CN108341822B - FXR receptor modulator and preparation method and application thereof - Google Patents

FXR receptor modulator and preparation method and application thereof Download PDF

Info

Publication number
CN108341822B
CN108341822B CN201710054416.5A CN201710054416A CN108341822B CN 108341822 B CN108341822 B CN 108341822B CN 201710054416 A CN201710054416 A CN 201710054416A CN 108341822 B CN108341822 B CN 108341822B
Authority
CN
China
Prior art keywords
fxr
preparation
methoxy
carboxylate
cyclopropyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710054416.5A
Other languages
Chinese (zh)
Other versions
CN108341822A (en
Inventor
邹晴安
张建存
李德耀
陈延维
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Henovcom Bioscience Co ltd
Original Assignee
Guangzhou Henovcom Bioscience Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Henovcom Bioscience Co ltd filed Critical Guangzhou Henovcom Bioscience Co ltd
Priority to CN201710054416.5A priority Critical patent/CN108341822B/en
Publication of CN108341822A publication Critical patent/CN108341822A/en
Application granted granted Critical
Publication of CN108341822B publication Critical patent/CN108341822B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses an FXR receptor regulator and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry. The FXR receptor modulators or pharmaceutically acceptable salts or stereoisomers or solvates or prodrugs thereof, which have the structural characteristics of formula I, can bind to FXR receptors and act as agonists or partial agonists of FXR receptors, and can be further applied to the prevention and treatment of diseases mediated by FXR, such as chronic intrahepatic or extrahepatic cholestasis, hepatic fibrosis caused by chronic cholestasis or acute intrahepatic cholestasisOr chronic hepatitis B, or gall bladder calculus, or liver cancer, or colon cancer, or intestinal inflammatory disease. In particular, wherein some of the compounds, EC are agonistic towards FXR50The FXR agonist activity is less than 100nM, the FXR agonist activity is very good, the application prospect is very excellent, and a new drug choice is provided for clinical treatment of diseases mediated by FXR.

Description

FXR receptor modulator and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an FXR receptor regulator and a preparation method and application thereof.
Background
Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily with ligand activity, which was first cloned in rat liver cDNA libraries by Forman et al in 1995 [ cell.1995; 81(5): 687-93], are named because their transcriptional activity can be enhanced by a supraphysiological concentration of a farnesyl ester derivative. Parks, Makishima and Tang discovered in 1999 that physiological levels of Bile Acids (BAs) were simultaneously endogenous ligands of FXR, hence FXR is also known as the BA receptor [ science.1999; 284, 1362-1365]. FXR is expressed mainly at high levels in the liver and intestinal tract, also at certain levels in the adrenal glands and kidneys, and also at lower levels in organs such as heart, lungs, adipose tissue and testes [ gene.2002; 290: 35-43].
Research finds that FXR, as a bile acid nuclear receptor, is involved in regulation of various physiological functions including bile acid metabolism, lipid metabolism, carbohydrate metabolism and the like by regulating expression of a series of genes [ Biochim BiophyActa.2010; 1802: 363-372]. More importantly, studies have demonstrated that FXR plays a critical role in protecting the liver and inhibiting the development of liver cancer. FXR protects the liver in several ways, including: maintaining the homeostasis of bile acid, inhibiting the apoptosis of liver cells, reducing the oxidative stress reaction of tissues, reducing the fibrosis level of liver, inhibiting inflammatory reaction, promoting the regeneration of liver cells, etc. Specifically, first, FXR protects against liver damage caused by bile acid hyperactivity by regulating the normal levels of bile acids in the body; secondly, FXR promotes the damage repair of the liver by preventing the apoptosis of liver cells and the cell necrosis caused by acute liver damage; thirdly, FXR inhibits secretion of extracellular matrix by reducing susceptibility of hepatic stellate cells to TGF- β, reducing the incidence of fibrosis [ J Pharmacol Exp ther.2005; 315: 58-68 ]; fourthly, FXR can inhibit the occurrence and development of liver cancer by modulating NF- κ B-mediated inflammatory responses of the liver [ hepatology.2007; 46: 590-7 ]; fifth, in the case of liver damage, bile acid levels increase in vivo, thereby activating FXR in vivo, promoting liver repair and regeneration [ J Huazhong Univ Sci technology Med Sci, 2010, 30 (1): 55-60 ]; sixth, FXR activation inhibits the expression of cholesterol regulatory element binding protein-1C (SREBP-1C) and Fatty Acid Synthase (FAS), increases the expression of peroxisome proliferator-activated receptors (PPARs) in hepatocytes and adipocytes, improves insulin resistance, reduces fat synthesis, and thereby reduces liver fat deposition [ hepatol ith 2010; 4: 741-748]. FXR has so much hepatoprotective effect suggesting that it may be a potential therapeutic target for NAFLAD.
In recent years, research on FXR agonists has been carried out by a number of well-known international pharmaceutical companies, and some breakthrough advances have been made, further demonstrating the feasibility of FXR agonists for treatment of NAFLD. Obeticholic acid (OCA), a bile acid FXR agonist developed by Intercept pharmaceutical company, has been marketed. The small molecule FXR agonist PX-104, purchased by gillidd science and developed by Phenex pharmaceutical company, is currently in phase II clinical research. FXR agonists have shown significant clinical utility and are expected to benefit more patients, particularly NAFLD patients. Therefore, the development of FXR agonists has broad application prospects and is also urgently needed.
Disclosure of Invention
Based on this, it is an object of the present invention to provide an FXR receptor modulator capable of binding to the FXR receptor and acting as an agonist or partial agonist of the FXR receptor.
In order to achieve the purpose, the invention adopts the following technical scheme:
an FXR receptor modulator having the structural features of formula I or a pharmaceutically acceptable salt or stereoisomer or solvate or prodrug thereof:
Figure BDA0001217186810000011
Figure BDA0001217186810000021
wherein:
m is selected from: c or N;
a is selected from: C. n or O;
x is selected from: C. n or O;
q is selected from: c or N;
R1selected from: 1 to 4R4Substituted or unsubstituted C5-10 aryl, 1-4R4Substituted or unsubstituted C5-10 heteroaryl, 1-4R4A substituted or unsubstituted C5-10 cycloalkyl group;
R2selected from: hydrogen, 1-4R5Substituted or unsubstituted C2-C6 alkyl, 1-4R5Substituted or unsubstituted C2-C6 alkenyl, 1-4R5Substituted or unsubstituted C2-C6 alkynyl, 1-4R5Substituted or unsubstituted C3-C6 cycloalkyl and 1-4R5Substituted or unsubstituted heterocyclic group, 1 to 4R5Substituted or unsubstituted aryl, 1-4R5Substituted or unsubstituted heteroaryl ring group;
l is selected from the following substituents:
Figure BDA0001217186810000022
c is selected from: 0.1, 2 or 3;
d is selected from: 0.1, 2 or 3;
e is selected from: 0.1, 2 or 3;
f is selected from: 0.1, 2 or 3;
and d and e cannot be 0 at the same time;
R6independently optionally from: hydrogen, halogen, 1-5R7Substituted or unsubstituted C1-C3 alkyl, 1-5R7Substituted or unsubstituted C1-C3 alkoxy, 1-5R7Substituted or unsubstituted C3-C6 cycloalkyl; and two independent substituents R3Can form a 3-to 6-membered carbocyclic, aryl, heteroaryl, or heterocyclic ring with the atoms to which they are attached;
w is a bond or
Figure BDA0001217186810000023
Ar is selected from: 1 to 3R8Substituted or unsubstituted phenyl, 1-3R8Substituted or unsubstituted naphthyl, 1-3R8Substituted or unsubstituted C5-C10 monocyclic or bicyclic heteroaryl;
R8selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C5 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, amido, sulfonamido, ester, cyano, OCH2F、OCHF2、OCF3、SCF3、N(CH3)2；
R3Selected from: COOR9、CONR9R10、C(O)NHSO2R9、P(O)(OR9)2、SO2NHC(O)R9、SO3R9Or tetrazole attached to Ar via a C atom;
R9、R10independently optionally from: hydrogen, substituted ammonium ion, metal ion, 1-5R11Substituted or unsubstituted C1-C6 alkyl, 1-5R11Substituted or unsubstituted C2-C6 alkenyl, 1-5R11Substituted or unsubstituted C2-C6 alkynyl, 1-5R11Substituted or unsubstituted C3-C6 cycloalkyl;
R4、R5、R7、R11independently optionally from: deuterium, halogen, cyano, amido, sulfonamido, amino, ester, nitro, C1-C3 alkyl, C1-C3 monohalogenated or polyhalogenated alkyl, C1-C3 alkoxy,C1-C3 monohalogenated or polyhalogenated alkoxy, C3-5 cycloalkyl substituted or unsubstituted with 1-3 fluorine atoms.
In the above compounds, preferably M and Q are C or N, and at least one of M and Q is C; a and X are C, N or O, and A and X cannot both be C.
In some of these embodiments, when L is selected from formula XI or XII, c is selected from 1 or 2, d is selected from 1;
when L is selected from formula XIII, L is selected from the following substituents:
Figure BDA0001217186810000031
when L is selected from formula XIV, L is selected from the following substituents:
Figure BDA0001217186810000032
when L is selected from formula XV, c is selected from 1.
In some of these embodiments, Ar is selected from the following groups:
Figure BDA0001217186810000033
R8selected from: hydrogen, halogen, C1-C4 alkyl and C1-C4 alkoxy.
In some of the embodiments described herein, the first and second,
when L is selected from formula XI, L-W-Ar is selected from the following substituents:
Figure BDA0001217186810000034
when L is selected from formula XII, L-W-Ar is selected from the following substituents:
Figure BDA0001217186810000035
Figure BDA0001217186810000041
when L is selected from formula XIII, L-W-Ar is selected from the following substituents:
Figure BDA0001217186810000042
Figure BDA0001217186810000051
when L is selected from formula XIV, L-W-Ar is selected from the following substituents:
Figure BDA0001217186810000052
when L is selected from formula XV, L-W-Ar-is selected from the following substituents:
Figure BDA0001217186810000053
in some embodiments, the compound is selected from compounds of formula II:
Figure BDA0001217186810000054
R1selected from: 1 to 4R4A substituted or unsubstituted C5-10 aryl group;
R2selected from: 1 to 4R5Substituted or unsubstituted C3-C6 cycloalkyl;
R4、R5independently optionally from: halogen, cyano, nitro, C1-C3 alkyl, C1-C3 monohalogenated or polyhalogenated alkyl, C1-C3 alkoxy, C1-C3 monohalogenated or polyhalogenated alkoxy;
ar is selected from the following groups:
Figure BDA0001217186810000061
R8selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy;
R3selected from: COO R9；
R9Selected from: hydrogen, metal ions.
In some of these embodiments, the compound is selected from compounds having the following structural features of formula III:
Figure BDA0001217186810000062
R1selected from: 1 to 3R4Substituted or unsubstituted phenyl;
R4selected from: halogen, C1-C3 alkyl substituted or unsubstituted by 1-3 fluorine atoms;
R2selected from: cyclopropane;
ar is selected from the following groups:
Figure BDA0001217186810000063
R8selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy;
R9selected from: hydrogen, metal ions.
In some of these embodiments, one of the following compounds is selected:
Figure BDA0001217186810000064
Figure BDA0001217186810000071
Figure BDA0001217186810000081
the invention also discloses a preparation method of the FXR receptor regulator, which comprises the following synthetic routes:
route one:
Figure BDA0001217186810000091
wherein: m, A, X, Q, L, R1R2 and Ar are as described above;
EL1selected from: halogen, alkylsulfonyloxy or arylsulfonyloxy;
EL2selected from: halogen;
r is selected from: C1-C6 alkyl.
In the step 1, the compound Ia and Ib undergo nucleophilic substitution reaction to obtain an intermediate Ic. The nucleophilic substitution reaction is carried out using methods conventional in the art, for example: dissolving the compound Ia in an organic solvent, adding a phase transfer catalyst and a basic reagent, reacting for 0.2 to 1 hour, then adding the compound Ib, and reacting for 1 to 24 hours at room temperature to 100 ℃. The organic solvent can be tetrahydrofuran, DMF, toluene, acetonitrile and the like, preferably tetrahydrofuran or acetonitrile; the phase transfer catalyst can be 18-crown-6, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate and the like, and 18-crown-6 is preferred; the alkaline reagent includes sodium hydrogen, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc., preferably potassium carbonate, potassium tert-butoxide or sodium tert-butoxide.
