl" means that the hydrogen on the alkyl group may be replaced by one or more halogen atoms, and the haloalkyl group is preferably C 1- C 6 Alkyl halides, the C 1- C 6 The number of carbon atoms in the haloalkyl group is selected from 1, 2, 3, 4, 5 or 6. 1- C 6 Preferred haloalkyl group: C 1 -C 2 , C 1 -C 3 , C 1 -C 4 or C 1 -C 5 haloalkyl; examples of the haloalkyl include: -CHF 2 , -CHCl 2 , -CF 3 , -CCl 3 、-CHFCH 2 F, -CHClCH 2 F, -CF 2 CHF 2 、-CH 2 CHF 2 、-CH 2 CF 3 、-CHFCH 3 、-CH 2 CH 2 F, -CF 2 CH 3 、-CH 2 CF 2 CHF 2 In one embodiment, C 1- C 6 The haloalkyl group contains a fluorine-substituted C 1- C 6 In another embodiment, C 1- C 4 The haloalkyl group contains a fluorine-substituted C 1- C 4 In another embodiment, C 1- C 3The haloalkyl group contains a fluorine-substituted C 1- C 3 alkyl.

[0094] The term "alkoxy" refers to an alkyl group with one or more carbon atoms substituted by oxygen, such as -O-(alkyl), wherein alkyl is as defined above, and the C 1 -C 6 The number of carbon atoms in the alkoxy group is selected from 1, 2, 3, 4, 5 or 6, and the alkoxy group is preferably C 1 -C 6 Alkoxy; the C 1 -C 6 Alkoxy is preferably: C 1 -C 2 , C 1 -C 3 , C 1 -C 4 or C 1 -C 5 Alkoxy, further, the alkoxy is specifically selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0095] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms; the haloalkoxy group is preferably C 1- C 6 Haloalkoxy, the C 1- C 6 The number of carbon atoms in the haloalkoxy group is selected from 1, 2, 3, 4, 5 or 6. 1- C 6 Preferred haloalkoxy groups are: C 1 -C 2 , C 1 -C 3 , C 1 -C 4 or C 1 -C 5 Halogenated alkoxy, further, the halogenated alkoxy is specifically selected from -OCHF 2 ,-OCHCl 2 、-OCF 3 、-OCCl 3 、-OCHFCH 2 F, -OCHClCH 2 F, -OCF 2 CHF 2 、-OCH 2 CHF 2 、-OCH 2 CF 3 、-OCHFCH3 、-OCH 2 CH 2 F, -OCF 2 CH 3 、-OCH 2 CF 2 CHF 2 In one embodiment, C 1- C 6 The haloalkoxy group contains a fluorine-substituted C 1- C 6 Alkoxy; in another embodiment, C 1- C 4 The haloalkyl group contains a fluorine-substituted C 1- C 4 Alkoxy; in yet another embodiment, C 1- C 3 The haloalkyl group contains a fluorine-substituted C 1- C 3 Alkoxy.

[0096] 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- C 8 Cycloalkyl, the C 3- C 8 Cycloalkyl has 3 to 8 carbon ring members. 3 , C 4 , C 5 , C 6 , C 7 or C 8 Cycloalkyl group, the C 3- C 8 The cycloalkyl group is preferably selected from: C 3- C 7 Cycloalkyl, C 3- C 6 Cycloalkyl, C 3- C 5 Cycloalkyl or C 3- C 4 Cycloalkyl, in one embodiment, the cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0097] The term "heterocycloalkyl" refers to one or more carbon atoms in the cycloalkyl group replaced by heteroatoms independently selected from N, O and S; the number of the heteroatoms is 1, 2, 3 or 4; the heterocycloalkyl group is preferably a 3-10 membered heterocycloalkyl group; the number of carbon atoms in the 3-10 membered heterocycloalkyl group is selected from 2, 3, 4, 5, 6, 7, 8 or 9, and the 3-10 membered heterocycloalkyl group is preferably selected from: 3-9 membered heterocycloalkyl group, 3-8 membered heterocycloalkyl group, 3-7 membered heterocycloalkyl group, 3-6 membered heterocycloalkyl group, 3-5 membered heterocycloalkyl group or 3-4 membered heterocycloalkyl group. In one embodiment, examples of the heterocycloalkyl group include, but are not limited to: aziridine group, oxirane group, azetidine group, oxetanyl group, pyrrolidine group 1 ,1 -dioxo-1,1- ... More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0098] The term "aryl" refers to a 6-14 membered monocyclic or polycyclic aromatic ring assembly, wherein all the ring atoms are carbon atoms. Generally, aryl is a 6-membered monocyclic, 10-12 membered bicyclic or 14-membered fused tricyclic aromatic ring system. As used herein, C A Aryl and C A-B Aryl represents an aromatic group in which A and B represent the number of carbon atoms in the ring system. 6 -C 12 Aryl, more preferably: C 6 -C 10 Aryl, C 6 -C 8 Aryl or C 6 -C 7 Aryl; in one embodiment, the aryl is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.;

[0099] 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 a 5-12 heteroaryl, further preferably a 5-10 heteroaryl, more preferably a 5-8 heteroaryl, most preferably a 5-, 6-, 7- or 8-membered heteroaryl. Heteroaryl may be, for example, a five- or six-membered monocyclic ring or a fused bicyclic structure formed by a fused five- and six-membered ring or two fused six-membered rings or as another example, two fused five-membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. The heteroaryl ring typically contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) will be less than five.

[0100] Examples of five-membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl. Examples of six-membered monocyclic heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl. Specific examples of bicyclic heteroaryls containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazolyl and imidazoimidazolyl. Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g., adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl. Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl. Particular heteroaryl groups are those derived from thienyl, pyrrolyl, benzothienyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0101] The term "halogen" is selected from F, Cl, Br or I;

[0102] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0103] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).

[0104] The term "stereoisomers" refers to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, etc.;

[0105] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0106] The term "racemate" refers to an equimolar mixture of two enantiomers, devoid of optical activity.

[0107] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. The present invention also contemplates quaternary ammonium salts formed by compounds of any group containing N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.

[0108] The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetable and mineral, cream base, lotion base, ointment base, etc. Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum protein, such as human serum protein; buffer substances such as phosphate; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon; magnesium trisilicate; polyvinyl pyrrolidone; polyacrylates; waxes; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; colorants; release agents; coatings; sweeteners; flavorings; fragrances; preservatives and antioxidants.

[0109] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0110] 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.

[0111] Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted to the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.

[0112] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0113] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, stabilize metabolism, and improve the in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom with the same atomic number (proton number) and a different mass number (proton and neutron sum). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H. 3 H. 13 C. 14 C. 15 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy inspection of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amount nor have radioactivity, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0114] For example, the compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0115] Furthermore, the compounds of the present invention may have one or more hydrogen atoms deuterated with isotopes of deuterium ( 2 After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, stabilizing metabolism and improving in vivo activity.

[0116] The preparation method of the isotope derivative generally includes: a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu 4 HSO 4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0117] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0118] 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.

[0119] The beneficial effects of the present invention compared with the prior art include but are not limited to:

[0120] Compared with the prior art, the RXFP1 receptor agonist of the present invention has a lower EC 50 value. DETAILED DESCRIPTION

[0121] The present invention is further described in detail below in conjunction with embodiments, but the content of the invention is not limited to the embodiments.

[0122] Example 1

[0123] Synthesis of (1s,4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methyl-cyclohexanecarboxylic acid

[0124] The specific synthetic route is as follows:

[0125]

[0126] Step A: Synthesis of 2,2-difluoro-6-iodo-1,3-benzenediol-5-amine

[0127] At room temperature, 2,2-difluoro-1,3-benzenediol-5-amine (930 mg, 5.37 mmol) was dissolved in N,N-dimethylformamide (10 ml) solution, cooled to 10°C, N-iodosuccinimide (1.27 g, 5.64 mmol) was added in batches, and the temperature was slowly raised to 25°C and stirred for 2 hours. LC-MS was used to monitor the reaction until it was complete.

[0128] The reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 1 time), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to obtain 1 g of 2,2-difluoro-6-iodo-1,3-benzenediol-5-amine. LC-MS: RT = 0.63 min, [M+H] + =299.9.

[0129] Step B: Synthesis of methyl 6-amino-2,2-difluoro-1,3-benzodiazole-5-carboxylate

[0130] At room temperature, 2,2-difluoro-6-iodo-1,3-benzenediol-5-amine (790 mg, 2.64 mmol), triethylamine (427 mg, 4.23 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (193 mg, 264 μmol) were dissolved in methanol (30 ml). The mixture was replaced and carbon monoxide was introduced, and the reaction was carried out at 70°C for 12 hours. After the reaction was complete, the temperature was lowered to room temperature.

[0131] The catalyst 1,1-bis(diphenylphosphino)ferrocenepalladium chloride was filtered off, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) to obtain 360 mg of methyl 6-amino-2,2-difluoro-1,3-benzodiazole-5-carboxylate.

[0132] Step C: Synthesis of 6-amino-2,2-difluoro-1,3-benzodiazole-5-carboxylic acid

[0133] At room temperature, methyl 6-amino-2,2-difluoro-1,3-benzodiazole-5-carboxylate (360 mg, 1.56 mmol) was dissolved in tetrahydrofuran (4 ml) and water (2 ml), and lithium hydroxide monohydrate (392 mg, 9.34 mmol) was added. Stir at 25°C for 12 hours. Then sodium hydroxide (622 mg, 15.5 mmol) was added and stirred at 50°C for 12 hours. The reaction was completely cooled to room temperature.

[0134] The pH value of the reaction solution was adjusted to 5 with 1 mol / L hydrochloric acid, extracted with ethyl acetate (25 ml x 2 times), the organic phases were combined, washed with saturated brine (10 ml x 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated. 330 mg of 6-amino-2,2-difluoro-1,3-benzodiazole-5-carboxylic acid was obtained. LC-MS: RT = 0.08 min, [MH]- = 216.0.

[0135] Step D: Synthesis of 6-amino-N-[(1-cyclopropylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide

[0136] At room temperature, N,N-diisopropylethylamine (446 mg, 3.45 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (394 mg, 1.04 mmol) were added to a solution of (1-cyclopropylcyclobutyl)methylamine (167 mg, 1.04 mmol) and 6-amino-2,2-difluoro-1,3-benzodiphenol-5-carboxylic acid (150 mg, 690 μmol) in N,N-dimethylformamide (2 ml). The mixture was stirred at 25°C for 2 hours and monitored by LC-MS until the reaction was complete.

[0137] The reaction solution was poured into water (10 ml), extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification (ethyl acetate / petroleum ether = 1 / 5) gave 190 mg of 6-amino-N-[(1-cyclopropylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide. LC-MS: RT = 0.639 min, [M+H] + =325.1.

[0138] Step E: Synthesis of naphth-1-ylmethyl (1s,4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0139] Phosphorus oxychloride (123 mg, 803 μmol) was added to a solution of 6-amino-N-[(1-cyclopropylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide (177 mg, 545 μmol), 4-fluoro-2-methoxy-5-((((1S,4s)-4-methyl-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (250 mg, 535 μmol) and pyridine (211 mg, 2.68 mmol) in dichloromethane (2 ml) at room temperature. The mixture was stirred at 25 degrees Celsius for 2 hours and monitored by LC-MS until the reaction was complete.

[0140] The reaction solution was poured into room temperature water (20 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification (ethyl acetate / petroleum ether = 1 / 5) gave 120 mg of naphthalene-1-ylmethyl (1s, 4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 0.789 min, [M+H] + =773.4.

[0141] Step F: Synthesis of (((1s,4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methyl-cyclohexanecarboxylic acid

[0142] Naphthalen-1-ylmethyl (1s,4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (100 mg, 129 μmol) was dissolved in tetrahydrofuran (5 ml) at room temperature, wet palladium / carbon (100 mg, 10% palladium / 55% water) was added, hydrogen was replaced and introduced, and the reaction was carried out at room temperature for 3 hours. LC-MS monitoring was performed until the reaction was completed.

[0143] The palladium / carbon was filtered off, and the mixture was washed with tetrahydrofuran (20 ml). The filtrate was concentrated, and the crude product was purified by reverse phase HPLC (Phenomenex luna C18, mobile phase: 0.1% formic acid aqueous solution and acetonitrile), and then freeze-dried to obtain 23 mg of (((1s, 4s)-4-(5-(6-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methyl-cyclohexanecarboxylic acid. LC-MS: RT = 0.721 min, [M+H] + =633.3.

[0144] NMR data of compound 1: 1 H NMR (400 MHz, DMSO-d 6)δ12.42-12.15(m,1H),11.93(s,1H),8.68(t,J=6.19Hz,1H),8.53(s,1H),7.75(d,J=9.88Hz,1H ),7.65(s,1H),7.22(d,J=12.76Hz,1H),4.29-4.16(m,1H),3.98(s,3H),3.44(d,J=6.13Hz,2H),2 .07(d,J=13.38Hz,2H),1.96-1.86(m,2H),1.82-1.69(m,3H),1.61(bs,1H),1.52-1.37(m,4H),1 .33-1.22(m,2H),1.11(s,3H),0.90-0.82(m,1H),0.30(d,J=8.25Hz,2H),0.18(d,J=4.50Hz,2H).

[0145] Example 2

[0146] Synthesis of (1s,4s)-4-(5-(2,2-difluoro-6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxanol-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0147] The specific synthetic route is as follows:

[0148]

[0149] Step A: Synthesis of 6-amino-N-[(1-methylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide

[0150] At room temperature, N,N-diisopropylethylamine (506 mg, 3.91 mmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (446 mg, 1.17 mmol) were added to a solution of (1-methylcyclobutyl)methylamine (159 mg, 1.17 mmol) and 6-amino-2,2-difluoro-1,3-benzodiphenol-5-carboxylic acid (170 mg, 783 μmol) in N,N-dimethylformamide (1 ml). The mixture was stirred at 25 degrees Celsius for 2 hours and monitored by LC-MS until the reaction was complete.

[0151] The reaction solution was poured into water (3 ml), extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase HPLC (Waters Xbridge Prep OBD C18, mobile phase: 0.1% aqueous ammonium bicarbonate solution and acetonitrile) to prepare 150 mg of 6-amino-N-[(1-methylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide. LC-MS: RT = 0.661 min, [MH] + =297.1.

[0152] Step B: Synthesis of naphth-1-ylmethyl (1s,4s)-4-(5-(6-((1-methylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0153] Phosphorus oxychloride (113 mg, 739 μmol) was added to a solution of 6-amino-N-[(1-methylcyclobutyl)methyl]-2,2-difluoro-1,3-benzodiazole-5-carboxamide (132 mg, 443 μmol), 4-fluoro-2-methoxy-5-((((1s,4s)-4-methyl-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (230 mg, 493 μmol) and pyridine (195 mg, 2.47 mmol) in dichloromethane (1 ml) at room temperature. The mixture was stirred at 25°C for 2 hours and monitored by LC-MS until the reaction was complete.

[0154] The reaction solution was poured into normal temperature water (20 ml), extracted with dichloromethane (5 ml x 2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain 120 mg of naphthalene-1-ylmethyl (1s, 4s)-4-(5-(6-((1-methylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate. LC-MS: RT = 0.779 min, [M+H] + =747.4.

[0155] Step C: Synthesis of (((1s,4s)-4-(5-(6-((1-methylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0156] At room temperature, naphthalen-1-ylmethyl (1s,4s)-4-(5-(6-((1-methylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (100 mg, 133 μmol) was dissolved in tetrahydrofuran (10 ml), wet palladium / carbon (100 mg, 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 completed.