In step 2, intermediate Ic is Boc deprotected to give intermediate Id by methods conventional in the art for Boc removal, for example: the intermediate Ic is dissolved in an organic solvent, an acidic reagent is added, and the reaction is carried out at 0 to 60 ℃ for 0.5 to 24 hours. The organic solvent can be dichloromethane, dichloroethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran, etc., preferably dichloromethane or dioxane; the acidic reagent comprises trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, hydrogen chloride ethyl acetate solution or hydrogen chloride dioxane solution, preferably trifluoroacetic acid, hydrogen chloride ethyl acetate solution or hydrogen chloride dioxane solution.
In the step 3, the intermediate Id and the intermediate Ie can be subjected to nucleophilic substitution reaction or metal-catalyzed coupling reaction to obtain an intermediate If. The nucleophilic substitution reaction is carried out using methods conventional in the art, for example: dissolving the intermediate Id in an organic solvent, adding an alkaline reagent and the intermediate Ie, and reacting for 1 to 24 hours at the temperature of between room temperature and 150 ℃. The organic solvent can be tetrahydrofuran, DMF, toluene, acetonitrile, propionitrile, NMP, etc., preferably DMF or acetonitrile; the alkaline reagent comprises sodium hydrogen, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, DIPEA, DBU and the like, and potassium carbonate, triethylamine or DIPEA is preferred; the reaction conditions are preferably 80 ℃ to 100 ℃. The metal-catalyzed coupling reaction is carried out using methods conventional in the art, for example: dissolving the intermediate Id in an organic solvent, adding a palladium catalyst, a phosphine ligand, an alkaline reagent and the intermediate Ie, and reacting for 8 to 48 hours at the temperature of between 80 and 150 ℃ under the protection of nitrogen or argon. The organic solvent can be toluene, xylene, dioxane, propionitrile, NMP and the like, and toluene, xylene or dioxane are preferred; the palladium catalyst can be palladium acetate and Pd2(dba)33nd Ruphos Pd, tetrakis (triphenylphosphine) palladium, etc., preferably palladium acetate or Pd2(dba)3(ii) a The phosphine ligand may be BINAP, Xantphos, tri (tert-butyl) phosphine, tri (o-tolyl) phosphine, etc., preferably BINAP or Xantphos; the basic agent may be potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, etc., with cesium carbonate or potassium tert-butoxide being preferred.
In the step 4, the intermediate If is hydrolyzed to obtain a compound Ig. The hydrolysis reaction may be carried out by methods conventional in the art, for example: dissolving the intermediate If into water and any organic solvent mutually soluble with water, and reacting for 1-24 hours at room temperature to 100 ℃ under alkaline conditions. The organic solvent can be any water-miscible solvent, preferably ethanol, methanol, tetrahydrofuran, dioxane, etc. The base used may be lithium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, etc., and preferably lithium hydroxide, sodium hydroxide or potassium hydroxide.
Or
And a second route:
Figure BDA0001217186810000101
wherein: m, A, X, Q, L, R1、R2And Ar is as described in claim 1;
EL1selected from: halogen, alkylsulfonyloxy or arylsulfonyloxy;
EL2selected from: halogen;
r is selected from: C1-C6 alkyl.
In step 1, intermediate Id and intermediate IIa can be reacted by condensation to form urea to obtain intermediate IIb. The condensation to urea reaction may be carried out by methods conventional in the art, for example: dissolving intermediate IIa in organic solvent, and reacting with triphosgene or CDI at 0-50 deg.c for 0.5-3 hr and then with Id at room temperature-80 deg.c for 1-24 hr under alkaline condition or neutral condition. The organic solvent can be tetrahydrofuran, acetonitrile, dichloromethane, dioxane, etc., preferably tetrahydrofuran and dichloromethane; the base may be triethylamine, DIPEA or DBU, preferably triethylamine or DIPEA.
In the step 2, the intermediate IIb is subjected to hydrolysis reaction to obtain a compound IIc. The hydrolysis reaction may be carried out by methods conventional in the art, for example: dissolving the intermediate IIa in water and any organic solvent which is mutually soluble with water, and reacting for 1-24 hours at room temperature to 100 ℃ under alkaline conditions. The organic solvent can be any water-miscible solvent, preferably ethanol, methanol, tetrahydrofuran, dioxane, etc. The base used may be lithium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, etc., and preferably lithium hydroxide, sodium hydroxide or potassium hydroxide.
The invention also discloses application of the FXR receptor modulator or pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof in preparing medicines for preventing and treating diseases mediated by FXR.
In some embodiments, the FXR-mediated disease comprises: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic cholestatic conditions, liver fibrosis resulting from chronic cholestatic conditions or acute intrahepatic cholestatic conditions, chronic hepatitis B, gall bladder stones, liver cancer, colon cancer, or intestinal inflammatory disease.
The invention also discloses a pharmaceutical composition, which comprises the FXR receptor modulator or pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and pharmaceutically acceptable auxiliary materials or carriers.
The pharmaceutically acceptable auxiliary material or carrier can be excipient or sustained release agent and the like. The pharmaceutical compositions may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, and may be presented in a suitable solid or liquid carrier or diluent. The pharmaceutical compositions of the present invention may also be stored in a suitable injection or drip sterilization device. The pharmaceutical composition may also comprise flavoring agent, etc.
Compared with the prior art, the invention has the following beneficial effects:
the FXR receptor modulator with the structural characteristics of formula I or a pharmaceutically acceptable salt, a stereoisomer, a solvate or a prodrug thereof can be combined with the FXR receptor and used as an agonist or a partial agonist of the FXR receptor, and further can be applied to prevention and treatment of diseases mediated by FXR, such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, chronic intrahepatic or extrahepatic cholestatic conditions, hepatic fibrosis caused by chronic cholestatic conditions or acute intrahepatic cholestatic conditions, chronic hepatitis B, gall bladder stones, liver cancer, colon cancer, intestinal inflammatory diseases and the like.
In particular, wherein some of the compounds, EC are agonistic towards FXR50The FXR agonist activity is less than 100nM, the FXR agonist activity is very good, the application prospect is very excellent, and a new drug choice is provided for clinical treatment of diseases mediated by FXR.
Detailed Description
As used herein, "bond" refers to a chemical bond, and is a generic term for the strong interaction between two or more adjacent atoms (or ions) in a pure molecule or crystal, i.e., W is absent, and L and Ar are directly linked.
As used herein, "alkyl" refers to saturated chain alkyl, "chain alkyl" refers to straight or branched chain alkyl, such as C1-C6 alkyl refers to saturated straight or branched chain alkyl having 1 to 6 carbon atoms, wherein examples of straight chain alkyl include, but are not limited to, ethyl, n-propyl, and the like, and examples of branched chain alkyl include, but are not limited to, isopropyl, tert-butyl, and the like; "cycloalkyl" refers to an alkyl group having a cyclic structure, such as C3-C4 cycloalkyl refers to an alkyl group having a cyclic structure having 3 to 4 carbon atoms, examples include, but are not limited to, cyclopropyl, cyclobutyl, methyl-substituted cyclopropyl, and the like. "alkenyl" means an unsaturated chain alkyl group, such as C2-C6 alkenyl, which represents a straight or branched chain alkenyl group having 2 to 6 carbon atoms with one double bond, and examples include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
The term "heterocycle" represents a saturated monocyclic ring system having 5 to 7 ring-forming atoms containing one to four heteroatoms selected from N, O, S. Examples include, but are not limited to: tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, and the like.
The term "heteroaromatic ring" denotes a monocyclic ring system having 5 to 6 ring-forming atoms, containing one to four heteroatoms (selected from N, O, S) and complying with Huckel's rule. Examples include, but are not limited to, pyridine rings, pyrimidine rings, pyridazine rings, pyrazine rings, furan rings, thiophene rings, thiazole rings, oxazole rings, isoxazole rings, isothiazole rings, imidazole rings, pyrazole rings, triazole rings, tetrazole rings, and the like.
The term "alkoxy" denotes a straight or branched chain alkyl group containing one oxygen atom at the end, examples including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
The term "substituted" refers to the replacement of a hydrogen radical in a particular structure with a radical of a specified substituent. In the present invention, the substitution on the alkyl group or the cycloalkyl group, if it is not specified to occur on a specific carbon atom, means that it may occur on any carbon atom for which the number of substituents has not yet reached saturation. When a plurality of substituents are selected from the same series, they may be the same or different. In the present invention, the substitution on the benzene ring, the aromatic heterocyclic ring or the heterocyclic ring, if it is not specified to occur on a specific atom, means that it may occur at any position not substituted by other atoms than hydrogen. When a plurality of substituents are selected from the same series, they may be the same or different.
The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water.
The circular dotted line in the general formula I indicates that an uncertain position in the five-membered ring has a double bond, and the whole ring forms a conjugated system.
In the general formula, a single line from the outside of the ring structure to the inside of the ring indicates that the ring structure has a substituent, but the substitution position is not fixed.
The invention includes the free forms of the compounds of formulae I-III, as well as pharmaceutically acceptable salts and stereoisomers and solvates and prodrugs thereof. Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
The compounds of the invention can be prepared by the methods in the following examples, in addition to standard methods known in the literature or exemplified in experimental procedures. The compounds and methods of synthesis described in the present invention can be better understood in conjunction with the synthetic schemes described below. All parameters in the examples and the rest of the description are based on mass unless otherwise stated. If not, all the fillers used for column chromatography are silica gel. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The synthetic schemes describe the methods that can be used to prepare the compounds of the present invention, and the methods are described as illustrative schemes for illustrative purposes only and do not limit the scope of the present invention.
Abbreviations used in the following examples are as follows:
DMF: n, N-dimethylformamide
CDI: n, N' -carbonyldiimidazole
THF: tetrahydrofuran (THF)
NMP: n-methyl pyrrolidone
Boc: tert-butyloxycarbonyl radical
DIPEA: n, N-diisopropylethylamine
DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene
3nd Ruphos Pd: methanesulfonic acid (2-dicyclohexylphosphino-2 ', 6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium
BINAP: 1, 1 '-binaphthyl-2, 2' -phenylphosphine
Xantphos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene
Example 1
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000121
The preparation was carried out according to the following scheme:
Figure BDA0001217186810000122
(1) preparation of 6-methoxy-1, 4-dihydro-9-aza-1, 4-methano-naphthalene-9-carboxylic acid tert-butyl ester.
2-amino-4-methoxybenzoic acid (3.9g, 23.4mmol) and N-Boc pyrrole (4.68mL, 28.0mmol) were dissolved in dichloromethane (40mL) and acetonitrile (30mL), and isoamyl nitrite (6.24mL, 46.7mmol) was dissolved in acetonitrile (20mL) and added dropwise to the reaction solution, after which it was reacted at 55 ℃ for 2 hours. After the reaction solution is cooled to room temperature, spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate: 40: 1) to obtain 2.66g of yellow oily substance, yield: 42 percent.
(2) Preparation of 6-methoxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester.
Dissolving 6-methoxy-1, 4-dihydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester (2.66g, 9.7mmol) in methanol (50mL), adding 10% Pd/C (300mg), introducing hydrogen, reacting overnight at room temperature, filtering with diatomite, spin-drying, and purifying by column chromatography to obtain a light yellow oily substance 2g, yield: 75 percent.
(3) Preparation of 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester.
Dissolving 6-methoxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester (2g, 7.26mmol) in dichloromethane (50mL), cooling to 0 ℃, dropwise adding a dichloromethane solution (10mL) of boron tribromide (768 μ L, 7.99mmol), continuing to react at 0 ℃ for 30 minutes, dropwise adding methanol to quench the reaction, and spin-drying. The resulting product was dissolved in dichloromethane (50mL) and triethylamine (4.03mL, 29.04mmol) and Boc were added2O (2.50mL, 10.9mmol), and reacted at room temperature for 2 hours. The reaction solution was poured into water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, dried by spin-drying, and purified by column chromatography to obtain yellow slurry 0.87g, yield: 46 percent.
(4) Preparation of 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester.
Tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate (0.87g, 3.33mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (1.21g, 4.00mmol) were dissolved in acetonitrile (30mL) and potassium carbonate (919mg, 6.66mmol) was added and reacted at 85 ℃ overnight. After the reaction solution was cooled to room temperature, spin-dried, dichloromethane (50mL) was added, filtered, spin-dried, and purified by column chromatography to give 1.36g (29823) of a pale yellow foam, yield: 78 percent.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.43-7.40(m，2H)，7.35-7.13(m，1H)，7.07(d，J＝8.0Hz，1H)，6.73(d，J＝2.4Hz，1H)，6.56(dd，J＝2.4Hz，8.0Hz，1H)，5.04(m，2H)，4.78(m，2H)，2.17(m，1H)，2.08(m，2H)，1.41(s，9H)，1.28(m，4H)，1.14(m，2H)。
(5) preparation of 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene.
6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester (1.36g, 2.58mmol) was dissolved in ethyl acetate (30mL), 2.2N HCl in ethyl acetate (8mL) was added and the reaction was allowed to proceed overnight at room temperature. The residue was dissolved in methylene chloride, washed with a saturated sodium bicarbonate solution and a saturated brine in this order, dried over anhydrous sodium sulfate, and then dried to obtain a foamy solid (1.04 g, 29824), yield: 95 percent.
(6) Preparation of ethyl 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylate.
6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene (70mg, 0.16mmol) and ethyl 2-chloro-4-methoxybenzo [ d ] thiazole-6-carboxylate (57mg, 0.21mmol) were dissolved in DMF (5mL) and triethylamine (45. mu.L, 0.32mmol) was added and reacted at 100 ℃ for 2 hours. After the reaction solution is cooled to room temperature, the reaction solution is poured into water, extracted by ethyl acetate, washed by saturated saline solution, dried by anhydrous sodium sulfate, dried by spinning, and purified by column chromatography to obtain yellow slurry 45mg, and the yield is as follows: 37 percent.
(7) Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylic acid.
29826(40mg, 0.06mmol) was dissolved in tetrahydrofuran (2mL), methanol (2mL) and water (1mL), and lithium hydroxide monohydrate (25mg, 0.6mmol) was added to the solution to react at room temperature overnight. Spin-drying, adding water, adjusting pH to about 3 with 1N HCl, filtering, and oven drying to obtain light yellow solid.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.00(m，1H)，7.59-7.57(m，2H)，7.52-7.48(m，1H)，7.38(m，1H)，7.20(d，J＝8.0Hz，1H)，6.88(d，J＝2.0Hz，1H)，6.57(dd，J＝2.0Hz，8.0Hz，1H)，5.31(s，2H)，4.80(m，2H)，3.90(s，3H)，2.38(m，1H)，2.18(m，2H)，1.29(m，2H)，1.14-1.08(m，4H)。
example 2
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000141
Prepared according to the procedure of example 1 except that ethyl 2-chloro-4-methoxybenzo [ d ] thiazole-6-carboxylate was replaced with ethyl 2-chloro-4-fluorobenzo [ d ] thiazole-6-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.26(m，1H)，7.63-7.58(m，3H)，7.53-7.49(m，1H)，7.22(d，J＝8.0Hz，1H)，6.90(d，J＝2.4Hz，1H)，6.58(dd，J＝2.4Hz，8.0Hz，1H)，5.38(s，2H)，4.81(m，2H)，2.39(m，1H)，2.20(m，2H)，1.31(m，2H)，1.24(m，1H)，1.14-1.10(m，3H)。
example 3
Preparation of 6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000142
The preparation was carried out according to the following scheme:
Figure BDA0001217186810000143
(1) preparation of methyl 6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] isothiazole-3-carboxylate.
Mixing 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy]-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene (90mg, 0.21mmol), 6-bromobenzo [ d]Isothiazole-3-carboxylic acid methyl ester (68mg, 0.25mmol), X-Phos (10mg, 0.021mmol), Pd2(dba)3(10mg, 0.011mmol) and cesium carbonate (137mg, 0.42mmol) were suspended in toluene (5mL) and reacted overnight at 100 ℃ under argon. Cooling the reaction solution to room temperature, filtering, spin-drying, and purifying by column chromatography to obtain a foamy solid 70mg, wherein the yield is as follows: 54 percent.
(2) Preparation of 6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Methyl 6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] isothiazole-3-carboxylate (70mg, 0.11mmol) was dissolved in tetrahydrofuran (2mL), methanol (2mL) and water (1mL), and lithium hydroxide monohydrate (47mg, 1.13mmol) was added to react at room temperature overnight. Spin-drying, adding water, adjusting pH to about 3 with 1N HCl, filtering, and oven drying to obtain gray solid.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.35(d，J＝8.8Hz，1H)，7.59-7.55(m，3H)，7.52-7.48(m，1H)，7.22(m，1H)，7.13(d，J＝8.0Hz，1H)，6.79(d，J＝1.6Hz，1H)，6.52(dd，J＝2.0Hz，8.0Hz，1H)，5.30(s，2H)，4.78(m，2H)，2.37(m，1H)，2.06(m，2H)，1.22(m，2H)，1.12-1.08(m，4H)。
example 4
Preparation of 4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -3-fluorobenzoic acid.
Figure BDA0001217186810000151
Prepared according to the procedure of example 3 except that methyl 4-bromo-3-fluorobenzoate is used instead of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.26(m，1H)，7.63-7.58(m，3H)，7.53-7.49(m，1H)，7.22(d，J＝8.0Hz，1H)，6.90(d，J＝2.4Hz，1H)，6.58(dd，J＝2.4Hz，8.0Hz，1H)，5.38(s，2H)，4.81(m，2H)，2.39(m，1H)，2.20(m，2H)，1.31(m，2H)，1.24(m，1H)，1.14-1.10(m，3H)。
example 5
Preparation of 3- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -5-fluorobenzoic acid.
Figure BDA0001217186810000152
Prepared according to the procedure of example 3 except that methyl 3-bromo-5-fluorobenzoate is used instead of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.40-7.38(m，3H)，7.36-7.33(m，1H)，7.19(m，1H)，7.11(d，J＝8.0Hz，1H)，6.76(m，2H)，6.56(m，1H)，5.02(m，2H)，4.77(m，2H)，2.20-2.12(m，3H)，1.36(m，2H)，1.27(m，2H)，1.12-1.12(m，2H)。
example 6
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } nicotinic acid.
Figure BDA0001217186810000153
Prepared according to the procedure of example 3 except that methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate was replaced with methyl 5-bromonicotinate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.73(s，1H)，8.41(s，1H)，7.89(s，1H)，7.40-7.38(m，2H)，7.33-7.31(m，1H)，7.13(d，J＝8.0Hz，1H)，6.77(d，J＝2.0Hz，1H)，6.56(dd，J＝2.0Hz，8.0Hz，1H)，5.11(m，2H)，4.77(m，2H)，2.21(m，2H)，2.15(m，1H)，1.43(m，2H)，1.28(m，2H)，1.11(m，2H)。
example 7
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000154
Prepared according to the procedure of example 1 except that ethyl 2-chloro-4-methoxybenzo [ d ] thiazole-6-carboxylate was replaced with methyl 5-chloropyrazine-2-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.90(s，1H)，8.02(s，1H)，7.44-7.42(m，2H)， 7.37-7.34(m，1H)，7.17(d，J＝6.4Hz，1H)，6.82(d，J＝1.6Hz，1H)，6.62(dd，J＝6.4Hz，J＝1.6Hz，1H)，5.53(m，2H)，4.80(m，2H)，2.24-2.14(m，3H)，1.32-1.29(m，4H)，1.17-1.13(m，2H)。
example 8
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000161
Prepared according to the procedure of example 1 except that ethyl 2-chloro-4-methoxybenzo [ d ] thiazole-6-carboxylate was replaced with ethyl 2-chlorobenzo [ d ] thiazole-6-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.39(s，1H)，7.87(m，1H)，7.57(m，3H)，7.50(m，1H)，7.21(d，J＝6.4Hz，1H)，6.88(d，J＝1.6Hz，1H)，6.57(dd，J＝6.4Hz，J＝1.6Hz，1H)，5.34(m，2H)，4.80(m，2H)，2.40-2.35(m，1H)，2.19(m，2H)，1.30(m，2H)，1.13-1.09(m，4H)。
example 9
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzofuran-2-carboxylic acid.
Figure BDA0001217186810000162
Prepared according to the procedure of example 3 except that ethyl 5-bromobenzofuran-2-carboxylate was used instead of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.44-7.39(m，4H)，7.34-7.32(m，1H)，7.18(m，1H)，7.14(d，J＝6.4Hz，1H)，7.09(s，1H)，6.79(d，J＝1.2Hz，1H)，6.59(dd，J＝6.4Hz，J＝1.2Hz，1H)，5.08(m，2H)，4.78(s，2H)，2.39(m，2H)，2.15(m，1H)，1.30(m，2H)，1.28-1.26(m，2H)，1.13-1.09(m，2H)。
example 10
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000163
The preparation method comprises the following steps:
Figure BDA0001217186810000171
(1) preparation of 6-methoxy-1-methylene-1, 2, 3, 4-tetrahydronaphthalene.
Ph is3P+CH3Br-(2.64g, 7.40mmol) was dissolved in 15ml of tetrahydrofuran, potassium tert-butoxide (0.83g, 7.40mmol) was added portionwise at 0 ℃ and the temperature was raised to room temperatureStirring for 2 h. At 0 deg.C, a solution of 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (1.0g, 5.70mmol) in tetrahydrofuran (10ml) was added dropwise over 15min, and the reaction was allowed to warm to room temperature overnight. The reaction solution was filtered through celite, the solvent was spin-dried, and column chromatography (eluent: petroleum ether: ethyl acetate: 50: 1) was performed to obtain 0.7g of colorless transparent liquid, yield: 70 percent.
(2) Preparation of 6 ' -methoxy-3 ', 4 ' -dihydro-2 ' H-spiro [ cyclobutane-1, 1 ' -naphthalen ] -3-one.
6-methoxy-1-methylene-1, 2, 3, 4-tetrahydronaphthalene (700mg, 4.0mmol) was dissolved in diethyl ether (15mL), zinc copper reagent (3.35g, 26.0mmol) was added, under Ar protection, trichloroacetyl chloride (1.34mL, 12.0mmol) in ethylene glycol dimethyl ether (5mL) was added dropwise at 0 deg.C, after 15min addition, the mixture was warmed to room temperature and reacted overnight.
The reaction solution was cooled to-10 ℃ and saturated ammonium chloride solution (10mL) was added dropwise to quench the reaction, followed by addition of methanol (10mL) and zinc powder (1.56g, 24.0mmol) and warming to room temperature overnight. Filtering with celite, spin-drying, adding water, extracting with ethyl acetate (30ml × 2), washing the organic layer with saturated brine, Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography (eluent: petroleum ether: ethyl acetate: 20: 1) to obtain yellow oil 400mg, yield: 46 percent.
(3) Preparation of 6 ' -methoxy-3 ', 4 ' -dihydro-2 ' H-spiro [ cyclobutane-1, 1 ' -naphthalen ] -3-one oxime.
Reacting 6 ' -methoxy-3 ', 4 ' -dihydro-2 ' H-spiro [ cyclobutane-1, 1 ' -naphthalene]-3-one (2.7g, 12.5mmol) was dissolved in ethanol (60mL), hydroxylamine hydrochloride (1.4g, 20.0mmol), sodium acetate (2.0g, 25.0mmol) and water (6mL) were added, and the mixture was heated under reflux at 80 ℃ for 1 h. Cooling the reaction solution to room temperature, spin-drying, extracting with ethyl acetate (50 ml. times.2), washing the organic layer with water, washing with saturated saline (50ml), and adding Na2SO4Drying, filtering, spin-drying, and pulping with petroleum ether to obtain white solid 2.4g with 83% yield.
(4) Preparation of 6-methoxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole-pyrrole ] -5' -one.
Reacting 6 ' -methoxy-3 ', 4 ' -dihydro-2 ' H-spiro [ cyclobutane-1, 1 ' -naphthalene]-3-ketoxime (100mg, 0.4)3mmol) was dissolved in tetrahydrofuran (5mL), sulfoxide chloride (92. mu.L, 1.30mmol) was added at 0 ℃ and the reaction was allowed to proceed for 1 hour at 0 ℃. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL. times.2), and the organic layer was washed with saturated brine (20mL), and washed with Na2SO4Drying, filtering, spin-drying, and purifying by column chromatography (eluent: dichloromethane: methanol 50: 1) to obtain brown solid 55mg, yield 55%.
(5) Preparation of 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole-pyrrole ] -5' -one.