[0157] The palladium / carbon was filtered off, and the mixture was washed with tetrahydrofuran (20 ml). The filtrate was concentrated, and the crude product was purified by reverse phase HPLC (Waters Xbridge, mobile phase: 0.1% aqueous ammonium bicarbonate solution and acetonitrile), and then freeze-dried to obtain 51 mg of (((1s, 4s)-4-(5-(6-((1-methylcyclobutyl)methyl)carbamoyl)-2,2-difluorobenzo[d][1,3]dioxy-5-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methyl-cyclohexanecarboxylic acid. LC-MS: RT=0.703 min, [M+H] + =607.3.

[0158] NMR data of compound 2: 1 H NMR (400 MHz, DMSO-d 6 )δ11.91(s,1H),8.65(t,J=5.88Hz,1H),8.53(s,1H),7.75(d,J=9.76Hz,1H ),7.66(s,1H),7.22(d,J=12.76Hz,1H),4.22(bs,1H),3.98(s,3H),3.30-3 .29(m,2H),2.07(d,J=13.13Hz,2H),1.99-1.87(m,4H),1.85-1.73(m,2H), 1.65-1.55(m,2H),1.42(bs,2H),1.34-1.22(m,2H),1.11(d,J=3.88Hz,6H).

[0159] Example 3

[0160] Synthesis of (1s,4s)-4-((5-(2-((1-cyclopropylcyclobutyl)methyl)aminomethyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)aminomethyl)-2-fluoro-4-methoxyphenyl)amino)-1-methylcyclohexane-1-carboxylic acid

[0161] The specific synthetic route is as follows:

[0162]

[0163] Step A: Synthesis of 3-amino-6-(trifluoromethyl)benzothiophene-2-carboxylate

[0164] Methyl thioglycolate (830 mg, 7.82 mmol) was added dropwise to a solution of 2-fluoro-4-(trifluoromethyl)benzonitrile (1 g, 5.29 mmol) and potassium carbonate (804 mg, 5.82 mmol) in N,N-dimethylformamide (10 ml) at 25°C, and stirred at 60°C for 5 hours. The reaction was completely cooled to room temperature.

[0165] The reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml x 2 times), the organic phases were combined, washed with saturated brine (50 ml x 6 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.1 g of 3-amino-6-(trifluoromethyl)benzothiophene-2-carboxylate

[0166] Step B: Synthesis of methyl 3-[[4-fluoro-2-methoxy-5-[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzamido]-6-(trifluoromethyl)benzothiophene-2-carboxylate

[0167] At room temperature, pyridine (849 mg, 10.7 mmol) and phosphorus oxychloride (494 mg, 3.22 mmol) were added to a solution of methyl 3-amino-6-(trifluoromethyl)benzothiophene-2-carboxylate (354.8 mg, 1.29 mmol) and 4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzoic acid (500 mg, 1.07 mmol) in dichloromethane (10 ml), respectively. The mixture was stirred at 25 degrees Celsius for 3 hours and monitored by LC-MS until the reaction was complete.

[0168] The reaction solution was poured into water (20 ml), extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 70%-100% B, continued for 15 minutes) to prepare 200 mg of methyl 3-[[4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzamido]-6-(trifluoromethyl)benzothiophene-2-carboxylic acid methyl ester. LC-MS: RT = 0.794 min, [M+H] + =723.3.

[0169] Step C: Synthesis of 3-[[4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzoyl]amino]-6-(trifluoromethyl)benzothiophene-2-carboxylic acid

[0170] Lithium hydroxide monohydrate (22.3 mg, 553 μmol) was dissolved in water (1 ml) and added to a solution of methyl 3-[[4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzoyl]amino]-6-(trifluoromethyl)benzothiophene-2-carboxylate (200 mg, 276 μmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at 25 degrees Celsius for 12 hours and monitored by LC-MS until the reaction was complete.

[0171] The pH was adjusted to 7 with 1 mol hydrochloric acid. The aqueous phase was extracted with ethyl acetate (10 ml x 3 times). The combined organic phase was washed with brine (10 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. 170 mg of 3-[[4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzoyl]amino]-6-(trifluoromethyl)benzothiophene-2-carboxylic acid was obtained. LC-MS: RT = 0.729 min, [M+H] + =709.3.

[0172] Step D: 1-naphthylmethyl 4-[5-[[2-[(1-cyclopropylcyclobutyl)methylcarbamate]-6-(trifluoromethyl)benzothiophen-3-ylcarbamate]-2-fluoro-4-methoxyanilino]-1-methyl-cyclohexanecarboxylate

[0173] At room temperature, N,N-diisopropylethylamine (87.5 mg, 677 μmol) and 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (128 mg, 338 μmol) were added to a solution of (1-cyclopropylcyclobutyl)methylamine (54.7 mg, 338 μmol) and 3-[[4-fluoro-2-methoxy-5-[[4-methyl-4-(1-naphthylmethoxycarbonyl)cyclohexyl]amino]benzoyl]amino]-6-(trifluoromethyl)benzothiophene-2-carboxylic acid (160 mg, 225 μmol) in N,N-dimethylformamide (1 ml), respectively. The mixture was stirred at 25°C for 1 hour and monitored by LC-MS until the reaction was complete.

[0174] The reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 1 time), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC column: Phenomenex luna C18 150 × 40 mm × 15 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 80%-100% B, continued for 15 minutes), and 150 mg of 1-naphthylmethyl 4-[5-[[2-[(1-cyclopropylcyclobutyl)methylcarbamate]-6-(trifluoromethyl)benzothiophen-3-ylcarbamate]-2-fluoro-4-methoxyaniline]-1-methyl-cyclohexanecarboxylate was prepared. LC-MS: RT = 0.750 min, [MH] + =816.2

[0175] Step E: Synthesis of (1s,4s)-4-((5-(2-((1-cyclopropylcyclobutyl)methyl)aminomethyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)aminomethyl)-2-fluoro-4-methoxyphenyl)amino)-1-methylcyclohexane-1-carboxylic acid

[0176] At room temperature, 1-naphthylmethyl 4-[5-[[2-[(1-cyclopropylcyclobutyl)methylcarbamate]-6-(trifluoromethyl)benzothiophen-3-ylcarbamate]-2-fluoro-4-methoxyaniline]-1-methyl-cyclohexanecarboxylate (150 mg, 133 μmol) was dissolved in tetrahydrofuran (5 ml), wet palladium / carbon (15 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 5 hours and monitored by LC-MS until the reaction was completed.

[0177] The palladium / carbon was filtered off, the product was washed with tetrahydrofuran, and the filtrate was concentrated. The crude product was subjected to reverse phase HPLC (chromatographic column: Waters Xbridge 150×25mm×5um; mobile phase: [water(ammonium bicarbonate)-acetonitrile]; gradient: 38%-68% B, over 9 minutes), and lyophilized to give 50 mg of (1s, 4s)-4-((5-(2-((1-cyclopropylcyclobutyl)methyl)aminomethyl)-6-(trifluoromethyl)benzo[b]thiophen-3-yl)aminomethyl)-2-fluoro-4-methoxyphenyl)amino)-1-methylcyclohexane-1-carboxylic acid, LC-MS: RT=0.670min, [MH]-=674.2.

[0178] NMR data of compound 3: 1 H NMR (400 MHz, DMSO-d 6)δ10.66-10.35(m,1H),8.59(s,1H),8.31(t,J=5.94Hz,1H),7.87(d,J=8.50Hz,1H),7.75(d, J=8.76Hz,1H),7.30(d,J=10.26Hz,1H),7.11(d,J=13.38Hz,1H),4.93(d,J=7.38Hz,1H),3.9 2(s,3H),2.07(d,J=11.38Hz,2H),1.88-1.53(m,8H),1.50-1.37(m,2H),1.33-1.20(m,4H),1 .09(s,3H),0.76(ddd,J=8.22,5.47,2.94Hz,1H),0.22(d,J=8.13Hz,2H),0.06-0.16(m,2H).