The 6-methoxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole pyrrole]-5' -Ketone (550mg, 2.4mmol) in dichloromethane (20mL) and BBr added dropwise at 0 deg.C3(330. mu.L, 3.6mmol) in dichloromethane (5mL) and reacted at 0 ℃ for 30 min. The reaction mixture was adjusted to pH 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (20mL), and the organic layer was washed with saturated brine (20mL) and Na2SO4Drying, filtering and spin-drying to obtain 430mg of brown solid with the yield of 82%.
(6) Preparation of 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole ].
Lithium aluminum hydride (300mg, 8.0mmol) was added to anhydrous THF (15mL) at 0 deg.C under argon shield, and 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole pyrrole was added dropwise]A solution of-5' -ketone (430mg, 2.0mmol) in dry THF (5mL) was heated at 60 ℃ for 2 h. After the reaction solution was cooled, water (1.2mL) was added dropwise to quench the reaction, and Na was added2SO4Stirring for 30min, adding diatomite, filtering, washing, spin-drying the filtrate to obtain crude oil 300mg, and carrying out the next reaction without purification.
(7) Preparation of 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylic acid tert-butyl ester.
6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole ] (300mg, 2.0mmol) was dissolved in THF (15mL), and triethylamine (400. mu.L, 3.0mmol) and Boc anhydride (550. mu.L, 2.4mmol) were added to react at room temperature for 2H. Spin-drying, and purifying by column chromatography (eluent: petroleum ether/ethyl acetate 5/1) to obtain white solid 80 mg.
(8) Preparation of tert-butyl 6- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylate.
Reference example 1 preparation of tert-butyl 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate by the method described above except that tert-butyl 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
(9) Preparation of 5-cyclopropyl-3- (2, 6-dichlorophenyl) -4- { [ (3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole ] -6-yl) oxy ] methyl } isoxazole.
Reference example 1 preparation of 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene was carried out by substituting 6- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylic acid tert-butyl ester for 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylic acid tert-butyl ester.
(10) Preparation of methyl 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylate.
Reference example 1 was made to the procedure for the preparation of ethyl 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylate except that 5-cyclopropyl-3- (2, 6-dichlorophenyl) -4- { [ (3, 4-dihydro-2H-spiro [ naphthalene-1, 3' -tetrahydropyrrole ] -6-yl) oxy ] methyl } isoxazole was used instead of 6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene and 5-chloropyrazine-2-carboxylic acid methyl ester instead of 2-chloro-4-methoxybenzo [ d ] thiazole-6-carboxylic acid ethyl ester.
(11) Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylic acid.
Prepared by the procedure of reference example 1 except that ethyl 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylate was replaced with methyl 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3) δ: 8.94(m, 1H), 7.82(m, 1H), 7.65(d, J ═ 6.8Hz, 1H), 7.44-7.42(m, 2H), 7.37-7.34(m, 1H), 7.13(d, J ═ 7.2Hz, 1H), 6.68(dd, J ═ 7.2Hz, J ═ 1.2Hz, 1H), 6.59(d, J ═ 1.2Hz, 1H), 4.81(s, 2H), 3.89-3.60(m, 4H), 2.81(m, 2H), 2.43(m, 1H), 2.24-2.13(m, 2H), 1.92-1.88(m, 2H), 1.84-1.75(m, 2H), 1.33-1.31 (m, 2H), 1.19-1.19 (m, 2H).
Example 11
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000191
Prepared by the method of reference example 10 except that 2-chlorobenzo [ d ] thiazole-6-carboxylic acid ethyl ester was used instead of 5-chloropyrazine-2-carboxylic acid methyl ester.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.42(d，J＝1.2Hz，1H)，8.11(dd，J＝6.8Hz，J＝1.2Hz，1H)，7.65(d，J＝6.8Hz，1H)，7.44-7.42(m，2H)，7.37-7.34(m，1H)，7.16(d，J＝7.2Hz，1H)，6.68(dd，J＝7.2Hz，J＝2.0Hz，1H)，6.59(d，J＝2.0Hz，1H)，4.81(s，2H)，3.94-3.69(m，4H)，2.81(m，2H)，2.45-2.41(m，1H)，2.24-2.14(m，2H)，1.96-1.82(m，4H)，1.33-1.31(m，2H)，1.19-1.15(m，2H)。
example 12
Preparation of 6- {7- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000192
The preparation method comprises the following steps of:
Figure BDA0001217186810000193
(1) preparation of 7-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylic acid tert-butyl ester.
Reference example 10 method for preparing tert-butyl 6-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -carboxylate, except that 7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one was used instead of 6-methoxy-3, 4-dihydronaphthalen-1 (2-one).
(2) Preparation of 6- {7- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] isothiazole-3-carboxylic acid.
Prepared by the method of reference example 2 except that tert-butyl 7-hydroxy-3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrolpyrrole ] -1' -carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.42(m，1H)，7.53(m，1H)，7.47(m，2H)，7.00(s，1H)，6.93(m，1H)，6.81(m，1H)，6.70(m，1H)，6.55(m，1H).4.77(s，2H)，3.53(m，2H)，3.45(m，2H)，2.68(m，2H)，2.38-2.27(m，3H)，1.75(m，4H)，1.15-1.07(m，4H)
example 13
Preparation of 5- {7- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000194
Prepared by the method of reference example 10 except that 7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one was used instead of 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.89(s，1H)，7.85(s，1H)，7.36(m，3H)，7.00(m，1H)，6.69(m，2H)，4.76(s，2H)，3.68(m，4H)，2.77(m，2H)，2.37(m，1H)，2.15(m，2H)，1.83(m，4H)，1.27(m，2H)，1.12(m，2H)。
example 14
Preparation of 2- {7- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -3, 4-dihydro-2H-spiro [ naphthalene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000201
Prepared by the method of reference example 13 except that 2-chlorobenzo [ d ] thiazole-6-carboxylic acid ethyl ester was used instead of 5-chloropyrazine-2-carboxylic acid methyl ester.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.44(s，1H)，8.13(d，J＝6.8Hz，1H)，7.65(d，J＝6.4Hz，1H)，7.48-7.35(m，3H)，7.01(d，J＝6.8Hz，1H)，6.74(d，J＝1.2Hz，1H)，6.67(dd，J＝1.2Hz，6.8Hz，1H)，4.77(s，2H)，3.79(m，4H)，2.79(m，2H)，2.44-2.42(m，2H)，1.95-1.80(m，4H)，1.28(m，2H)，1.12(m，2H)。
example 15
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000202
Prepared by the method of reference example 10 except that 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one is replaced with 6-methoxy-2, 3-dihydro-1H-inden-1-one.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.95(s，1H)，7.84(s，1H)，7.42-7.39(m，2H)，7.35-7.32(m，1H)，7.15(d，J＝6.8Hz，1H)，6.74(dd，J＝6.8Hz，J＝1.6Hz，1H)，6.64(d，J＝1.6Hz，1H)，4.80(s，2H)，3.90-3.55(m，4H)，2.95(m，2H)，2.34-2.29(m，1H)，2.23-2.12(m，4H)，1.32-1.30(m，2H)，1.17-1.13(m，2H)。
example 16
6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] isothiazole-3-carboxylic acid
Figure BDA0001217186810000203
Prepared by the method of reference example 12 except that 6-methoxy-2, 3-dihydro-1H-inden-1-one was used instead of 7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.78(m，1H)，7.28-7.11(m，4H)，6.68-6.43(m，4H)，4.73(s，2H)，3.52-3.37(m，4H)，2.89(m，3H)，2.13(m，6H)，1.25-1.08(m，4H)。
example 17
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } -1-methyl-1H-indole-2-carboxylic acid.
Figure BDA0001217186810000211
Prepared by the method of reference example 16 except that methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate was replaced with methyl 5-bromo-1-methyl-1H-indole-2-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.39-7.35(m，2H)，7.35-7.32(m，3H)，7.28-7.25(m，1H)，7.12(d，J＝7.2Hz，1H)，6.94(dd，J＝7.2Hz，J＝1.6Hz，1H)，6.76(d，J＝1.6Hz，1H)，6.70(m，2H)，4.80(m，2H)，4.10(s，3H)，3.63-3.54(m，2H)，3.46(m，2H)，2.92(m，2H)，2.27-2.20(m，2H)，2.20-2.10(m，3H)，1.30-1.28(m，2H)，1.15-1.11(m，2H)。
example 18
Preparation of 6- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } -1-methyl-1H-indole-3-carboxylic acid.
Figure BDA0001217186810000212
Prepared by the method of reference example 16 except that 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester was used instead of 6-bromobenzo [ d ] isothiazole-3-carboxylic acid methyl ester.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.09(m，1H)，7.74(m，1H)，7.39-7.35(m，1H)，7.35-7.31(m，1H)，7.29-7.26(m，1H)，7.13(m，1H)，6.76(m，1H)，6.72-6.66(m，2H)，6.42(m，1H)，4.80(m，2H)，3.81(s，3H)，3.64(m，2H)，3.50(s，2H)，2.94(m，2H)，2.33-2.22(m，2H)，2.20-2.11(m，3H)，1.30-1.28(m，2H)，1.16-1.12(m，2H)。
example 19
3- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } -5-fluorobenzoic acid
Figure BDA0001217186810000213
Prepared by the method of reference example 16 except that methyl 3-bromo-5-fluorobenzoate is used instead of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.42-7.35(m，2H)，7.34-7.31(m，1H)，7.14-7.10(m，3H)，6.71(m，1H)，6.61(m，1H)，6.48(m，1H)，4.79(s，2H)，3.62-3.50(m，2H)，3.43(s，2H)，3.92(m，2H)，2.27-2.16(m，3H)，2.15-2.07(m，2H)，1.30-1.28(m，2H)，1.17-1.12(m，2H)。
example 20
Preparation of 5- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } -nicotinic acid.
Figure BDA0001217186810000221
Prepared by the method of reference example 16 except that methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate was replaced with methyl 5-bromonicotinate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.72(s，1H)，8.18(s，1H)，7.74(s，1H)，7.41-7.35(m，2H)，7.33-7.31(m，1H)，7.12(d，J＝6.4Hz，1H)，6.70(d，J＝6.4Hz，1H)，6.61(s，1H)，4.79(s，2H)，3.69-3.56(m，2H)，3.48(s，2H)，2.92(m，2H)，2.32-2.23(m，1H)，2.21-2.10(m，4H)，1.30-1.28(m，2H)，1.17-1.10(m，2H)。
example 21
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -2, 3-dihydrospiro [ indene-1, 3 '-tetrahydropyrrole ] -1' -yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000222
Prepared by the method of reference example 15 except that 2-chlorobenzo [ d ] thiazole-6-carboxylic acid ethyl ester was used instead of 5-chloropyrazine-2-carboxylic acid methyl ester.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.44(s，1H)，8.12(d，J＝6.8Hz，1H)，7.65(d，J＝6.8Hz，1H)，7.41-7.37(m，2H)，7.34-7.32(m，1H)，7.14(d，J＝6.4Hz，1H)，6.72(d，J＝6.4Hz，1H)，6.65(s，1H)，4.80(s，2H)，3.97-3.67(m，4H)，2.95(m，2H)，2.35-2.29(m，1H)，2.27-2.22(m，1H)，2.12-2.15(m，3H)，1.30(m，2H)，1.17-1.13(m，2H)。
example 22
4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxamido } benzoic acid
Figure BDA0001217186810000223
The preparation was carried out according to the following scheme:
Figure BDA0001217186810000224
(1) preparation of 4- (1H-imidazole-1-carboxamido) methyl benzoate.
4-aminobenzoate (0.71g, 4.70mmol) and CDI (1.05g, 6.48mmol) were dissolved in dichloroethane (10mL) and reacted at 50 ℃ for 1 hour. The reaction liquid is cooled to 0 ℃, filtered and dried to obtain 0.8g of off-white solid, namely 4- (1H-imidazole-1-formamido) methyl benzoate.
(2) Preparation of methyl 4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-carboxamido } benzoate.
6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene (60mg, 0.14mmol) and methyl 4- (1H-imidazole-1-carboxamido) benzoate (34mg, 0.14mmol) were dissolved in tetrahydrofuran and reacted by heating at 50 ℃ for 2 hours. Spin-drying, and purifying by column chromatography (petroleum ether: ethyl acetate: 2: 1) to obtain 50mg of slurry, namely 4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-formamido } methyl benzoate.
(3) Preparation of 4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxamido } benzoic acid.