[0179] Example 4

[0180] Synthesis of (1s,4s)-4-(5-((2-(((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0181] The specific synthetic route is as follows:

[0182]

[0183] Step A: Synthesis of methyl 3-(4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate

[0184] At room temperature, 4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzoic acid (1 g, 2.14 mmol) was dissolved in tetrahydrofuran (20 ml), 3-amino-6-(trifluoromethyl)benzothiophene-2-carboxylic acid methyl ester (590 mg, 2.14 mmol) was added, followed by phosphorus oxychloride (330 mg, 2.14 mmol) and pyridine (510 mg, 6.42 mmol), and the mixture was reacted at room temperature for 3 hours. The reaction was monitored by LC-MS until completion.

[0185] Most of the phosphorus oxychloride was concentrated, and ice water was added to quench the reaction (10 ml), and ethyl acetate was used for extraction (30 ml × 3 times). The organic phases were combined, washed with saturated brine (20 ml × 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification (ethyl acetate / petroleum ether = 1 / 3) gave 0.5 g of 3-(4-fluoro-2-methoxy-5-((1s, 4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid methyl ester. LC-MS: RT = 2.62 min, [M+H] + =724.06.

[0186] Step B: Synthesis of 3-(4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0187] At room temperature, methyl 3-(4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (500 mg, 0.69 mmol) was dissolved in 10 ml of tetrahydrofuran and 10 ml of water. Lithium hydroxide (83 mg, 3.45 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS until completion.

[0188] Most of the tetrahydrofuran was concentrated off, and the pH was adjusted to 4-5 with 1 mol hydrochloric acid. The aqueous phase was extracted with ethyl acetate (20 ml × 3 times). The combined organic phase was washed with brine (20 ml × 1 time), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography purification (ethyl acetate / petroleum ether = 1 / 1) gave 0.22 g of 3-(4-fluoro-2-methoxy-5-((1s, 4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid. LC-MS: RT = 2.43 min, [M+H]+ = 710.01.

[0189] Step C: Synthesis of naphth-1-ylmethyl (1s,4s)-4-(5-((2-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate

[0190] At room temperature, 3-(4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-((naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxy)benzamido)-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (170 mg, 0.24 mmol) and (1-cyclopropylcyclobutyl)methanamine (30 mg, 0.24 mmol) were dissolved in dichloromethane (10 ml), N,N-diisopropylethylamine (160 mg, 1.2 mmol) was added, the temperature was lowered to 0 degrees Celsius, propylphosphonic anhydride (460 mg, 0.72 mmol, 50% mass fraction ethyl acetate solution) was added, the temperature was slowly raised to room temperature, the reaction was stirred for 1 hour, and the reaction was monitored by LC-MS until completion.

[0191] The reaction solution was diluted with water (10 ml), extracted with dichloromethane (10 ml x 2 times), the organic phases were combined, washed with saturated brine (20 ml x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 4). 100 mg of naphthalene-1-ylmethyl (1s, 4s)-4-(5-((2-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate was obtained. LC-MS: RT = 2.54 min, [M+H] + =815.08.

[0192] Step D: Synthesis of (1s,4s)-4-(5-((2-(((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0193] At room temperature, naphthalen-1-ylmethyl (1s, 4s)-4-(5-((2-((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylate (100 mg, 0.12 mmol) was dissolved in ethanol (10 ml), wet palladium / carbon (10 mg, 10% palladium / 55% water) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 5 hours and monitored by LC-MS until the reaction was completed.

[0194] The palladium / carbon was filtered off, ethanol (10 ml) was used for elution, the filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / n-hexane = 1 / 3) to obtain 9.3 mg of the product (1s, 4s)-4-(5-((2-(((1-cyclopropylcyclobutyl)methyl)carbamoyl)-6-(trifluoromethyl)benzothiophen-3-yl)carbamoyl)-2-fluoro-4-methoxyphenoxy)-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT = 2.25 min, [M+H] + =677.03.

[0195] Example 5 (Compound 17D)

[0196] Synthesis of (1s,4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylic acid

[0197] The specific synthetic route is as follows:

[0198]

[0199] Step A: Synthesis of methyl 2,2-dideuterio-1,3-benzodiazole-5-carboxylate

[0200] At room temperature, methyl 3,4-dihydroxybenzoate (1.00 g, 5.95 mmol), deuterated dichloromethane (775 mg, 8.92 mmol) and cesium carbonate (5.81 g, 17.8 mmol) were dissolved in N,N-dimethylformamide (8 mL) and heated in a microwave tube at 80 °C for 4 h. The product was monitored by TLC.

[0201] The reaction solution was diluted with ice water (10 ml), extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 3 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product of 2 batches was purified by thin layer chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain 1.00 g of 2,2-dideutero-1,3-benzodiazole-5-carboxylic acid methyl ester

[0202] Step B: Synthesis of methyl 2,2-dideuterio-6-nitro-1,3-benzodiazole-5-carboxylate

[0203] At 15°C, nitric acid (5.60 g, 87.0 mmol, 4.00 ml, 98% purity) was added dropwise to a solution of 2,2-dideutero-1,3-benzodiazole-5-carboxylic acid methyl ester (0.8 g, 4.39 mmol) in acetic acid (8 ml) under nitrogen atmosphere, and stirred at 25°C for 5 hours. The reaction was complete when monitored by TLC.

[0204] The reaction mixture was slowly poured into ice water (50 ml). The precipitate was collected by filtration, washed with water (100 ml), and concentrated in vacuo to give 0.8 g of methyl 2,2-dideutero-6-nitro-1,3-benzodiazole-5-carboxylate.

[0205] Step C: Synthesis of methyl 6-amino-2,2-dideutero-1,3-benzodiazole-5-carboxylate

[0206] At room temperature, methyl 2,2-dideuterio-6-nitro-1,3-benzodiazole-5-carboxylate (0.80 g, 3.52 mmol) was dissolved in a mixed solution of ethanol (8 ml) and water (4 ml), and ammonium chloride (376 mg, 7.04 mmol) and iron powder (983 mg, 17.6 mmol) were added under nitrogen atmosphere. The mixture was stirred at 80 degrees Celsius under nitrogen atmosphere for 1 hour. TLC was monitored until the reaction was complete.

[0207] The reaction mixture was filtered through celite and concentrated to obtain 700 mg of methyl 6-amino-2,2-dideutero-1,3-benzodiazole-5-carboxylate.

[0208] Step D: Synthesis of 6-amino-2,2-dideutero-1,3-benzodiazole-5-carboxylic acid

[0209] At room temperature, sodium hydroxide (97.3 mg, 2.43 mmol) was added to a mixed solution of methyl 6-amino-2,2-dideutero-1,3-benzodiazole-5-carboxylate (0.4 g, 2.03 mmol) in tetrahydrofuran (4 ml) and water (2 ml), and the mixture was stirred at 80°C for 1 hour. The reaction was monitored by LCMS until completion.

[0210] The mixture was adjusted to pH 5 with 1M (hydrochloric acid). The precipitate was collected by filtration, washed with water (100 ml), and concentrated in vacuo to obtain 280 mg of 6-amino-2,2-dideutero-1,3-benzodiazole-5-carboxylic acid.

[0211] Step E: Synthesis of 6-amino-2,2-dideuterio-n-[(1-methylcyclobutyl)methyl]-1,3-benzodiazole-5-carboxamide

[0212] A mixture of 6-amino-2,2-dideutero-1,3-benzotriazole-5-carboxylic acid (0.28 g, 1.53 mmol), (1-methylcyclobutyl)methylamine (181 mg, 1.83 mmol), diisopropylethylamine (592 mg, 4.59 mmol 798.83 μL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (697.53 mg, 1.83 mmol) in dimethylformamide (3 mL) was degassed at room temperature, purged with nitrogen three times, and then stirred at 25°C under nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS until completion.

[0213] The mixture was poured into ice water (50 ml), and the aqueous phase was extracted with ethyl acetate (50 ml × 3 times). The combined organic phase was washed with brine (50 ml × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. TLC analysis (ethyl acetate / petroleum ether = 1 / 5) was used to obtain 0.3 g of 6-amino-2,2-dideuterio-n-[(1-methylcyclobutyl)methyl]-1,3-benzodiazole-5-carboxamide. LC-MS: RT = 0.465 min, [M+H] + =265.1.

[0214] Step F: Synthesis of 1-naphthylmethyl 4-[5-[[2,2-dideuterio-6-[(1-methylcyclobutyl)methylcarbamate]-1,3-phenylenedioxy-5-yl]carbamate]-2-fluoro-4-methoxy-phenoxy]-1-methylcyclohexanecarboxylate

[0215] At room temperature, 4-fluoro-2-methoxy-5-((1,4s)-4-methyl-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxybenzoic acid (200 mg, 428 μmol) and 6-amino-2,2-dideutero-n-[(1-methylcyclobutyl)methyl]-1,3-benzodiazole-5-carboxamide (113 mg, 428 μmol) were dissolved in acetonitrile (5 ml), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (240 mg, 857 μmol) and N-methylimidazole (105 mg, 1.29 mmol) were added. The mixture was reacted at 25°C for 1 hour and the reaction was completed after being monitored by TLC.

[0216] The precipitate from the reaction solution was filtered, and the filter cake was concentrated to obtain 0.2 g of 1-naphthylmethyl 4-[5-[[2,2-dideuterio-6-[(1-methylcyclobutyl)methylcarbamate]-1,3-phenylenedioxy-5-yl]carbamate]-2-fluoro-4-methoxy-phenoxy]-1-methylcyclohexanecarboxylate. LC-MS: RT = 0.771 min, [M+H] + =713.4.

[0217] Step G: Synthesis of (1s,4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylic acid

[0218] At room temperature, 1-naphthylmethyl 4-[5-[[2,2-dideuterio-6-[(1-methylcyclobutyl)methylcarbamate]-1,3-phenylenedioxy-5-yl]carbamate]-2-fluoro-4-methoxy-phenoxy]-1-methylcyclohexanecarboxylate (200 mg, 280 μmol) was dissolved in tetrahydrofuran (10 ml), wet palladium / carbon (200 mg, 10% palladium / 55% water) was added, and hydrogen (15 psi) was introduced after replacement. The reaction was carried out at room temperature for 12 hours and monitored by LC-MS until the reaction was completed.

[0219] The palladium / carbon was filtered off, the filtrate was concentrated, and the crude product mixture was lyophilized by high performance liquid chromatography (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; gradient: 28%-58% B over 9min) to obtain 85 mg of (1s, 4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylic acid. LC-MS: RT=0.435min, [MH]-=571.2.

[0220] NMR data of compound 17D: 1 H NMR (400 MHz, DMSO-d 6 )δ12.02(s,1H)8.49(brt,J=6.20Hz,1H)8.18(s,1H)7.72(d,J=9.76Hz,1H)7.23(s,1H )7.19(d,J=12.76Hz,1H)4.38-4.12(m,1H)3.96(s,3H)3.27(d,J=6.12Hz,2H)2.07(br d,J=13.24Hz,2H)2.00-1.87(m,4H)1.86-1.71(m,2H)1.66-1.54(m,2H)1.51-1.36(m,2H)1.34-1.23(m,2H)1.16-1.06(m,6H).

[0221] Example 6 Compounds 18, 18A and 18B, 18AD and 18BD

[0222]

[0223] Compounds 18A and 18B

[0224]

[0225] Compounds 18A and 18B were prepared according to the method of Example 5 (Compound 17D), and the products were separated by chiral SFC (Chiralpak AS-3, 150*4.6 mm, mobile phase: IPA (0.05% DEA) and fluid CO 2 ) to give compound 18A (RT = 4.64 min), LC-MS: RT = 2.16 min, [M + H] + = 582.91 and compound 18B (RT = 5.49 min), LC-MS: RT = 2.16 min, [M + H] + = 582.92.

[0226] Compounds 18AD and 18BD

[0227]

[0228] Compounds 18AD and 18BD were prepared by referring to the method of 5 (compound 17D), and the products were separated by chiral SFC (Chiralpak IH-3, 50*4.6mm, mobile phase: IPA (0.05% DEA) and fluid CO 2 ) to give compound 18AD (RT = 3.71 min), LC-MS: RT = 2.18 min, [M + H] + = 585.0. and compound 18BD (RT = 4.01 min), LC-MS: RT = 2.18 min, [M + H] + = 585.04.

[0229] Example 7

[0230] Synthesis of (1s,4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)aminomethoxy)-2,3-dihydrobenzofuran-6-yl)aminomethoxy)-1-methylcyclohexane-1-carboxylic acid

[0231] The specific synthetic route is as follows:

[0232]

[0233] Step A: Synthesis of 5-iodo-6-nitro-2,3-dihydrobenzofuran

[0234] At room temperature, 6-nitro-2,3-dihydrobenzofuran-5-amine (2.00 g, 11.1 mmol) was dissolved in concentrated hydrochloric acid (20 ml) and heated to 100 degrees Celsius and stirred for ten minutes. The reaction solution was cooled to 0 degrees, and sodium nitrite (919 mg, 13.3 mmol, 1.2 equivalents) was dissolved in 5 ml of water and added dropwise to the reaction solution, and stirred for 20 minutes. Potassium iodide (2.76 g, 16.6 mmol, 1.5 equivalents) was dissolved in 5 ml of water and added to the reaction solution, and reacted at 70 degrees for 2 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 10 / 1, product Rf = 0.54) showed that the reactants were consumed and two new spots were detected.

[0235] Dilute with 10 mL of water, extract with ethyl acetate (10 mL × 2 times), wash the organic layer with saturated NaCl (10 mL × 2 times), dry over sodium sulfate, filter and concentrate under reduced pressure to give 5-iodo-6-nitro-2,3-dihydrobenzofuran (1.5 g, 5.15 mmol) as a yellow solid.

[0236] Step B: Synthesis of 5-iodo-2,3-dihydrobenzofuran-6-amine

[0237] At room temperature, 5-iodo-6-nitro-2,3-dihydrobenzofuran (500 mg, 1.72 mmol) was dissolved in 10 ml of ethanol and 5 ml of water, and iron powder (959 mg, 17.1 mmol) and ammonium chloride NH 4 Cl (918 mg, 17.1 mmol), react at 70 °C for 2 h, and the reaction was complete after LC-MS monitoring.

[0238] The reaction solution was filtered through celite, the filtrate was concentrated, diluted with 10 mL of water, extracted with ethyl acetate (10 mL × 2 times), the organic layer was washed with saturated NaCl (10 mL × 2 times), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 5-iodo-2,3-dihydrobenzofuran-6-amine (440 mg, 1.69 mmol) as a yellow solid.

[0239] Step C: Synthesis of methyl 6-amino-2,3-dihydrobenzofuran-5-carboxylate

[0240] At room temperature, 5-iodo-2,3-dihydrobenzofuran-6-amine (440 mg, 1.69 mmol) was dissolved in anhydrous methanol (10 ml), triethylamine (341 mg, 3.37 mmol, 469 μl) and (123 mg, 168 μmol) were added, and carbon monoxide (50 Psi) was introduced and replaced. The reaction was carried out at 70 °C for 8 hours. The reaction was completed after monitoring by LCMS.