Reference example 1 was made to the procedure except that methyl 4- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-carboxamido } benzoate was used in place of ethyl 2- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：9.22(s，1H)，7.81(m，2H)，7.62-7.50(m，5H)，7.14(d，J＝8.0Hz，1H)，6.82(d，J＝1.6Hz，1H)，6.56(dd，J＝1.6Hz，8.0Hz，1H)，5.31(m，2H)，4.82(m，2H)，2.40(m，1H)，2.04(m，2H)，1.19-1.11(m，6H)。
example 23
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000231
(1) Preparation of 4-methylenepiperidine-1-carboxylic acid tert-butyl ester.
Methyltriphenylphosphonium bromide (14.7g, 40.5mmol) and potassium tert-butoxide (4.38g, 39mmol) were added to diethyl ether (90mL) at 0 ℃ and stirred at room temperature for 2 hours after the addition. The reaction mixture was cooled in an ice bath, and tert-butyl 4-oxopiperidine-1-carboxylate (5.98g, 30mmol) was dissolved in diethyl ether (30mL) and added dropwise to the reaction mixture, followed by reaction at room temperature overnight. Filtering, spin-drying, and purifying by column chromatography (50: 1 petroleum ether: ethyl acetate) to obtain 5.2g of colorless oily liquid, namely, 4-methylenepiperidine-1-carboxylic acid tert-butyl ester, with the yield: 88 percent.
The characterization data are:1H NMR(400MHz，CDCl3)δ：4.75(s，2H)，3.43(t，J＝5.6Hz，4H)，2.19(t，J＝5.6Hz，4H)，1.48(s，9H)。
(2) preparation of 1, 2-dichloro-2-oxo-7-aza [3.5] nonane-7-carboxylic acid tert-butyl ester.
Tert-butyl 4-methylenepiperidine-1-carboxylate (1g, 5.07mmol) was dissolved in diethyl ether (20mL), copper zinc reagent (4.4g, 34.5mmol) was added, under nitrogen, and a solution of trichloroacetyl chloride (1.84mL, 16.5mmol) in DME (5mL) was added dropwise at 10 deg.C, and the reaction was continued at room temperature overnight. Slowly pouring the reaction solution into saturated saline (30mL) at-10 ℃, filtering by using kieselguhr, extracting by using ethyl acetate (20mL multiplied by 3), washing by using saturated saline (30mL multiplied by 2), drying, spin-drying, and purifying by using column chromatography (petroleum ether: ethyl acetate: 15: 1) to obtain 880mg of brown oily liquid which is the 1, 2-dichloro-2-oxo-7-aza [3.5] nonane-7-tert-butyl formate, wherein the yield is as follows: 56 percent. The impurities are directly used for the next reaction.
(3) Preparation of tert-butyl 2-oxo-7-aza [3.5] nonane-7-carboxylate.
Tert-butyl 1, 2-dichloro-2-oxo-7-aza [3.5] nonane-7-carboxylate (880mg, 2.88mmol) was dissolved in methanol (10mL), and a saturated ammonium chloride solution (10mL) and zinc powder (1.12g) were added to the solution to react at room temperature overnight. Filtering, spin-drying, adding water (20mL), extracting with ethyl acetate (20mL × 2), washing with saturated brine (20mL × 2), drying the organic layer over anhydrous sodium sulfate, spin-drying, and purifying by column chromatography (petroleum ether: ethyl acetate: 8: 1) to obtain colorless oil 490mg, which is tert-butyl 2-oxo-7-aza [3.5] nonane-7-carboxylate, with yield: 72 percent.
The characterization data are:1H NMR(400MHz，CDCl3)δ：3.43(t，J＝5.6Hz，4H)，2.84(s，4H)，1.72(t，J＝ 5.6Hz，4H)，1.49(s，9H)。
(4) preparation of 2-hydroxy-7-aza [3.5] nonane-7-carboxylic acid tert-butyl ester.
Tert-butyl 2-oxo-7-aza [3.5] nonane-7-carboxylate (490mg, 2.05mmol) was dissolved in methanol (10mL), cooled in an ice bath, and added portionwise with sodium borohydride (156mg, 4.10mmol) and reacted at room temperature for 1 hour. Spin-drying, adding water (20mL), extracting with ethyl acetate (20mL × 2), washing with saturated brine (20mL × 2), drying the organic layer over anhydrous sodium sulfate, spin-drying, and purifying by column chromatography (petroleum ether: ethyl acetate ═ 3: 1) to obtain 450mg of a white solid, i.e., tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate, yield: 91 percent.
The characterization data are:1H NMR(400MHz，CDCl3)δ：4.35(m，1H)，3.33(m，4H)，2.30(m，2H)，1.70(m，3H)，1.53(m，4H)，1.47(m，9H)。
(5) preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } pyrazine-2-carboxylic acid.
Reference example 7 was prepared except that tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H-NMR(400MHz，CDCl3)δ：8.79(s，1H)，8.07(s，1H)，7.46(m，2H)，7.40(m，1H)，4.21(s，2H)，3.96(m，1H)，3.58(m，4H)，2.17(m，1H)，2.07(m，2H)，1.54(m，6H)，1.30(m，2H)，1.16(m，2H)。
example 24
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000241
Prepared according to the procedure of example 3 except that tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate is used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
Product characterization data were:1H-NMR(400MHz，CDCl3)δ：8.61(s，1H)，7.47(m，2H)，7.40-7.37(m，1H)，7.18(m，2H)，4.22(s，2H)，3.99(m，1H)，3.25(m，4H)，2.20(m，1H)，2.07(m，2H)，1.63-1.55(m，6H)，1.31(m，2H)，1.17(m，2H)。
example 25
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } benzofuran-2-carboxylic acid.
Figure BDA0001217186810000242
Prepared according to the procedure of example 24 except that methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate was replaced with ethyl 5-bromobenzofuran-2-carboxylate.
Product characterization data were:1H-NMR(400MHz，CDCl3)δ：7.54(m，1H)，7.52-7.46(m，3H)，7.44-7.40(m，3H)，4.22(s，2H)，3.98(m，1H)，3.20(m，4H)，2.18(m，1H)，2.11(m，2H)，1.82(m，4H)，1.57(m，2H)，1.30(m，2H)，1.16(m，2H)。
example 26
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } nicotinic acid.
Figure BDA0001217186810000251
Prepared according to the procedure of example 23 except that methyl 6-chloronicotinate is used instead of methyl 5-chloropyrazine-2-carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：8.84(d，J＝1.6Hz，1H)，8.02(dd，J＝8.8Hz，J＝1.6Hz，1H)，7.46-7.43(m，2H)，7.39-7.35(m，1H)，6.59(d，J＝8.8Hz，1H)，4.19(s，2H)，3.99-3.92(m，1H)，3.62(t，J＝5.2Hz，2H)，3.55(t，J＝5.2Hz，2H)，2.16(m，1H)，2.10-2.04(m，2H)，1.57-1.51(m，6H)，1.28(m，2H)，1.14(m，2H)。
example 27
Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } isonicotinic acid.
Figure BDA0001217186810000252
Prepared according to the procedure of example 23 except that methyl 2-chloroisonicotinate is used instead of methyl 5-chloropyrazine-2-carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：8.31(d，J＝4.8Hz，1H)，7.46-7.44(m，2H)，7.41-7.33(m，2H)，7.13(d，J＝4.8Hz，1H)，4.20(s，2H)，3.99-3.92(m，1H)，3.54(t，J＝5.2Hz，2H)，3.47(t，J＝5.2Hz，2H)，2.20-2.13(m，1H)，2.09-2.04(m，2H)，1.59-1.51(m，6H)，1.28(m，2H)，1.16-1.13(m，2H)。
example 28
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } pyridine-2-carboxylic acid.
Figure BDA0001217186810000253
Prepared according to the procedure of example 24 except that ethyl 2-chlorobenzo [ d ] thiazole-6-carboxylate is replaced with methyl 5-chloropyridine-2-carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：8.18(s，1H)，8.02(m，1H)，7.46-7.44(m，2H)，7.39-7.35(m，1H)，7.21(m，1H)，4.20(s，2H)，3.96(m，1H)，3.31(m，2H)，3.26(m，2H)，2.20-2.13(m，1H)，2.10-2.05(m，2H)，1.63-1.53(m，6H)，1.30-1.26(m，2H)，1.17-1.12(m，2H)。
example 29
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } nicotinic acid.
Figure BDA0001217186810000254
Prepared according to the method of example 24 except that ethyl 2-chlorobenzo [ d ] thiazole-6-carboxylate is replaced with methyl 5-chloronicotinate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：8.74(s，1H)，8.48(s，1H)，7.95(s，1H)，7.46-7.44(m，2H)，7.39-7.35(m，1H)，4.19(s，2H)，3.95(m，1H)，3.24(m，2H)，3.18(m，2H)，2.20-2.13(m，1H)，2.08-2.03(m，2H)，1.62(m，4H)，1.55-1.51(m，2H)，1.30-1.28(m，2H)，1.17-1.12(m，2H)。
example 30
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } pyrazine-3-carboxylic acid.
Figure BDA0001217186810000261
Prepared according to the procedure of example 23 except that methyl 6-chloropyridazinecarboxylate was used in place of methyl 5-chloropyrazine-2-carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：7.95(d，J＝9.6Hz，1H)，7.46-7.44(m，2H)，7.39-7.35(m，1H)，6.97(d，J＝9.6Hz，1H)，4.20(s，2H)，3.97(m，1H)，3.70(m，2H)，3.63(m，2H)，2.19-2.13(m，1H)，2.11-2.06(m，2H)，1.66-1.52(m，6H)，1.28-1.26(m，2H)，1.17-1.12(m，2H)。
example 31
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } -1-methyl-1H-indole-2-carboxylic acid.
Figure BDA0001217186810000262
Prepared according to the procedure of example 24 except that methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate was replaced with methyl 5-bromo-1-methyl-1H-indole-2-carboxylate.
Product characterization data were:1H NMR(400MHz，CD3OD)δ：7.59-7.56(m，2H)，7.54-7.40(m，1H)，7.42(d，J＝9.2Hz，1H)，7.29(d，J＝2.0Hz，1H)，7.21(dd，J＝9.2Hz，J＝2.0Hz，1H)，7.18(s，1H)，4.22(s，2H)，4.04(s，3H)，3.98(m，1H)，3.08(t，J＝5.2Hz，2H)，3.02(t，J＝5.2Hz，2H)，2.28(m，1H)，2.11-2.06(m，2H)，1.73(t，J＝5.2Hz，2H)，1.68(t，J＝5.2Hz，2H)，1.52-1.47(m，2H)，1.20(m，2H)，1.19(m，2H)。
example 32
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } -1-methyl-1H-indole-3-carboxylic acid.
Figure BDA0001217186810000263
Prepared according to the procedure of example 24 except that methyl 6-bromo-1-methyl-1H-indole-3-carboxylate was used in place of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
Product characterization data were:1H NMR(400MHz，CD3OD)δ：7.93(d，J＝8.8Hz，1H)，7.80(s，1H)， 7.59-7.56(m，2H)，7.54-7.40(m，1H)，7.01(dd，J＝8.8Hz，2.0Hz，1H)，6.97(d，J＝2.0Hz，1H)，4.22(s，2H)，3.98(m，1H)，3.82(s，3H)，3.09(t，J＝5.6Hz，2H)，3.03(t，J＝5.6Hz，2H)，2.28(m，1H)，2.10-2.05(m，2H)，1.70(t，J＝5.6Hz，2H)，1.65(t，J＝5.6Hz，2H)，1.50-1.45(m，2H)，1.21(m，2H)，1.19(m，2H)。
example 33
Preparation of 3- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } -5-fluorobenzoic acid.
Figure BDA0001217186810000271
Prepared according to the procedure of example 24 except that methyl 3-bromo-5-fluorobenzoate is used instead of methyl 6-bromo-benzo [ d ] isothiazole-3-carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：7.46-7.43(m，2H)，7.40-7.35(m，2H)，7.18(m，1H)，6.78(m，1H)，4.19(s，2H)，3.98-3.92(m，1H)，3.92(s，3H)，3.16(t，J＝5.2Hz，2H)，3.11(t，J＝5.2Hz，2H)，2.20-2.13(m，1H)，2.07-2.02(m，2H)，1.62-1.57(m，4H)，1.54-1.49(m，2H)，1.30-1.28(m，2H)，1.17-1.12(m，2H)。
example 34
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } benzo [ d ] isoxazole-3-carboxylic acid.
Figure BDA0001217186810000272
Prepared according to the procedure of example 24 except that 6-bromo-benzo [ d ] isoxazole-3-carboxylic acid ethyl ester was used instead of 6-bromo-benzo [ d ] isothiazole-3-carboxylic acid methyl ester.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：7.46-7.43(m，2H)，7.38-7.34(m，1H)，7.26(m，1H)，6.43(m，1H)，6.33(s，1H)，4.19(s，2H)，3.94(s，1H)，3.21(t，J＝4.8Hz，2H)，3.16(t，J＝4.8Hz，2H)，2.16(m，1H)，2.06-2.01(m，2H)，1.61-1.43(m，6H)，1.30-1.28(m，2H)，1.18-1.10(m，2H)。
example 35
Preparation of 6- {6- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -3, 4-dihydroisoquinolin-2 (1H) -yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000273
Reference example 24 was made except that tert-butyl 6-hydroxy-6-azaspiro [3.4] octane-6-carboxylate was replaced with tert-butyl 6-hydroxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.64(d，J＝6.8Hz，1H)，7.43(m，2H)，7.36(m，1H)，7.22(m，2H)，7.10(m，J＝6.4Hz，1H)，6.74(d，J＝6.4Hz，1H)，6.67(s，1H)，4.84(s，2H)，4.51(s，2H)，3.71(m，2H)，2.98(m，2H)，2.22(m，1H)，1.32(m，2H)，1.17(m，2H)。
example 36
Preparation of 5- {6- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -3, 4-dihydroisoquinolin-2 (1H) -yl } benzofuran-2-carboxylic acid.
Figure BDA0001217186810000281
Prepared according to the procedure of example 25 except that tert-butyl 6-hydroxy-6-azaspiro [3.4] octane-6-carboxylate was replaced with tert-butyl 6-hydroxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.38(m，4H)，7.09-6.96(m，3H)，6.66-6.57(m，2H)，4.79(s，2H)，4.21(m，2H)，3.39(m，2H)，2.86(m，2H)，2.18(m，1H)，1.28(m，2H)，1.13(m，2H)。
example 37
Preparation of 6- {6- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -3, 4-dihydroisoquinolin-2 (1H) -yl } benzo [ d ] isoxazole-3-carboxylic acid.
Figure BDA0001217186810000282
Prepared according to the procedure of example 34 except that tert-butyl 6-hydroxy-6-azaspiro [3.4] octane-6-carboxylate was replaced with tert-butyl 6-hydroxy-3, 4-dihydroisoquinoline-2 (1H) -carboxylate.
Product characterization data were:1H NMR(400MHz，CDCl3)δ：7.89(d，J＝6.8Hz，1H)，7.48-7.45(m，2H)，7.40-7.36(m，1H)，6.69(m，1H)，6.53(m，1H)，4.26(s，2H)，4.02(m，1H)，3.38(m，2H)，3.29(m，2H)，2.20(m，3H)，1.99(m，2H)，1.86(m，2H)，1.31(m，2H)，1.17(m，2H)。
example 38
Preparation of 2- {7- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -4, 5-dihydro-1H-benzo [ d ] azepin-3 (2H) -yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000283
Prepared according to the procedure of example 8 except that tert-butyl 7-hydroxy-4, 5-dihydro-1H-benzo [ d ] azepine-3 (2H) -carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.40(s，1H)，8.10(d，J＝8.0Hz，1H)，7.59(d，J＝8.0Hz，1H)，7.42(m，2H)，7.36-7.32(m，1H)，7.03(m，1H)，6.64(m，2H)，4.81(s，2H)，3.89(m，4H)，3.01(m，4H)，2.20(m，1H)，1.30(m，2H)，1.15(m，2H)。
example 39
Preparation of 2- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000284
(1) Preparation of 8- (Methoxycarbonylmethylene) -1, 4-dioxaspiro [4.5] decane.
1, 4-dioxaspiro [4.5] decan-8-one (5g, 32mmol) and methoxymethylformyltriphenylphosphine (13.9g, 41.6mm0l) were dissolved in toluene (60mL), and the reaction was heated under reflux overnight. After the reaction solution was cooled to room temperature, spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate: 10: 1) to obtain 5.75g of colorless oil, i.e., 8- (methoxyformylmethylene) -1, 4-dioxaspiro [4.5] decane.
The characterization data are:1H NMR(400MHz，CDCl3)δ：5.66(m，1H)，3.96(m，4H)，3.67(s，3H)，3.00(m，2H)，2.38(m，2H)，1.76(m，4H)。
(2) preparation of methyl 2- (8- (nitromethyl) -1, 4-dioxa [4.5] decan-8-yl) acetate.
8- (Methoxycarbonylmethylene) -1, 4-dioxaspiro [4.5] decane (5.75g, 27mmol) was dissolved in tetrahydrofuran (50mL), nitromethane (2.2mL, 40.6mmol) and tetrabutylammonium fluoride (27mL, 27mmol, 1M tetrahydrofuran solution) were added, and the reaction was heated under reflux overnight. Tetrahydrofuran was removed by evaporation, water was added, extraction was performed with ethyl acetate (50mL × 2), the organic layer was washed with saturated brine, dried, evaporated, and purified by column chromatography (petroleum ether: ethyl acetate: 8: 1) to give 5.8g of a pale yellow oily substance, i.e., methyl 2- (8- (nitromethyl) -1, 4-dioxa [4.5] decan-8-yl) acetate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：4.74(s，2H)，3.96(s，4H)，3.71(s，3H)，2.59(s，2H)，1.72(m，8H)。
(3) preparation of 2-azaspiro [4.5] decane-3, 8-dione.
Methyl 2- (8- (nitromethyl) -1, 4-dioxa [4.5] decan-8-yl) acetate (2.38g, 8.7mmol) was dissolved in ethanol (70mL) and water (30mL) and iron powder (5.6g, 100mmol) and ammonium chloride (2.7g, 50mmol) were added. After reaction at 80 ℃ for 3 hours, the reaction solution was cooled to room temperature, filtered through celite, part of the solvent was removed by rotary evaporation, water was added, DCM was used for extraction (50mL × 2), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary dried to give 1.65g of a white solid. The resulting white solid was dissolved in 2N hydrochloric acid and reacted at room temperature overnight. Adjusting pH to about 8 with sodium bicarbonate solution, extracting with DCM (50mLx2), washing organic layer with saturated saline solution, drying with anhydrous sodium sulfate, spin-drying, and pulping to obtain 0.89g white solid, i.e. 2-azaspiro [4.5] decane-3, 8-dione.
The characterization data are:1H NMR(400MHz，CDCl3)δ：6.28(br，1H)，3.36(m，2H)，2.41(m，6H)，1.99(m，4H)。
(4) preparation of tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate.
Lithium aluminum hydride (0.81g, 21.3mmol) was suspended in anhydrous tetrahydrofuran (25mL), cooled to 0 deg.C, and 2-azaspiro [4.5] was added dropwise]A solution of decane-3, 8-dione (0.89g, 5.32mmol) in tetrahydrofuran (15mL) was heated under reflux for 2 hours after the addition. The reaction mixture was cooled to 0 ℃ and quenched by dropwise addition of water (0.9mL), 1M NaOH (0.9mL) and water (2.7mL) were added in this order, and after stirring for 10 minutes, sodium sulfate (10g) was added, and after stirring for 15 minutes, the mixture was filtered through celite, and spin-dried to give 0.45g of a pale yellow oil. The resulting yellow oil was dissolved in dichloromethane (20mL) and Boc was added2O (1mL, 4.35mmol) and triethylamine (0.81mL, 5.80mmol) were reacted at room temperature for 2 hours. Spin-drying, and purifying by column chromatography to obtain light yellow0.41g of a colored oily substance was obtained, i.e., 8-hydroxy-2-azaspiro [ 4.5%]Decane-2-carboxylic acid tert-butyl ester.
The characterization data are:1H NMR(400MHz，CDCl3)δ：3.73(m，1H)，3.37(m，2H)，3.17(m，2H)，1.86(m，2H)，1.75(m，1H)，1.67(m，2H)，1.48(m，13H)。
(5) preparation of 2- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } benzo [ d ] thiazole-6-carboxylic acid.
Prepared according to the procedure of example 8 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was prepared instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.38(m，1H)，8.08(m，1H)，7.61(m，1H)，7.46-7.43(m，2H)，7.39-7.33(m，1H)，4.32(m，2H)，3.65(m，2H)，3.44-3.30(m，3H)，2.17(m，1H)，1.90(m，2H)，1.69(m，1H)，1.64-1.55(m，3H)，1.47(m，1H)，1.38-1.29(m，5H)，1.17-1.13(m，2H)。
example 40
Preparation of 5- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000301
Prepared according to the procedure of example 1 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was prepared instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.86(m，1H)，8.08(m，1H)，7.76(s，1H)，7.45-7.43(m，2H)，7.37-7.33(m，1H)，4.32(s，2H)，3.59(m，2H)，3.32(m，3H)，2.17(m，1H)，1.86(m，2H)，1.68-1.43(m，6H)，1.38-1.28(m，4H)，1.14(m，2H)。
EXAMPLE 41
Preparation of 3- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } -5-fluorobenzoic acid.
Figure BDA0001217186810000302
Prepared according to the procedure of example 5 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.46-7.43(m，2H)，7.40-7.34(m，1H)，7.07-7.01(m，2H)，6.40(m，1H)，4.33(m，1H)，3.35(m，3H)，3.08(m，2H)，2.18(m，1H)，1.83(m，2H)，1.71-1.51(m，4H)，1.42(m，1H)，1.33-1.27(m，5H)，1.14(m，2H)。
example 42
Preparation of 6- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000303
Prepared according to the procedure of example 3 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was prepared instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.57(m，1H)，7.67-7.64(m，2H)，7.59-7.54(m，1H)，7.01(m，1H)，6.86(m，1H)，4.26(s，1H)，3.26(m，2H)，3.18(m，1H)，3.13(m，1H)，3.05(m，1H)，2.32(m，1H)，1.78-1.74(m，2H)，1.54(m，2H)，1.40-1.32(m，3H)，1.28-1.19(m，3H)，1.15-1.10(m，4H)。
example 43
Preparation of 5- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } nicotinic acid.
Figure BDA0001217186810000304
Prepared according to the procedure of example 6 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.32(m，1H)，8.10(m，1H)，7.68-7.66(m，1H)，7.65(m，1H)，7.60-7.55(m，1H)，7.26(m，1H)，4.27(m，2H)，3.32(m，2H)，3.30(m，1H)，3.09(m，1H)，3.03(m，1H)，2.33(m，1H)，1.78-1.70(m，2H)，1.61-1.51(m，2H)，1.45-1.38(m，1H)，1.36-1.30(m， 2H)，1.25-1.19(m，3H)，1.17-1.13(m，2H)，1.10-1.07(m，2H)。
example 44
Preparation of 6- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } -1-methyl-1H-indole-3-carboxylic acid.
Figure BDA0001217186810000311
Prepared according to the procedure of example 42 except that methyl 6-bromo-1-methyl-1H-indole-3-carboxylate was used in place of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.02(m，1H)，7.69(m，1H)，7.46-7.43(m，2H)，7.38-7.34(m，1H)，6.65(m，1H)，6.31(s，1H)，4.34(m，2H)，3.77(m，3H)，3.40(m，2H)，3.35-3.25(m，1H)，3.15(m，2H)，2.19(m，1H)，1.87-1.82(m，2H)，1.75-1.55(m，5H)，1.50-1.40(m，2H)，1.37-1.31(m，2H)，1.30-1.28(m，2H)，1.17-1.12(m，2H)。
example 45
Preparation of 2- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } -4-methoxybenzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000312
Prepared according to the procedure of example 1 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.07(m，1H)，7.56(m，1H)，7.47-7.42(m，2H)，7.40-7.33(m，1H)，4.32(m，2H)，4.06(m，3H)，3.65(m，2H)，3.50-3.40(m，2H)，3.33(m，1H)，2.17(m，1H)，1.89(m，2H)，1.73-1.66(m，1H)，1.65-1.58(m，2H)，1.56-1.53(m，1H)，1.50-1.40(m，2H)，1.38-1.32(m，3H)，1.30-1.28(m，3H)，1.17-1.12(m，2H)。
example 46
Preparation of 2- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } -4-fluorobenzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000313
Prepared according to the procedure of example 2 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.18(m，1H)，7.80(m，1H)，7.47-7.42(m，2H)，7.40-7.33(m，1H)，4.33(m，2H)，3.64(m，2H)，3.46(m，2H)，3.34(m，1H)，2.17(m，1H)，1.90(m，2H)，1.75-1.70(m，1H)，1.65-1.55(m，3H)，1.50-1.40(m，2H)，1.40-1.30(m，3H)，1.30-1.28(m，2H)，1.27-1.24(m，1H)，1.17-1.12(m，2H)。
example 47
Preparation of 4- {8- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -2-azaspiro [4.5] decan-2-yl } -3-fluorobenzoic acid.