[0241] The reaction solution was filtered through celite, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain crude product 6-amino-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester (250 mg, 1.29 mmol)

[0242] Step D: Synthesis of 6-amino-2,3-dihydrobenzofuran-5-carboxylic acid

[0243] 6-amino-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester (200 mg, 1.04 mmol) was dissolved in ethanol (5 ml) and water (5 ml), and then lithium hydroxide (86.8 mg, 2.07 mmol) was added and stirred at 75°C for 6 hours. LCMS showed that the reactant was consumed. Thin layer chromatography (petroleum ether: ethyl acetate = 2 / 1, product Rf = 0.15) showed that the reactant was consumed and a new spot was detected. The pH of the reaction mixture was adjusted to pH = 5 with 1 mol of dilute hydrochloric acid, and filtered and concentrated under reduced pressure to obtain 200 mg of yellow solid crude 6-amino-2,3-dihydrobenzofuran-5-carboxylic acid.

[0244] Step E: Synthesis of 6-amino-n-((1-methylcyclobutyl)methyl)-2,3-dihydrobenzofuran-5-carboxamide

[0245] At room temperature, 6-amino-2,3-dihydrobenzofuran-5-carboxylic acid (150 mg, 837 μmol) and (1-methylcyclobutyl)methylamine hydrochloride (147 mg, 1.09 mmol) were dissolved in N,N-dimethylformamide (5 ml). (7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (381 mg, 1.00 mmol) and diisopropylethylamine (432 mg, 3.35 mmol, 583 μl) were added. The mixture was reacted at 25 degrees for 1 hour. The reaction was completed after monitoring by LCMS.

[0246] The reaction solution was diluted with water (10 ml), extracted with ethyl acetate (10 ml x 2 times), the organic phases were combined, washed with saturated brine (10 ml x 2 times), dried over anhydrous sodium sulfate, filtered and concentrated to give 220 mg of crude product 6-amino-n-((1-methylcyclobutyl)methyl)-2,3-dihydrobenzofuran-5-carboxamide.

[0247] Step F: Synthesis of naphthalene-1-methyl (1s, 4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylate

[0248] To (4-fluoro-2-methoxy-5-((1s,4s)-4-methyl-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyl)oxybenzoic acid (232 mg, 499 μmol) and 6-amino-n-((1-methylcyclobutyl)methyl)-2,3-dihydrobenzofuran-5-carboxamide (232 mg, 499 μmol) were dissolved in N,N-dimethylformamide (5 ml) at room temperature. Tetramethyl chlorouronium hexafluorophosphate (210 mg, 749 μmol) and N-methylimidazole (82.0 mg, 998 μmol, 79.6 μl) were added. The mixture was reacted at 25°C for 2 h. The reaction was completed when monitored by LCMS.

[0249] The reaction solution was diluted with water (4 ml), and a white solid precipitated. The solution was filtered and concentrated. The crude product was purified by slurrying with methyl tert-butyl ether to give naphthalene-1-methyl (1s, 4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylate (200 mg).

[0250] Step G Synthesis of (1s,4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid

[0251] Naphthalene-1-methyl (1s, 4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)carbamoyl)phenoxy-1-methylcyclohexane-1-carboxylate (140 mg, 197 μmol) was dissolved in tetrahydrofuran (5 ml) and then palladium carbon (140 mg, 131 μmol, 10% purity) was added at 25 degrees and replaced with hydrogen three times. The mixture was stirred under a hydrogen atmosphere at 25 degrees for 2 hours. LCMS showed that the reactants were consumed. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (chromatographic column: Waters Xbridge OBDC18150*40mm*10um, mobile phase: [water (NH 4 HCO 3 )-ACN], gradient: 30% to 60% B, time: 15 minutes) to obtain (1s, 4s)-4-(2-fluoro-4-methoxy-5-(5-((1-methylcyclobutyl)methyl)carbamoyl)-2,3-dihydrobenzofuran-6-yl)carbamoylphenoxy)-1-methylcyclohexane-1-carboxylic acid (80.0 mg), LC-MS: RT = 0.602 min, [M+H] + = 569.2.

[0252] NMR data of compound 27: 1 H NMR (400 MHz, DMSO-d 6 )12.40-12.19(m,1H),12.17-12.07(m,1H),8.45(br t,J=6.0Hz,1H),8.12-7.98(m,1H),7.77-7.65(m,1H),7.63-7.49(m,1H),7.27- 7.11(m,1H),4.75-4.53(m,2H),4.32-4.11(m,1H),4.02-3.81(m,3H),3.29-3.24 (m,2H),3.23-3.16(m,2H),2.14-2.01(m,2H),2.00-1.86(m,4H),1.86-1.72(m, 2H),1.64-1.55(m,2H),1.50-1.36(m,2H),1.34-1.21(m,2H),1.17-1.05(m,6H).

[0253] Example 8 Compounds 31AD and 31BD

[0254] Compound 31AD or 31BD (1s,4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid

[0255] Compound 31BD or 31AD (1r,4r)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid

[0256] The specific synthetic route is as follows:

[0257]

[0258] Step A: Synthesis of 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester

[0259] Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 44.6 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), cooled to -78 degrees Celsius, and then lithium diisopropylamide (2 mol per liter, 28 ml) was added dropwise. After reacting for 1 hour, bromo(methoxy)methane (11.6 g, 93.3 mmol, 7.62 ml) was added dropwise. The reaction was continued at -78 degrees Celsius for 1 hour. The reaction was complete after monitoring by TLC.

[0260] The reaction solution was poured into an ice-cold saturated ammonium chloride solution (200 ml) with stirring, then extracted with ethyl acetate (100 ml × 3 times). The organic phases were combined, washed with saturated brine (150 ml × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column to obtain 10.7 g of 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester.

[0261] NMR data: 1H NMR (400MHz, CDCl 3 -d)δ=4.18(q,J=7.2Hz,2H),3.98-3.90(m,4H),3.30(s,3H),2.22-2.11(m,2H),1.70-1.51(m,8H),1.26(t,J=7.2Hz,3H)

[0262] Step B: Synthesis of 8-(methoxymethyl)-1,4-dioxopyrimidine[4.5]decane-8-carboxylic acid

[0263] Ethyl 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (10.7 g, 41.4 mmol) was dissolved in water (35 ml), methanol (35 ml) and tetrahydrofuran (35 ml), cooled to zero degrees Celsius, sodium hydroxide (4.97 g, 124 mmol) was added, and the mixture was reacted at 60 degrees Celsius for 12 hours. The reaction was completed after monitoring by TLC.

[0264] The reaction solution was adjusted to pH = 1 with 1 mol / L hydrochloric acid, then extracted with ethyl acetate (100 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 9.53 g of 8-(methoxymethyl)-1,4-dioxopyrimidine[4.5]decane-8-carboxylic acid.

[0265] NMR data: 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.94 (t, J = 3.2Hz, 4H), 3.44 (s, 2H), 3.35 (s, 3H), 2.23-2.10 (m, 2H), 1.77-1.55 (m, 6H)

[0266] Step C: Synthesis of 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylic acid

[0267] At room temperature, 8-(methoxymethyl)-1,4-dioxopyrimidine[4.5]decane-8-carboxylic acid (9.53 g, 41.3 mmol) was dissolved in tetrahydrofuran (50 mL), and then hydrochloric acid (4 mol, 50 mL) was added. The reaction was carried out at room temperature for 12 hours. TLC monitoring showed that ∼10% of the starting material remained.

[0268] The reaction solution was diluted with water (100 ml), extracted with ethyl acetate (50 ml x 4 times), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7.9 g of crude 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylic acid.

[0269] NMR data: 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.52 (s, 2H), 3.38 (s, 3H), 2.61-2.49 (m, 2H), 2.49-2.32 (m, 4H), 1.78 (dt, J = 4.8, 12.8Hz, 2H)

[0270] Step D: Synthesis of naphthalene-1-methyl 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylate

[0271] At room temperature, 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylic acid (7.59 g, 40.7 mmol) was dissolved in acetonitrile (80 ml), and then sodium iodide (672 mg, 4.48 mmol) and diisopropylethylamine (11.0 g, 85.6 mmol, 11.9 ml) were added. The reaction was heated at 60 °C for 2 hours and the reaction was complete when monitored by TLC.