Figure BDA0001217186810000321
Prepared according to the procedure of example 4 except that tert-butyl 8-hydroxy-2-azaspiro [4.5] decane-2-carboxylate was used instead of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.76-7.64(m，2H)，7.45-7.42(m，2H)，7.38-7.32(m，1H)，6.51(m，1H)，4.33(s，2H)，3.55(m，2H)，3.28(m，3H)，2.18(m，1H)，1.80-1.71(m，2H)，1.70-1.60(m，2H)，1.58-1.50(m，2H)，1.47-1.34(m，2H)，1.32-1.26(m，4H)，1.16-1.11(m，2H)。
example 48
Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000322
(1) 2-hydroxy-6-azaspiro [3.51 nonane-6-carboxylic acid tert-butyl ester
Reference example 23 preparation of tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate, except that tert-butyl 3-oxopiperidine-1-carboxylate was used instead of tert-butyl 4-oxopiperidine-1-carboxylate.
(2) Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } benzo [ d ] thiazole-6-carboxylic acid.
Prepared according to the procedure of example 8 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.35(m，1H)，7.87-7.83(m，1H)，7.70-7.64(m，2H)，7.60-7.54(m，1H)，7.46-7.41(m，1H)，4.12(m，2H)，3.96(m，1H)，3.87(m，1H)，3.52(m，2H)，3.45(m，1H)，3.39(m，1H)，2.34-2.30(m，1H)，2.02-1.97(m，1H)，1.92-1.87(m，1H)，1.56(m，2H)，1.49(m，2H)，1.44-1.39(m，1H)，1.29-1.24(m，1H)，1.17-1.13(m，2H)，1.10-1.07(m，2H)。
example 49
Preparation of 5- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } pyrazine-2-carboxylic acid.
Figure BDA0001217186810000323
Prepared according to the procedure of example 7 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.60(m，1H)，8.32(m，1H)，7.70-7.63(m，2H)，7.58-7.54(m，1H)，4.11(m，2H)，3.99(m，1H)，3.84(m，1H)，3.58(m，2H)，3.55(m，1H)，3.51(m，1H)，2.35-2.28(m，1H)，1.95-1.88(m，1H)，1.86-1.80(m，1H)，1.58-1.50(m，2H)，1.49-1.42(m，2H)，1.42-1.35(m，1H)，1.25-1.19(m，1H)，1.17-1.11(m，2H)，1.10-1.06(m，2H)。
example 50
Preparation of 3- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } nicotinic acid.
Figure BDA0001217186810000331
Prepared according to the procedure of example 6 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.51-8.45(m，2H)，7.66-7.63(m，3H)，7.59-7.53(m，1H)，4.12(m，2H)，3.98(m，1H)，3.89(m，1H)，3.09(m，2H)，3.00(m，1H)，2.92(m，1H)，2.32(m，1H)，1.99-1.93(m，1H)，1.91-1.86(m，1H)，1.59-1.54(m，1H)，1.51-1.42(m，2H)，1.38-1.32(m，2H)，1.27-1.22(m，1H)，1.17-1.13(m，2H)，1.10-1.07(m，2H)。
example 51
Preparation of 3- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } -5-fluorobenzoic acid.
Figure BDA0001217186810000332
Prepared according to the procedure of example 5 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：7.67-7.63(m，2H)，7.60-7.53(m，1H)，7.26(m，1H)，7.01-7.53(m，2H)，4.11(s，2H)，3.97(m，1H)，3.88(m，1H)，3.05(m，2H)，2.97(m，1H)，2.91(m，1H)，2.31(m，1H)，1.97-1.92(m，1H)，1.90-1.85(m，1H)，1.57-1.51(m，1H)，1.50-1.40(m，2H)，1.36-1.29(m，2H)，1.26-1.21(m，1H)，1.15-1.12(m，2H)，1.10-1.07(m，2H)。
example 52
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000333
Prepared according to the procedure of example 3 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are：1H NMR(400MHz，DMSO)δ：8.42(m，1H)，7.63(m，2H)，7.58-7.49(m，1H)，7.40(m，1H)，7.18-7.12(m，1H)，4.12(m，2H)，4.00(m，1H)，3.88(m，1H)，3.14(m，2H)，3.07(m，1H)，3.02(m，1H)，2.32(m，1H)，2.00-1.95(m，1H)，1.90-1.85(m，1H)，1.60-1.55(m，1H)，1.54-1.45(m，2H)，1.42-1.37(m，2H)，1.26-1.22(m，1H)，1.17-1.13(m，2H)，1.10-1.07(m，2H)。
Example 53
Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } -4-methoxybenzo [ d ] thiazole-3-carbohydrase.
Figure BDA0001217186810000341
Prepared according to the procedure of example 1 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.00(m，1H)，7.71(m，1H)，7.65(m，1H)，7.61-7.56(m，1H)，7.39(m，1H)，4.12(s，2H)，3.95(m，1H)，3.90(m，3H)，3.86(m，1H)，3.48(m，2H)，3.41(m，2H)，2.31(m，1H)，2.02-1.97(m，1H)，1.92-1.87(m，1H)，1.55(m，2H)，1.47(m，2H)，1.38-1.33(m，1H)，1.28-1.24(m，1H)，1.17-1.13(m，2H)，1.09-1.07(m，2H)。
example 54
Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } -4-fluorobenzo [ d ] thiazole-3-carboxylic acid.
Figure BDA0001217186810000342
Prepared according to the procedure of example 2 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.21(m，1H)，7.69(m，1H)，7.66-7.54(m，3H)，4.12(s，2H)，3.91(m，1H)，3.52(m，4H)，2.31(m，1H)，2.02-1.88(m，2H)，1.56-1.48(m，4H)，1.40-1.36(m，1H)，1.29-1.24(m，1H)，1.17-1.09(m，4H)。
example 55
Preparation of 4- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } -3-fluorobenzoic acid.
Figure BDA0001217186810000343
Prepared according to the procedure of example 4 except that tert-butyl 2-hydroxy-6-azaspiro [3.5] nonane-6-carboxylate was used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.82(m，1H)，7.43(m，1H)，7.42-7.38(m，2H)，7.36-7.30(m，1H)，6.90(m，1H)，4.19(m，2H)，3.96(m，1H)，3.06(m，2H)，2.96(s，2H)，2.17(m，2H)，2.00(m，1H)，1.69-1.43(m，6H)，1.28(m，2H)，1.14(m，2H)。
example 56
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -6-azaspiro [3.5] nonan-6-yl } -1-methyl-1H-indole-3-carboxylic acid.
Figure BDA0001217186810000351
Prepared according to the procedure of example 52 except that methyl 6-bromo-1-methyl-1H-indole-3-carboxylate was used in place of methyl 6-bromobenzo [ d ] isothiazole-3-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：13.51(br，1H)，8.77(m，1H)，8.20(m，1H)，7.88(m，1H)，7.43-7.35(m，2H)，7.33-7.30(m，1H)，7.20(m，1H)，4.20(m，2H)，3.99-3.89(m，4H)，3.18(m，4H)，2.42(m，1H)，2.16(m，1H)，2.08-1.41(m，7H)，1.27(m，2H)，1.14(m，2H)。
example 57
3- {6- [ (5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxamido } benzoic acid
Figure BDA0001217186810000352
Prepared according to the method of example 22 except that methyl 4-aminobenzoate is replaced with methyl 3-aminobenzoate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：1H NMR(400MHz，DMSO)δ：7.90(s，1H)，7.77(m，2H)，7.41-7.39(m，2H)，7.34-7.30(m，2H)，7.11(d，J＝7.6Hz，1H)，6.79(m，2H)，6.59(dd，J＝2.0Hz，8.0Hz，1H)，5.15(m，2H)，4.78(m，2H)，2.22-2.14(m，3H)，1.35(m，2H)，1.28(m，2H)，1.14(m，2H)。
example 58
Preparation of 6- {6- [ (5-cyclopropyl-3- (2, 6-dimethylphenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] isothiazole-3-carboxylic acid
Figure BDA0001217186810000353
Prepared according to the method of example 3 except that 2, 6-dimethylbenzaldehyde is used instead of 2, 6-dichlorobenzaldehyde.
The characterization data are:1H NMR(400MHz，CDCl3)δ：1H NMR(400MHz，CDCl3)δ：8.56(d，J＝8.8Hz，1H)，7.77(m，1H)，7.46(m，1H)，7.20(m，2H)，7.13(m，1H)，7.08(d，J＝8.0Hz，1H)，6.77(d，J＝1.6Hz，1H)，6.56(dd，J＝1.6Hz，8.0Hz，1H)，5.13(m，2H)，4.60(s，2H)，2.43(m，1H)，2.22(m，2H)，2.13(s，6H)，1.40(m，2H)，1.16-1.10(m，4H)。
example 59
Preparation of 2- {6- [ (5-cyclopropyl-3- (2, 6-dimethylphenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalen-9-yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000354
Prepared according to the method of example 8 except that 2, 6-dimethylbenzaldehyde is used instead of 2, 6-dichlorobenzaldehyde.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.37(d，J＝1.2Hz，1H)，8.06(m，1H)，7.63(d，J＝8.4Hz，1H)，7.21(m，1H)，7.17(d，J＝8.0Hz，1H)，7.08(m，2H)，6.81(d，J＝2.0Hz，1H)，5.98(dd，J＝2.0Hz，8.0Hz，1H)，5.30(m，2H)，4.61(m，2H)，2.32(m，2H)，2.12(m，7H)，1.45(m，2H)，1.28(m，2H)，1.11(m，2H)。
example 60
4- {6- [ (5-cyclopropyl-3- (2, 6-dimethylphenyl) isoxazol-4-yl) methoxy ] -1, 2, 3, 4-tetrahydro-9-aza-1, 4-methanonaphthalene-9-carboxamido } benzoic acid
Figure BDA0001217186810000361
Prepared according to the method of example 22 except that 2, 6-dimethylbenzaldehyde is used instead of 2, 6-dichlorobenzaldehyde.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.01(m，2H)，7.46(m，2H)，7.22(m，1H)，7.13-7.08(m，3H)，6.78(m，1H)，6.72(m，1H)，6.59(dd，J＝1.6Hz，8.0Hz，1H)，5.14(m，2H)，4.63(m，2H)，2.23-2.14(m，9H)，1.37(m，2H)，1.29(m，2H)，1.14(m，2H)。
example 61
Preparation of 6- {2- { [ 5-cyclopropyl-3- (2, 6-dimethylphenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } benzo [ d ] isothiazole-3-carboxylic acid.
Figure BDA0001217186810000362
Prepared according to the method of example 24 except that 2, 6-dimethylbenzaldehyde is used instead of 2, 6-dichlorobenzaldehyde.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.62(m，1H)，7.25(m，1H)，7.12(m，4H)，4.01(s，2H)，3.90(m，1H)，3.24-3.18(m，4H)，2.15(m，7H)，2.04(m，2H)，1.60(m，4H)，1.46(m，2H)，1.28(m，2H)，1.14(m，2H)。
example 62
Preparation of 2- {2- { [ 5-cyclopropyl-3- (2, 6-dimethylphenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonan-7-yl } benzo [ d ] thiazole-6-carboxylic acid.
Figure BDA0001217186810000363
Prepared according to the procedure of example 59 except that tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate is used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：8.37(s，1H)，8.06(m，1H)，7.54(d，J＝8.4Hz，1H)，7.25(m，1H)，7.13(m，2H)，4.02(s，2H)，3.92(m，1H)，3.60(t，J＝5.2Hz，2H)，3.52(t，J＝5.2Hz，2H)，2.15(m，7H)，2.08(m，2H)，1.62(m，4H)，1.47(m，2H)，1.28(m，2H)，1.14(m，2H)。
example 63
Preparation of 4- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonane-7-carboxamido } benzoic acid.