[0272] The reaction solution was diluted with water (100 ml), extracted with ethyl acetate (50 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column to obtain 8.64 g of naphthalene-1-methyl 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylate.

[0273] NMR data: 1 H NMR(400MHz,CHLOROFORM-d)δ=8.08-8.00(m,1H),7.93-7.85(m,2H),7.61-7.50(m,3H),7.47(dd,J=7.2,8 .0Hz,1H),5.68(s,2H),3.44(s,2H),3.23(s,3H),2.51-2.34(m,4H),2.32-2.21(m,2H),1.78-1.65(m,2H)

[0274] Step E: Synthesis of naphthalene-1-methyl-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate

[0275] Naphthalene-1-methyl 1-(methoxymethyl)-4-oxocyclohexane-1-carboxylate (3 g, 9.19 mmol) was dissolved in anhydrous ethanol (30 ml), cooled to 0°C, sodium borohydride (0.79 g, 20.8 mmol) was added in batches, and the mixture was reacted at 0°C for 1 hour. The reaction was completed after monitoring by TLC.

[0276] Under nitrogen flow protection and at zero degrees Celsius, saturated aqueous ammonium chloride solution (20 ml) was added dropwise to the reaction solution, and then extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column to obtain 3 g of naphthalene-1-methyl-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate. LCMS: RT = 0.535 min, [M+Na] + =351.1

[0277] Step F: Synthesis of methyl 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoate

[0278] At room temperature, naphthalene-1-methyl-4-hydroxy-1-(methoxymethyl)cyclohexane-1-carboxylate (500 mg, 1.52 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml), and methyl 4-fluoro-5-hydroxy-2-methoxybenzoate (304 mg, 1.52 mmol), triphenylphosphine (479 mg, 1.83 mmol), diisopropyl azodicarboxylate (369 mg, 1.83 mmol, 0.354 ml) were added. The mixture was reacted at room temperature for 12 hours. The reaction was completed after monitoring by LCMS.

[0279] The reaction solution was concentrated to remove the organic solvent, and the crude product was purified by reverse phase (0.1% formic acid) to obtain 500 mg of methyl 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoate. LC-MS: RT = 0.642 min, [M+Na] + =533.2

[0280] Step G: Synthesis of 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoic acid

[0281] At room temperature, methyl 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoate (800 mg, 1.57 mmol) was dissolved in water (3 ml), ethanol (3 ml) and tetrahydrofuran (3 ml), and sodium hydroxide (94 mg, 2.35 mmol) was added. The mixture was reacted at room temperature for 12 hours and the reaction was completed after monitoring by LCMS.

[0282] The reaction solution was adjusted to pH=1 with 1 mol / L hydrochloric acid, then extracted with ethyl acetate (10 ml×3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by reverse phase (0.1% formic acid) to obtain 460 mg of 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoic acid. LCMS: RT=0.602 min, [M+Na] + =519.2

[0283] Step H: Synthesis of naphthalene-1-methyl 4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylate

[0284] At room temperature, 4-fluoro-2-methoxy-5-((4-(methoxymethyl)-4-(naphthalen-1-ylmethoxy)carbonyl)cyclohexyloxy)benzoic acid (50 mg, 0.1 mmol) and 6-amino-N-((1-methylcyclobutyl)methyl)benzo[d][1,3]dioxazole-2,2-d2-5-carboxamide (30.2 mg, 0.1 mmol) were dissolved in acetonitrile (0.5 ml) and dichloromethane (0.5 ml), and tetramethyl chlorouronium hexafluorophosphate (113 mg, 0.402 mmol) and N-methylimidazole (49.6 mg, 0.604 mmol, 0.048 ml) were added. The mixture was reacted at room temperature for 1 hour. The reaction was completed after monitoring by LCMS.

[0285] The reaction solution was diluted with water (10 ml), extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml × 2 times), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative purification (column: Phenomenexluna C18150*25mm*10um; mobile phase: [water(FA)-ACN]; gradient: 70%-100% B over 9 min) to obtain 55 mg of naphthalene-1-methyl 4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylate. LC-MS: RT = 0.703 min, [M+H] + =743.4

[0286] Step I: Synthesis of (1s,4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid & (1r,4r)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid

[0287] At room temperature, naphthalene-1-methyl-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylate (55 mg, 0.074 mmol) was dissolved in tetrahydrofuran (3 ml), wet palladium / carbon (50 mg, 10% palladium) was added, and hydrogen was replaced and introduced. The reaction was carried out at room temperature for 2 hours. The reaction was completed after monitoring by LC-MS.

[0288] The palladium / carbon was filtered off, washed with tetrahydrofuran (50 ml), and the filtrate was concentrated. The crude product was purified by preparation (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (NH 4 HCO 3)-ACN]; gradient: 22%-52% B over 9min) to give 3.69 mg of compound 31AD or 31BD (1s, 4s)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid. LC-MS: RT = 0.585 min, [M+H] + = 603.3; and 15.47 mg of single chiral compound 31BD or 31AD (1r, 4r)-4-(2-fluoro-4-methoxy-5-(6-((1-methylcyclobutyl)methyl)carbamoyl)benzo[d][1,3]dioxy-5-yl-2,2-d2)carbamoyl)phenoxy-1-(methoxymethyl)cyclohexane-1-carboxylic acid. LC-MS: RT = 0.601 min, [M+H] + = 603.3

[0289] NMR data of compound 31AD or 31BD: 1H NMR (400 MHz, DMSO-d 6 )δ=12.59-12.11(m,1H),12.01(s,1H),8.47(t,J=6.0Hz,1H),8.17(s,1H),7.7 1(d,J=10.0Hz,1H),7.25-7.14(m,2H),4.25-4.12(m,1H),3.96(s,3H),3.31(br s,2H),3.26(d,J=6.0Hz,2H),3.21(s,3H),2.06(br d,J=13.2Hz,2H),1.99-1.86(m,4H),1.86-1.70(m,2H),1.64-1.53(m,2H),1.52-1.40(m,2H),1.39-1.28(m,2H),1.09(s,3H)

[0290] NMR data of compound 31BD or 31AD: 1H NMR (400 MHz, DMSO-d 6 )δ=12.48-12.07(m,1H),12.02(s,1H),8.47(br t,J=6.0Hz,1H),8.16(s,1H),7.71(d,J=10.0Hz,1H),7.33-7.08(m,2H),4.40(br s,1H),3.96(s,3H),3.39(s,2H),3.26(d,J=6.0Hz,2H),3.24(s,3H),2.00-1.88(m,2H),1.86-1.52(m,12H),1.09(s,3H)

[0291] Example 9

[0292] Compounds 5-17, 19-26, 28-29, 31D, 32-36

[0293] Compounds 5-17, 19-26, 28-29, 31D, and 32-36 were prepared by referring to the method of Example 1-8. The structures and characterization data (mass spectra and liquid phase retention times) of the compounds 5-17, 19-26, 28-29, 31D, and 32-36 are as follows:

[0294]

[0295]

[0296] Experiment 10: In vitro activity test of human RXFP1 receptor agonists

[0297] In this experiment, a CHO-K1 cell line stably transfected with human RXFP1 receptor was used to evaluate the activity of the compound by detecting the cAMP produced after stimulating the RXFP1 receptor coupled to Gs protein.

[0298] Main reagents: cAMP detection kit (Cisbio), 1M HEPES (Invitrogen), HBSS (Invitrogen), BSA (Sigma), IBMX (Sigma).

[0299] Test process:

[0300] (1) Compound preparation: The test compound was dissolved in DMSO and diluted 4-fold to 10 concentration gradients. 250 nL of each concentration was transferred to the test plate (OptiPlate-384-well plate) using Echo;

[0301] (2) Assay buffer: 1X stimulation buffer, 500 μM IBMX, deionized water;

[0302] (3) Cell preparation: After thawing, the frozen cells (RXFP1 cAMP cells) were washed twice with HBSS and then resuspended in stimulation buffer;

[0303] (4) Add 10 μL of cell suspension containing 10,000 cells to each well of the test plate, centrifuge at 1,000 rpm for 5 seconds, and then incubate at 37°C for 60 minutes;

[0304] (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;

[0305] (6) Read the plate using EnVision microplate reader.

[0306] 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.

[0307] %Effect=100×(Sample Raw Value-Low ControlAverage) / (HighControlAverage-Low ControlAverage)

[0308] Table 1 Human RXFP1 receptor agonist activity test data

[0309] Compound No. <![CDATA[EC 50 (nM)]]> 1 36.36 2 19.92 5 65.71 6 25.69 11 35.39 12 19.43 14 11.88 16 13.77 18A 45.9 18AD 46.15 18BD 88.51 23 58.81 24 26.36 33AD 66.08 35 7.3

[0310] It can be seen from the data in Table 1 that the compounds of the present invention have good agonist activity on RXFP1 receptor.

[0311] Embodiment 11

[0312] Pharmacokinetic study of the compounds in beagle dogs

[0313] (1) Experimental Materials

[0314] Beagle dogs: male, 8-13 kg, purchased from Beijing Mas Biotechnology Co., Ltd.

[0315] Reagents: physiological saline, EDTA-2K, acetonitrile, methanol, formic acid, propranolol (internal standard) are all commercially available.

[0316] Instrument: AB SCIEX QTRAP 5500+

[0317] (2) Experimental methods

[0318] Weigh the compound and dissolve it in DMSO-PEG-400-normal saline (5:60:35, v / v / v) system. After intravenous or oral administration to beagle dogs, collect 200μL of venous blood in EDTA-K2 anticoagulation EP tubes at 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h (5min for iv group), centrifuge at 12000rpm for 2min, and freeze the plasma at -80℃ for testing. Accurately weigh a certain amount of the test substance and dissolve it in DMSO to 2mg / mL as the stock solution. Accurately draw an appropriate amount of the test substance stock solution, add acetonitrile to dilute and prepare a standard series of solutions. Accurately draw 10μL of each of the above standard series solutions, add 90μL of blank plasma, vortex and mix, and prepare plasma samples equivalent to plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000ng / mL. Perform double sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma (5 minutes, 15 minutes, and 30 minutes of intravenous administration, plasma diluted 5 times), add 150 μL of acetonitrile solution of internal standard propranolol (50 ng / mL), vortex mix, add 100 μL of purified water, vortex mix again, centrifuge at 4000 rpm for 5 minutes, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0319] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0320] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0321]

[0322]

[0323] (3) Data processing

[0324] 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.

[0325] Table 2. Beagle PK data

[0326]

[0327] It can be seen from the experimental results in Table 2 that the series of compounds of the present invention have good pharmacokinetic characteristics in beagle dogs, and the exposure, half-life and absolute bioavailability are better than the positive control compound of Example 1 of CN116547270A.

[0328] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For ordinary technicians in this field, they can be improved or transformed according to the above description, and all these improvements and transformations should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A RXFP1 receptor agonist, or an isomer, racemate or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the RXFP1 receptor agonist is shown in general formula (I): in: The Y, Z or T are independently selected from CR 1 , CR9, CR 10 or N; said R 1 , R9 or R 10 are independently selected from hydrogen, halogen or cyano; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The ring A is selected from: The R5, R6, R7 or R8 are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-12 membered heteroaryl; The R 11 Independently selected from: H, hydroxyl, C1-C6 alkoxy; The R 12 Independently selected from: C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl; The W is selected from The n is an integer selected from 0, 1 or 2; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group or a 3-10 membered heterocycloalkyl group; The R 4 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 Aryl, substituted or unsubstituted 5-12 membered heteroaryl; The "substituted" substituents are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 One or more of aryl or 5-12 membered heteroaryl.

2. The RXFP1 receptor agonist according to claim 1, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The Y, Z or T are independently selected from CR 1 , CR9, CR 10 or N; said R 1 , R9 or R 10 are independently selected from hydrogen, halogen or cyano; Said X is selected from -O-, -NH-, -N(Me)- or -CH2-; The ring A is selected from: The R5, R6, R7 or R8 are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 Aryl or 5-12 membered heteroaryl; The W is selected from The n is an integer selected from 0, 1 or 2; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl, substituted or unsubstituted 5-12 membered heteroaryl, and R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group or a 3-10 membered heterocycloalkyl group; The R 4 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 Aryl, substituted or unsubstituted 5-12 membered heteroaryl; The "substituted" substituents are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 One or more of aryl or 5-12 membered heteroaryl; Preferably, the R 1 , R9 or R 10 are independently selected from hydrogen, fluorine, chlorine or cyano; The R 11 Independently selected from: H, hydroxyl, methoxy; The R 12 Independently selected from: methyl, methoxyethyl; said X is selected from -O- or -NH-; The ring A is selected from: Said R5, R6, R7 or R8 are independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; The W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, and R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group or a 3-8 membered heterocycloalkyl group; The R 4 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl; The "substituted" substituents are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 One or more of aryl or 5-12 membered heteroaryl; More preferably, the ring A is selected from: The R 1 , R9 or R 10 are independently selected from hydrogen, chlorine or fluorine; The R 11 Independently selected from: H, hydroxyl, methoxy; The R 12 Independently selected from: methyl, methoxyethyl; X is selected from -O- or -NH-; said W is selected from The n is an integer selected from 0 or 1; the R 2 and R 3 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and R 2 and R 3 Not at the same time H; Or the R 2 and R 3 Together with the carbon atom to which it is attached, it forms a C3-C8 cycloalkyl group; The R 4 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl; The "substituted" substituents are independently selected from -OH, halogen, -NH2, -CN, -COOH, -SO3H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 12 One or more of aryl or 5-12 membered heteroaryl; Further preferably, the ring A is selected from: The R 1 , R9 or R 10 are independently selected from hydrogen, chlorine or fluorine; said X is selected from -O- or -NH-; The W is selected from:

3. The RXFP1 receptor agonist according to claim 1, or its isomer, racemate or pharmaceutically acceptable salt thereof, characterized in that: The RXFP1 receptor agonist has a structure shown in general formula (IIA) or general formula (IIB): Wherein, the definitions of X, Y, Z, T, W and ring A are the same as those in claim 1; Preferably, the RXFP1 receptor agonist has a structure represented by general formula (IIC) or general formula (IID): Wherein, the definitions of X, Y, Z, T, W and ring A are the same as those in claim 2.

4. The RXFP1 receptor agonist according to any one of claims 1 to 3, or its isomer, racemate or pharmaceutically acceptable salt, characterized in that: The RXFP1 receptor agonist is selected from the structure shown in formula (IIIA), (IIIB), or formula (IIIC): Wherein, the definitions of X, Y, Z, T and W are the same as those in claim 1 or 2.

5. The RXFP1 receptor agonist according to any one of claims 1 to 4, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The RXFP1 receptor agonist is selected from:

6. The RXFP1 receptor agonist according to any one of claims 1 to 5, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The RXFP1 receptor agonist is selected from:

7. A deuterated compound of the RXFP1 receptor agonist according to any one of claims 1 to 6, or an isomer, a racemate or a pharmaceutically acceptable salt thereof.

8. The RXFP1 receptor agonist according to claim 7, characterized in that The deuterated compound is selected from the following structures:

9. A pharmaceutical composition, characterized in that The invention comprises the RXFP1 receptor agonist according to any one of claims 1 to 8, or its isomer, racemate or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

10. Use of the RXFP1 receptor agonist according to any one of claims 1 to 8, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9, in the preparation of a drug for preventing or treating a disease associated with the RXFP1 receptor; preferably, the RXFP1 receptor-associated disease is selected from heart failure.

Images