Figure BDA0001217186810000371
Prepared according to the procedure of example 22 except that tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate is used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，DMSO)δ：8.76(s，1H)，7.79(m，2H)，7.68-7.66(m，2H)，7.61-7.57(m，1H)，7.53(m，2H)，4.11(s，2H)，3.88(m，1H)，3.33(m，2H)，3.26(m，2H)，2.32(m，1H)，1.95(m，2H)，1.40(m，2H)，1.33-1.24(m，4H)，1.15(m，2H)，1.10(m，2H)。
example 64
Preparation of 3- {2- { [ 5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl ] methoxy } -7-azaspiro [3.5] nonane-7-carboxamido } benzoic acid.
Figure BDA0001217186810000372
Prepared according to the method of example 57 except that tert-butyl 2-hydroxy-7-aza [3.5] nonane-7-carboxylate is used in place of tert-butyl 6-hydroxy-1, 2, 3, 4-tetrahydro-9-aza-1, 4-methano-naphthalene-9-carboxylate.
The characterization data are:1H NMR(400MHz，CDCl3)δ：7.91(s，1H)，7.77(m，2H)，7.46-7.44(m，2H)，7.41-7.35(m，2H)，6.64(m，1H)，4.69(br，1H)，4.19(s，2H)，3.94(m，1H)，3.39(m，2H)，3.33(m，2H)，2.16(m，1H)，2.04(m，2H)，1.54-1.49(m，6H)，1.29(m，2H)，1.14(m，2H)。
examples of the experiments
The compounds prepared in the above examples were subjected to in vitro testing for FXR agonistic activity.
AlphaScreen test, the effect of compounds on human farnesoid receptor protein binding to its co-activator (SRC1-2) was tested using the hexahistidine detection kit (Perkins-Elmer) from Perkins Elmer, Inc.:
1) preparing a mixture, wherein the mixture comprises human farnesol receptor protein hFXR (100nM, 15 muL/well), polypeptide bSRC1-2(50nM, 15 muL/well), 10 × AlphaScreen buffer solution (15 muL/well) and deionized water (60 muL/well), transferring the mixture into a 96-well plate, and transferring the mixture into 105 muL/well;
2) the compound prepared in the above example was diluted 12 times at a 2-fold ratio, 15. mu.L/well;
3) the total volume of the donor beads and the acceptor beads is 30 mu L/hole; (Note: operation in the dark)
4) Incubating for 2h at room temperature in a dark place;
5) transfer 384 well plates, 40. mu.L/well, 3 multiple wells. Instantaneously centrifuging at 1000rpm for 1 minute to fully mix the liquid drops at the bottom of the hole; (Note: operation in the dark)
6) In the dark, the instrument reads the plate (homogeneous luminescent immunoassay system), EC50Processed by data processing software GraphPad Prism 5.
The results are shown in table 1 below:
TABLE 1FXR agonistic Activity test results
Figure BDA0001217186810000373
Figure BDA0001217186810000381
Note: nM is n mol/L, A represents EC50< 100nM, B represents 100nM < EC50< 1000nM, C stands for EC50> 1000nM, GW4064 as a positive control compound, and controls 1 and 2 as control compounds, respectively, having the following structures:
Figure BDA0001217186810000382
as can be seen from the above results, the compounds of the present invention have a superior agonistic activity against FXR, particularly some of them, EC against FXR agonism50Reaching below 100nM, very good FXR agonistic activity is shown.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (7)

1. An FXR receptor modulator having the structural features of formula II:
Figure FDA0002896813520000011
wherein:
R1selected from: 1 to 4R4A substituted or unsubstituted C5-10 aryl group;
R2selected from: 1 to 4R5Substituted or unsubstituted C3-C6 cycloalkyl;
l is selected from the following substituents:
Figure FDA0002896813520000012
c is selected from: 0. 1;
f is selected from: 0. 1;
R6independently optionally from: hydrogen, halogen, 1-5R7Substituted or unsubstituted C1-C3 alkyl, 1-5R7Substituted or unsubstituted C1-C3 alkoxy, 1-5R7Substituted or unsubstituted C3-C6 cycloalkyl;
R4、R5、R7independently give play toSelected from: halogen, cyano, nitro, C1-C3 alkyl, C1-C3 monohalogenated or polyhalogenated alkyl, C1-C3 alkoxy, C1-C3 monohalogenated or polyhalogenated alkoxy;
ar is selected from the following groups:
Figure FDA0002896813520000013
R8selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy;
R3selected from: COO R9；
R9Selected from: hydrogen, metal ions.
2. The FXR receptor modulator according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by being selected from compounds having the following structural features of general formula III:
Figure FDA0002896813520000014
R1selected from: 1 to 3R4Substituted or unsubstituted phenyl;
R4selected from: halogen, C1-C3 alkyl substituted or unsubstituted by 1-3 fluorine atoms;
R2selected from: cyclopropane;
ar is selected from the following groups:
Figure FDA0002896813520000015
Figure FDA0002896813520000021
R8selected from: hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy;
R9selected from: hydrogen, metal ions.
3. An FXR receptor modulator or a pharmaceutically acceptable salt thereof, selected from one of the following compounds:
Figure FDA0002896813520000022
4. the process for the preparation of FXR receptor modulators of claim 1, characterized by comprising the following synthetic route:
route one:
Figure FDA0002896813520000023
wherein: m is selected from: c; a is selected from: n; x is selected from: o; q is selected from: c;
L、R1、R2and Ar is as described in claim 1;
EL1selected from: halogen, alkylsulfonyloxy or arylsulfonyloxy;
EL2selected from: halogen;
r is selected from: C1-C6 alkyl.
5. Use of an FXR receptor modulator according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and treatment of diseases mediated by FXR.
6. Use according to claim 5, characterized in that the FXR mediated diseases are: non-alcoholic fatty liver disease, chronic intrahepatic or extrahepatic cholestatic conditions, liver fibrosis resulting from chronic cholestatic conditions or acute intrahepatic cholestatic conditions, chronic hepatitis B, gallstone, liver cancer, colon cancer, or intestinal inflammatory disease.
7. A pharmaceutical composition comprising the FXR receptor modulator of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant or carrier.
CN201710054416.5A 2017-01-23 2017-01-23 FXR receptor modulator and preparation method and application thereof Active CN108341822B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710054416.5A CN108341822B (en) 2017-01-23 2017-01-23 FXR receptor modulator and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710054416.5A CN108341822B (en) 2017-01-23 2017-01-23 FXR receptor modulator and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN108341822A CN108341822A (en) 2018-07-31
CN108341822B true CN108341822B (en) 2021-04-16

Family

ID=62962885

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710054416.5A Active CN108341822B (en) 2017-01-23 2017-01-23 FXR receptor modulator and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN108341822B (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3277286B1 (en) 2015-03-31 2021-04-21 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
TW201808283A (en) 2016-08-05 2018-03-16 廣東東陽光藥業有限公司 Nitrogen-containing tricyclic compounds and uses thereof in medicine
AU2017338853A1 (en) 2016-10-04 2019-04-18 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
US10689391B2 (en) 2017-12-12 2020-06-23 Enanta Pharmaceuticals, Inc. Isoxazole analogs as FXR agonists and methods of use thereof
CN110128432B (en) 2018-02-02 2021-03-02 广东东阳光药业有限公司 Nitrogenous tricyclic compound and application thereof in medicine
US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
CN110818704B (en) * 2018-08-08 2023-08-01 广州市恒诺康医药科技有限公司 Spiro bridged ring compounds, pharmaceutical compositions thereof and uses thereof
EP3889149A4 (en) * 2018-11-26 2022-08-24 CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Solid form, crystalline form, and crystal form a of fxr agonist, and preparation method therefor and application thereof
WO2020231917A1 (en) 2019-05-13 2020-11-19 Enanta Pharmaceuticals, Inc. Isoxazole derivatives as fxr agonists and methods of use thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101472889A (en) * 2006-04-22 2009-07-01 拜尔农作物科学股份公司 Alkoxyalkyl-substituted cyclic ketoenols
CN101674886A (en) * 2007-03-09 2010-03-17 独立行政法人产业技术综合研究所 Electrode catalyst for fuel cell
CN102872018A (en) * 2012-10-23 2013-01-16 张健存 Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
CN103917094A (en) * 2011-03-18 2014-07-09 建新公司 Glucosylceramide synthase inhibitors
CN106146483A (en) * 2015-04-23 2016-11-23 上海迪诺医药科技有限公司 Heterocyclic method Buddhist nun's ester derivant X receptor modulators
CN106946867A (en) * 2016-01-06 2017-07-14 广州市恒诺康医药科技有限公司 FXR receptor modulators and its production and use
CN108218852A (en) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 A kind of spiro-compound, preparation method, composition and purposes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101472889A (en) * 2006-04-22 2009-07-01 拜尔农作物科学股份公司 Alkoxyalkyl-substituted cyclic ketoenols
CN101674886A (en) * 2007-03-09 2010-03-17 独立行政法人产业技术综合研究所 Electrode catalyst for fuel cell
CN103917094A (en) * 2011-03-18 2014-07-09 建新公司 Glucosylceramide synthase inhibitors
CN102872018A (en) * 2012-10-23 2013-01-16 张健存 Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
CN106146483A (en) * 2015-04-23 2016-11-23 上海迪诺医药科技有限公司 Heterocyclic method Buddhist nun's ester derivant X receptor modulators
CN106946867A (en) * 2016-01-06 2017-07-14 广州市恒诺康医药科技有限公司 FXR receptor modulators and its production and use
CN108218852A (en) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 A kind of spiro-compound, preparation method, composition and purposes

Also Published As

Publication number Publication date
CN108341822A (en) 2018-07-31

Similar Documents

Publication Publication Date Title
CN108341822B (en) FXR receptor modulator and preparation method and application thereof
CN111757875B (en) Dihydrobenzofuran and indene analogs as myocardial segment inhibitors
CN109071468B (en) Heterocyclic compound and preparation method and application thereof
WO2017118294A1 (en) Fxr receptor modulator, preparation method therefor, and uses thereof
WO2017176958A1 (en) Monofunctional intermediates for ligand-dependent target protein degradation
CA2900695A1 (en) Heterocyclic amides as kinase inhibitors
WO2008104077A1 (en) Small molecule inhibitors of protein arginine methyltransferases (prmts)
BR112021003496A2 (en) compound, pharmaceutical composition, and, methods for treating heart disease, for treating a disease or condition associated with hypertrophic cardiomyopathy, or condition that is associated with secondary thickening of the left ventricular wall, or condition that is associated with the small cavity of the left ventricle and cavity obliteration, hyperdynamic contraction of the left ventricle, myocardial ischemia or cardiac fibrosis, or a condition selected from muscular dystrophies and glycogen storage diseases to inhibit cardiac sarcomere
WO2017006953A1 (en) HETEROCYCLIC DERIVATIVE HAVING TrkA-INHIBITING ACTIVITY
WO2019208812A1 (en) Benzisoxazole compound
KR20200081436A (en) Alkene compounds as farnesoid X receptor modulators
KR20200083529A (en) Alkene spirocyclic compounds as farnesoid X receptor modulators
AU2013325615A1 (en) Imidazole derivative
CN112300153A (en) Heterocyclic compound, pharmaceutical composition and application
AU2022202463A1 (en) Tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing same, and use thereof
BR112021015963A2 (en) BICYCLIC COMPOUNDS SUBSTITUTED AS FARNESOID X RECEPTOR MODULATORS
KR20150000900A (en) Novel 1-substituted indazole derivative
CN106565674B (en) Octahydrocyclopenta [ c ] pyrrole derivative, preparation method and medical application thereof
CN107849047A (en) A kind of biphenyl derivatives and preparation method thereof and purposes in medicine
CN117062813A (en) Polycyclic compound and application thereof
WO2019062657A1 (en) Nitrogen heterocyclic derivative, preparation method therefor, and pharmaceutical use thereof
EP3681881B1 (en) Hormone receptor modulators for treating metabolic mutagenic and fibrotic conditions and disorders
WO2019214656A1 (en) Fluorine-containing isoxazole compound, preparation method therefor, and pharmaceutical composition and use thereof
TWI832132B (en) 2-pyridone derivatives, their preparation method and application in medicine
KR20200100615A (en) 3-(5-Fluorobenzofuran-3-yl)-4-(5-methyl-5H-[1,3]dioxolo[4,5-f]indol-7-yl)pyrrole-2,5- Dion&#39;s solid form

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant