CN109071468B

CN109071468B - Heterocyclic compound and preparation method and application thereof

Info

Publication number: CN109071468B
Application number: CN201880001611.4A
Authority: CN
Inventors: 刘钢; 于华; 杨定菊; 何婷; 康熙伟; 蔡家强; 刘金明; 吴勇勇; 曾宏; 宋宏梅; 苏东海; 周信; 谭玉婷; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2017-01-20
Filing date: 2018-01-12
Publication date: 2022-09-02
Anticipated expiration: 2038-01-12
Also published as: WO2018133730A1; CN109071468A

Abstract

The present invention relates generally to Farnesoid X Receptor (FXR) agonist compounds, methods of preparation and uses thereof. In particular, the present invention provides FXR agonist compounds containing heterocycles, as well as stereoisomers, tautomers, polymorphs, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof. The invention also provides processes for the preparation of said compounds, pharmaceutical compositions and kits comprising said compounds and their use for the treatment of diseases or conditions mediated by FXR.

Description

Heterocyclic compound and preparation method and application thereof

Technical Field

The present invention relates to a heterocyclic compound for use in the treatment of a disease or disorder mediated by Farnesoid X Receptor (FXR), more particularly to FXR agonist compounds, as well as stereoisomers, tautomers, polymorphs, solvates (e.g. hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof. The invention also relates to processes for the preparation of said compounds, pharmaceutical compositions and kits comprising said compounds and their therapeutic use.

Background

Farnesoid X receptors (FXR, NR1H4) are expressed in The liver, The entire gastrointestinal tract including The esophagus, stomach, duodenum, small intestine, colon, kidney and adrenal gland (Kuipers, f. et al, The Farnesoid X Receptor (FXR) as Modulator of double Acid metabolism, rev. endocrine metals. disorders,2004, 5: 319-. FXR is a member of transcription factors known to be activated by ligands of nuclear receptors. Bile acids such as chenodeoxycholic acid (CDCA) or its taurine or glycine amide conjugates are endogenous ligands of FXR. Binding of bile acids to FXR activates FXR, controlling the expression of a variety of genes, including those involved in bile acid, cholesterol, triglyceride, lipoprotein homeostasis in the liver and circulation, by heterodimeric complexes with Retinoid X Receptors (RXR) (Kalaany, N.Y.; Mangelsdorf, D.J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism, Annu.Rev.Physiol.,2006,68, 159-. FXR also appears to be involved in paracrine and endocrine signaling by upregulation of fibroblast growth factor 15 (rodent) or fibroblast growth factor 19 (monkey, human) (t.inagaki et al.fiberlast growth factor 15 functional as an endogenous fatty signal to regulated biological acid hormone. cell method, 2005,2(4), 217-225).

Bile acids are amphiphilic molecules that form micelles and emulsify lipids in the diet. If the concentration of bile acid is too high, cytotoxicity may occur, and thus there is a mechanism for strictly controlling the concentration of bile acid physiologically. FXR plays a key role in controlling the in vivo stable state of Bile acids (Makishima, M., nucleic acids Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile acids Metabolism by nucleic acids Receptors J.Pharmacol.Sci.,2005,97:177 183.).

In addition, FXR has also been shown to regulate complex biological processes beyond metabolism, such as liver regeneration or integrity of the intestinal barrier. FXR also controls the intestinal and hepatic immune systems and has some anti-inflammatory effect (Modica, s.; Gadaleta, r.m.; moschatta, a.; differentiation the nuclear acid receptor FXR paramigim.nucl.receiver.signal., 2010,8, e 005.).

Obeticholic Acid (6-Et CDCA) is an FXR receptor agonist with higher activity than the endogenous ligand CDCA, and shows significant improvement in insulin sensitivity and other metabolic beneficial effects in phase IIa clinical studies of non-alcoholic fatty liver disease (NAFLD) (Mudaliar, S., Henry, R.R.; Sanyal, A.J.et. Et. effective and safety of the fatty X receptor agonist in tissues with type 2 diabetes and non-alcoholic fatty liver disease. gastroenterology,2013,145, 574. and 582.). Phase IIb studies of obeticholic acid showed that 72 weeks of treatment was also beneficial for histopathological improvement of non-alcoholic hepatitis (NASH). In a phase III study of Primary Biliary Cirrhosis (PBC), patients have improved liver function impairment (Nevens, f., Andreone, p., Mazzella, g., et al, the first Primary Biliarlity Cirrhosis (PBC) phase 3 ternary in two decades-an international study of the FXR aginst inflammatory acid in PBC Patients.j. hepatol.,2014,60, S525-S526).

However, there remains a need in the art for FXR agonist compounds with good pharmacodynamic or pharmacokinetic properties for the treatment of diseases or disorders mediated by FXR.

Summary of The Invention

The present invention relates generally to FXR agonist compounds of general formula (I) or stereoisomers, tautomers, polymorphs, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof:

wherein

R ¹ Selected from: hydrogen, halogen, hydroxy, amino, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 alkyl-O-, -C (O) NR ⁷ (CHR ⁴ ) _q CO ₂ R ⁵ 、-C(O)NR ⁷ (CHR ⁴ ) _q SO ₃ R ⁶ 、-E-R ⁵ 、-E-OR ⁵ 、-E-CN、-E-NR ⁵ R ⁶ 、C _3-10 cycloalkyl-O-, -O-C _1-6 alkyl-OR ⁵ 3-to 10-membered heterocycloalkyl-O-, -E-C (O) OR ⁵ 、-E-C(O)R ⁵ 、-E-C(O)NR ⁵ R ⁶ 、-E-C(O)NR ⁵ SO ₂ R ⁵ 、-E-NR ⁵ C(O)R ⁵ 、-E-SO _p -R ⁵ 、-E-SO ₃ H、-E-SO ₂ -NR ⁵ R ⁶ 、-E-SO ₂ -NR ⁶ C(O)R ⁵ 、-E-NR ⁵ -SO ₂ -R ⁶ 、-E-SO ₂ -3 to 10 membered heterocycloalkyl, and 5,6 or 7 membered monocyclic nitrogen containing heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl and heteroaryl are unsubstituted or independently selected from halogen, CN, C _1-3 Alkyl, halo C _1-3 Alkyl, hydroxy, oxo, C (O) OH, SO ₃ H、C _1-3 alkyl-O-and halo-C _1-3 1,2,3 or 4 substituents of alkyl-O-;

e is a bond, C _1-6 Alkyl or C _3-8 A cycloalkyl group;

R ⁴ 、R ⁶ and R ⁷ Each independently selected from hydrogen, C _1-6 Alkyl, halo C _1-6 Alkyl and C _3-6 A cycloalkyl group;

each R is ⁵ Independently selected from hydrogen, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-8 Cycloalkyl, -C _1-6 alkyl-C _3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -C _1-6 Alkyl-3 to 8 membered heterocycloalkyl, 5 or 6 memberedHeteroaryl and aryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or selected from halogen, CN, hydroxy, oxo, C (O) OH, C _1-3 Alkyl, halo C _1-3 Alkyl, SO ₃ H、C _1-3 alkyl-O-, halo-C _1-3 alkyl-O-and-SO ₂ -C _1-3 1,2,3 or 4 substituents of alkyl;

p is 0, 1 or 2;

q is 1,2,3, 4,5 or 6;

b is selected from C _6-14 Aryl and 5 to 14 membered monocyclic or bicyclic heteroaryl comprising 1,2,3, 4 or 5 heteroatoms independently selected from N, O and S; wherein said aryl or heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: halogen, hydroxy, CN, amino, C _1-6 Alkyl radical, C _1-6 alkyl-O-, C _1-6 alkyl-O-C _1-6 alkyl-O-, halo-C _1-6 Alkyl, halo C _1-6 alkyl-O-, hydroxy-C _1-6 Alkyl, CN-C _1-6 Alkyl radical, C _3-6 Cycloalkyl and 3 to 6 membered heterocycloalkyl containing 1,2 or 3 heteroatoms independently selected from N, O and S and C _1-6 alkyl-S (O) _p -；

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl or a saturated or partially unsaturated 3 to 10 membered heterocyclyl optionally substituted by oxo, wherein said heteroaryl or heterocyclyl contains 1,2 or 3 heteroatoms independently selected from N, O and S; and is provided with

May be attached to the B group through the C ring atom or, where present, through the N ring atom;

x is selected from N and CRc';

each R is ² Independently selected from hydrogen, halogen, CN, hydroxyl, amino, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-, C _3-8 Cycloalkyl and halo C _3-8 A cycloalkyl group;

each R is ³ Independently selected from hydrogen, halogen, CN, hydroxyl, amino, C _1-6 Alkyl, halo C _1-6 Alkyl, hydroxy C _1-6 Alkyl radical, C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-, C _3-8 Cycloalkyl and halo C _3-8 A cycloalkyl group;

m, n are each independently 0, 1,2,3 or 4;

d is:

z is:

or Rd;

w is selected from N, N-O and CRc';

each Ra is independently selected from C _1-6 Alkyl radical, C _3-8 Cycloalkyl radical, C _1-6 alkyl-O-, halo-C _1-6 Alkyl, halo C _3-8 Cycloalkyl and halo C _1-6 alkyl-O-;

rb, Rc and Rc' are each independently selected from hydrogen, halogen, hydroxy, CN, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl radical, C _3-8 cycloalkyl-O-and halo-C _3-8 cycloalkyl-O-;

rd is selected from C _3-10 Cycloalkyl or C _5-14 A bridged ring system, a fused ring system or a spiro ring system; wherein said cycloalkyl, saturated bridged ring system, saturated fused ring system, or saturated spiro ring system is optionally substituted with 1,2, or 3 Re;

each Re is independently selected from hydrogen, halogen, hydroxy, CN, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl and C _6-10 A monocyclic or bicyclic aryl group;

with the following conditions:

(1) and ring

The B group not being linked to

The groups are directly adjacent;

(2) when the ring

Is composed of

When R is ² Is not a hydroxyl group; and is

(3) When X is N, the ring

Is not provided with

Wherein from the ring

With C or N ring atoms extending therefrom

Denotes that the C or N atom is directly bonded to the B group from the ring

Extended out

Indicating ring

And

and bonding the groups.

In one class of embodiments, when X is CRc', the ring

Is not

Another aspect of the invention is a pharmaceutical composition comprising a compound of the general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (e.g., a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may further comprise one or more other therapeutic agents suitable for preventing or treating a disease or condition mediated by FXR.

The invention also includes a method of preventing or treating a disease or disorder mediated by FXR, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or a prodrug thereof, or the pharmaceutical composition.

The invention also includes a kit for preventing or treating a disease or condition mediated by FXR, comprising:

a) a first container comprising at least one compound of the general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or a prodrug thereof as a first therapeutic agent or the pharmaceutical composition as a first pharmaceutical composition;

b) optionally a second container comprising at least one further therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising said further therapeutic agent as a second pharmaceutical composition; and

c) optionally, packaging instructions.

The invention also includes a compound of the general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or a prodrug thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease or condition mediated by FXR.

The invention also includes the use of a compound of the general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or a prodrug thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prophylaxis or treatment of a disease or condition mediated by FXR.

The invention also includes methods of making the compounds of the invention.

The compound of the general formula (I) has excellent in vivo or in vitro pharmacodynamic or pharmacokinetic properties, shows good FXR activation activity and activation effect and excellent plasma drug exposure and bioavailability, and thus has good pharmaceutical activity and in vivo metabolic advantages. In addition, the compound of the invention also shows better drug safety.

Detailed Description

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and molecular formulae. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that the invention is not limited to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the cited documents, patents, and similar materials differ or contradict this application (including but not limited to defined terms, usage of terms, described techniques, etc.), this application controls.

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "alkyl" as used herein means having from 1 to 12 carbon atoms (C) _1-12 ) Wherein the alkyl group may be optionally substituted with one or more (e.g. 1,2,3 or 4) suitable substituents. In some embodiments, the alkyl group has 1 to 8 carbon atoms (C) _1-8 ) Especially 1 to 6 carbon atoms (C) _1-6 ). In other embodiments, the alkyl group has 1 to 4 carbon atoms (C) _1-4 ) Especially 1 to 3 carbon atoms (C) _1-3 ) Or 1 to 2 carbon atoms (C) _1-2 ). Examples of alkyl groups include, but are not limited to: methyl (Me), ethyl (Et), 1-propyl (n-Pr), 2-propyl (i-Pr or isopropyl), 1-butyl (n-Bu or n-butyl), 2-methyl-1-propyl (i-Bu or isobutyl), 2-butyl (s-Bu or sec-butyl), 2-methyl-2-propyl (t-Bu or tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl group, 2-methyl-2-butyl group, 3-methyl-1-butyl group, 2-methyl-1-butyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2-methyl-2-pentyl group (-C (CH). ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl, 1-octyl and the like.

Unless specifically limited, the terms "carbocyclyl" and "carbocycle" are used interchangeably herein to mean any ring system wherein all ring atoms are carbon and which contains from 3 to 14 ring carbon atoms, more suitably from 3 to 12 carbon atoms, more suitably from 3 to 10 carbon atoms, and even more suitably from 3 to 8 carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings or non-aromatic rings fused to aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic and tricyclic ring systems, particularly monocyclic and bicyclic ring systems. Carbocyclyl groups include bridged ring systems (e.g., bicyclo [2.2.1] heptyl), fused ring systems (e.g., bicyclo [3.1.0] hexyl), or spiro ring systems (e.g., spiro [2.3] hexyl).

As used herein, the term "cycloalkyl" refers to a compound having 3 to 12 carbon atoms (C) _3-12 ) In particular 3 to 10 carbon atoms (C) _3-10 ) Or 3 to 8 carbon atoms (C) _3-8 ) A saturated carbocyclic ring in the form of a monocyclic ring. In some embodiments, cycloalkyl has 3 to 6 carbon atoms (C) _3-6 ) For example 3,4, 5 or 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Cycloalkyl groups may be optionally substituted with one or more (e.g., 1,2,3, or 4) suitable substituents.

The term "bridged ring system" as used herein, unless otherwise specified, means having from 5 to 14 ring carbon atoms (C) _5-14 ) Carbocyclyl in the form of a bicyclic ring in which the two carbocycles share more than two (e.g., 3,4 or 5) carbon atoms, the carbon chain formed by these shared carbon atoms acting as a bridge, the two carbon atoms at either end of the bridge being referred to as the bridgehead carbon. Such bridged ring systems may have 5 to 11 ring carbon atoms (C) _5-11 ) In particular 6 to 10 ring carbon atoms (C) _6-10 ) For example 7, 8 or 9 ring carbon atoms. Examples of such bridged ring systems include, but are not limited to, bicyclo [2.1.1]Hexyl, bicyclo [2.2.1]Heptyl, bicyclo [2.2.1]Heptenyl, bicyclo [2.2.2]Octyl and bicyclo [3.2.2]And (4) nonyl. The bridged ring system may be optionally substituted with one or more (e.g., 1,2,3, or 4) suitable substituents.

Unless otherwise specifically limited, the term "fused ring system" as used herein means having from 5 to 14 ring carbon atoms (C) _5-14 ) Wherein the two fused carbocyclic rings share two carbon atoms bonded to each other. Thus, the fused ring system is a fused bicyclic carbocyclic ring sharing two carbon atoms bonded to each otherAnd (4) a base. Such fused ring systems may have, for example, from 5 to 10 ring carbon atoms (C) _5-10 ) In particular 7 to 10 ring carbon atoms (C) _7-10 ). Said C is _7-10 The two carbocyclic rings of the fused ring system may be arranged to form 4-and 5-membered rings (bicyclo [4,5 ] rings]System), two 5-membered rings (bicyclo [5,5 ]]System), 5-and 6-membered rings (bicyclo [5,6 ]]Systems), or two 6-membered rings (bicyclo [6,6 ]]A system). Examples of such fused ring systems include, but are not limited to, bicyclo [3.1.0]]Hexyl, bicyclo [3.2.0]Heptyl, bicyclo [4.3.0]Nonyl or bicyclo [4.4.0]A decyl group. The fused ring system may be optionally substituted with one or more (e.g. 1,2,3 or 4) suitable substituents.

The term "spiro ring system" as used herein, unless otherwise specified, means having from 5 to 14 ring carbon atoms (C) _5-14 ) Carbocyclyl in which two carbocycles share 1 carbon atom (referred to as a "spiro atom"). The spiro ring system may have, for example, 5 to 11 ring carbon atoms (C) _5-11 ) In particular 6 to 10 ring carbon atoms (C) _6-10 ) For example 7, 8 or 9 ring carbon atoms. Examples of spiro ring systems include, but are not limited to, spiro [2.2 ]]Pentyl, spiro [2.3]]Hexyl, spiro [2.4 ]]Heptyl, spiro [3.3 ]]Heptyl, spiro [2.5 ]]Octyl, spiro [3.4 ]]Octyl, spiro [3.5 ]]Nonyl, spiro [4.4 ]]Nonyl, spiro [4.5 ]]Decyl and spiro [5.5 ]]An undecyl group. The spiro ring system may optionally be substituted with one or more (e.g. 1,2,3 or 4) suitable substituents.

The term "aryl" as used herein means C _6-14 Aromatic monocyclic or polycyclic, in particular bicyclic, radicals (C) _6-14 Aryl) suitably including C _6-12 Aryl radicals, more suitably including C _6-10 Monocyclic or bicyclic aryl radicals, preferably meaning C ₆ An aryl group (i.e., phenyl). The aryl group contains at least one aromatic ring (e.g., one ring or two rings), but may also contain additional rings that are not aromatic. An example of a typical aryl group containing one aromatic ring is phenyl. An example of a typical aryl group containing two aromatic rings is naphthyl. And C _5-8 Carbocyclyl (suitably, C) _5-6 Carbocyclyl) fused phenyl (e.g., indane) is also an example of an aryl group. Said aryl group being optionally substituted by one or more of (A), (B), (C) and C)E.g., 1,2,3, or 4) suitable substituents.

The terms "heterocycle" and "heterocyclyl" are used interchangeably herein and refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group having, for example, 3 to 10 (suitably 3 to 8, more suitably 3,4, 5, or 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O and S and the remaining ring atoms are C. For example, a "3-to 10-membered heterocyclyl" is a saturated or partially unsaturated heterocyclyl having 2 to 9 (e.g., 2,3, 4,5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1,2,3, or 4) heteroatoms independently selected from N, O and S. Examples of saturated heterocyclic groups (i.e., heterocycloalkyl groups) include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; examples of partially unsaturated heterocyclyl groups include, but are not limited to, dioxolyl (dioxolinyl) and pyrrolinyl. The heterocyclyl group may be optionally substituted with one or more (e.g. 1,2,3 or 4) suitable substituents.

The term "heteroaryl" as used herein refers to a monocyclic or polycyclic (e.g. bicyclic or tricyclic) aromatic ring system having 5 to 14 ring atoms, for example 5,6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1,2,3, 4 or 5 identical or different heteroatoms independently selected from N, O and S. Heteroaryl groups may be benzo-fused. Examples of heteroaryl groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridinyl, quinolyl, indolyl, pyrrolopyridazinyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, isoquinolyl, tetrahydroisoquinolinyl, benzimidazolyl, cinnolinyl, indolizinyl, phthalazinyl, isoindolyl, pteridinyl, purinyl, furazanyl, benzofurazanyl, quinoxalinyl, naphthyridinyl or furopyridyl. Preferably, the heteroaryl group is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzothiazolyl, benzo [ d ] isothiazolyl, imidazo [1,2-a ] pyridyl, quinolinyl, 1H-indolyl, pyrrolo [1,2-b ] pyridazinyl, benzofuranyl, benzo [ b ] thienyl, 1H-indazolyl, benzo [ d ] oxazolyl, benzo [ d ] isoxazolyl, quinazolinyl, 1H-pyrrolo [3,2-c ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyridyl, and 1H- [1,2,3] triazolo [4,5-b ] pyridyl. Heteroaryl groups may be optionally substituted with one or more (e.g., 1,2,3, or 4) suitable substituents.

Where possible, the heterocyclyl (e.g., heterocycloalkyl) or heteroaryl may be carbon-bonded (carbon-linked) or nitrogen-bonded (nitrogen-linked). By way of example and not limitation, a carbon-bonded heterocycle or heteroaryl is bonded at the following positions: the 2,3, 4,5 or 6 position of pyridine, the 3,4, 5 or 6 position of pyridazine, the 2,4, 5 or 6 position of pyrimidine, the 2,3, 5 or 6 position of pyrazine, the 2,3, 4 or 5 position of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, the 2,4 or 5 position of oxazole, imidazole or thiazole, the 3,4 or 5 position of isoxazole, pyrazole or isothiazole, the 2 or 3 position of aziridine, the 2,3 or 4 position of azetidine, the 2,3, 4,5, 6, 7 or 8 position of quinoline, or the 1,3,4, 5,6, 7 or 8 position of isoquinoline.

By way of example, and not limitation, a nitrogen-bonded heterocycle or heteroaryl is bonded at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1-position of 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β -carboline.

The term "halo" or "halogen" as used herein includes F, Cl, Br or I. "halo" includes, but is not limited to, mono-, di-, or tri-substituted, and the halogen atoms used for substitution may be the same or different.

The term "substituted" means that one or more (e.g., 1,2,3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "optionally substituted" means optionally substituted with a specified group, radical or moiety.

When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

The term "chiral" refers to molecules that have non-superimposability of mirror image pairs, while the term "achiral" refers to molecules that may be superimposed on their mirror image pairs.

The term "stereoisomers" refers to compounds having the same chemical composition but differing in the spatial arrangement of atoms or groups.

"diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography.

"enantiomer" refers to two stereoisomers of a compound that are nonsuperimposable mirror images of each other.

The stereochemical definitions and rules used herein generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers thereof, as well as mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to designate the absolute configuration of the chiral center of the molecule. The prefixes d and l or (+) and (-) are used to indicate the sign of a compound rotating plane polarized light, where (-) or 1 means that the compound is left-handed. Compounds with the prefix (+) or d are dextrorotatory. For a particular chemical structure, these stereoisomers are identical except that they are mirror images of each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur without stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, with no optical activity. In one aspect, stereoisomers of the invention may exist in predominant forms, for example, greater than 50% ee (enantiomeric excess), greater than 80% ee, greater than 90% ee, greater than 95% ee, or greater than 99% ee.

Where the process for preparing the compounds of the invention produces a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared by enantioselective synthesis or by resolution. For example, the compounds may be resolved into their enantiomeric components by standard techniques, for example by formation of diastereomeric pairs by salt formation with an optically active acid such as (-) -di-p-toluoyl-d-tartaric acid and/or (+) -di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds can also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic purification and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

The term "tautomer" or "tautomeric form" refers to energetically different structural isomers that can interconvert through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions through recombination of some of the bonding electrons.

The present invention encompasses all possible crystalline forms or polymorphs of the compound of formula (I), which may be a single polymorph or a mixture of more than one polymorph in any ratio.

It will be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, esters, solvates, metabolites, N-oxides, and chemically protected forms and prodrugs thereof, which upon administration to a subject in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

Thus, when reference is made herein to "a compound of formula (I)", "a compound of the invention" or "a compound of formula (I) of the invention", it is also intended to encompass solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides of said compound of formula (I) as well as chemically protected forms and prodrugs thereof.

The term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, acetate, chloride, iodide, nitrate, bisulfate, acid phosphate, isonicotinate, salicylate, acid citrate, oleate, tannate, pantothenate, bitartrate, ascorbate, gentisate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, and pamoate (i.e., 1' -methylene-bis (2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may include the inclusion of another molecule such as an acetate ion, succinate ion, or other counter ion. The counter ion may be any organic or inorganic ion that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. The plurality of charged atoms may be part of a pharmaceutically acceptable salt and may have a plurality of counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid and the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, and the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other components comprising the formulation and/or the mammal being treated therewith.

The term "ester" as used herein means an ester derived from a compound of formula (I), including physiologically hydrolysable esters, which can be hydrolysed under physiological conditions to release the compound of formula (I) of the invention in free acid or alcohol form. The compounds of the general formula (I) according to the invention may themselves also be esters.

The compounds of the invention may exist in the form of solvates, such as hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

A "metabolite" is a product produced by the in vivo metabolism of a particular compound or salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art and their activity can be determined using assays such as those described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method comprising contacting a compound of general formula (I) of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair is required for oxidation of the nitrogen to the oxide; one skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-; s.v.ley, ed., Pergamon Press; M.Tisler and B.Stanovnik, Comprehensive Heterocyclic Chemistry, vol.3, pp 18-20.

In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, for example, as described in Protective Groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The present invention further includes within its scope prodrugs of the compounds of the present invention. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Thus, in these instances, the term "administering" as used in the treatment methods of the present invention shall include treating various diseases or conditions with a prodrug form of one or more of the claimed compounds, but which is converted in vivo to the above-described compounds upon administration to a subject. Conventional methods for selecting and preparing suitable Prodrug derivatives are described, for example, in "Design of produgs", ed.h. bundgaard, Elsevier, 1985.

Any formula or structure shown herein, including compounds of formula (I), is also intended to represent unlabeled forms and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be contained in compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and ¹²⁵ I. various isotopically-labeled compounds of the invention, for example, those comprising ³ H、 ¹³ C and ¹⁴ those of the radioactive isotopes of C. Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as Positron Emission Tomography (PET) or single photon emission tomography (SPECT), including drug or substrate tissue distribution assays, or in the radiation treatment of patients. Deuterium labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. ¹⁸ The F-labeled compounds are useful for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and the preparative procedures described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Furthermore, with heavier isotopes, in particular deuterium (i.e. deuterium) ² H or D) substitution may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium is considered as a substituent in the compounds of formula (I) in this case. The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is explicitly designated as "H" or "hydrogen," it is understood that the position has hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom explicitly designated as deuterium (D) is intended to represent deuterium.

The term "pharmaceutical composition" as used herein includes products comprising a therapeutically effective amount of a compound of formula (I) of the present invention, as well as any product which results, directly or indirectly, from combination of compounds of formula (I) of the present invention.

Compound (I)

The present invention provides compounds of general formula (I) or stereoisomers, tautomers, polymorphs, solvates (e.g. hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof.

The compounds of formula (I) have the following structure:

wherein

e is a bond, C _1-6 Alkyl or C _3-8 A cycloalkyl group;

R ⁴ 、R ⁶ and R ⁷ Each independently selected from hydrogen and C _1-6 Alkyl, halo C _1-6 Alkyl and C _3-6 A cycloalkyl group;

each R is ⁵ Independently selected from hydrogen, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _3-8 Cycloalkyl, -C _1-6 alkyl-C _3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl, -C _1-6 Alkyl-3 to 8 membered heterocycloalkyl, 5 or 6 membered heteroaryl and aryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or selected from halogen, CN, hydroxy, oxo, C (O) OH, C _1-3 Alkyl, halo C _1-3 Alkyl, SO ₃ H、C _1-3 alkyl-O-, halo-C _1-3 alkyl-O-and-SO ₂ -C _1-3 1,2,3 or 4 substituents of alkyl;

p is 0, 1 or 2;

q is 1,2,3, 4,5 or 6;

b is selected from C _6-14 Aryl and a 5 to 14 membered monocyclic or bicyclic heteroaryl comprising 1,2,3, 4 or 5 heteroatoms independently selected from N, O and S, wherein said aryl or heteroaryl is unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: halogen, hydroxy, CN, amino, C _1-6 Alkyl (e.g. methyl, ethyl, isopropyl or tert-butyl), C _1-6 alkyl-O-, C _1-6 alkyl-O-C _1-6 alkyl-O-, halo-C _1-6 Alkyl (e.g. CHF) ₂ ) Halogen substituted C _1-6 alkyl-O-, hydroxy-C _1-6 Alkyl, CN-C _1-6 Alkyl radical, C _3-6 Cycloalkyl and 3 to 6 membered heterocycloalkyl containing 1,2 or 3 heteroatoms independently selected from N, O and S and C _1-6 alkyl-S (O) _p -；

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl or a saturated or partially unsaturated 3 to 10 membered heterocyclyl optionally substituted by oxo; wherein said heteroaryl or heterocyclyl group contains an independently selected group1,2 or 3 heteroatoms from N, O and S; and is

x is selected from N and CRc';

m, n are each independently 0, 1,2,3 or 4;

d is:

z is:

or Rd;

w is selected from N, N-O and CRc';

each Re is independently selected from hydrogen, halogen, hydroxy, CN, C _1-6 Alkyl, halo C _1-6 Alkyl radical, C _1-6 alkyl-O-, halo-C _1-6 alkyl-O-, C _3-8 Cycloalkyl, halo C _3-8 Cycloalkyl and C _6-10 Monocyclic or bicyclic aryl;

with the following conditions:

(1) and ring

The B group not being linked to

The groups are directly adjacent;

(2) when the ring

Is composed of

Or

When R is ² Is not a hydroxyl group; and is

(3) When X is N, the ring

Is not

Wherein from the ring

With C or N ring atoms extending therefrom

Denotes that the C or N atom is directly bonded to the B group from the ring

Extended out

Indicating ring

And with

And bonding the groups.

In some embodiments, R ¹ Selected from: -E-C (O) OR ⁵ and-E-C (O) NR ⁵ R ⁶ (ii) a More preferably, R ¹ is-E-C (O) OR ⁵ 。

In a preferred embodiment, E is a bond.

In some embodiments, R ⁴ 、R ⁶ And R ⁷ Each independently selected from hydrogen, C _1-3 Alkyl, halo C _1-3 Alkyl and cyclopropyl; preferably, R ⁴ 、R ⁶ And R ⁷ Each independently hydrogen.

In some embodiments, each R is ⁵ Independently selected from hydrogen and C _1-6 Alkyl (e.g. C) _1-4 Alkyl, especially C _1-3 Alkyl); more preferably, R ⁵ Selected from hydrogen, methyl and ethyl.

In some embodiments of the invention q is 1,2 or 3, preferably 1.

In a preferred embodiment, R ¹ is-E-C (O) OR ⁵ E is a bond, and R ⁵ Selected from hydrogen and C _1-6 Alkyl (preferably C) _1-4 Alkyl groups). More preferably, R ¹ Selected from C (O) OH, C (O) OCH ₃ 、C(O)OCH ₂ CH ₃ 、C(O)O(CH ₂ ) ₂ CH ₃ And C (O) OCH (CH) ₃ ) ₂ 。

In an embodiment of the compounds of the invention, B is selected from C _6-10 Monocyclic or bicyclic aryl and 5 or 6 membered monocyclic heteroaryl comprising 1,2,3 or 4 heteroatoms independently selected from N, O and S; in particular, said aryl is selected from phenyl; the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl, more particularly, the heteroaryl group is selected from the group consisting of pyridyl and pyrazolyl. Said aryl or heteroaryl being unsubstituted or substituted with 1,2 or 3 substituents independently selected from the group consisting of: c _1-6 Alkyl radicals, e.g. C _1-3 Alkyl, preferably methyl, ethyl or isopropyl; halogen substituted C _1-6 Alkyl radicals, e.g. halogeno C _1-3 Alkyl, preferably CHF ₂ (ii) a And 3 to 6 membered heterocycloalkyl containing 1,2 or 3 heteroatoms independently selected from N, O and S, such as oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, aziridinyl, azetidinyl and pyrrolidinyl, especially oxiranyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, preferably oxetanyl.

In one class of embodiments of the compounds of the present invention, X is N, a ring

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl group or a saturated or partially unsaturated 3 to 10 membered heterocyclyl group optionally substituted by oxo, preferably a 5 or 6 membered heteroaryl group or a saturated or partially unsaturated 4,5 or 6 membered heterocyclyl group optionally substituted by oxo, wherein said heteroaryl or heterocyclyl group comprises 1,2 or 3 heteroatoms independently selected from N, O and S; and is provided with

The attachment to the B group may be through the C ring atom or, where present, through the N ring atom.

In another class of embodimentsWherein X is CRc '(Rc' is preferably H), a ring

Is not provided with

Or

Ring(s)

The method comprises the following steps:

a 5 to 14 membered monocyclic or bicyclic heteroaryl, a partially unsaturated 3 to 10 membered heterocyclyl optionally substituted by oxo, a saturated 3 to 10 membered heterocyclyl substituted by oxo, or an unsubstituted saturated 3 or 5 to 10 membered heterocyclyl, preferably a 5 or 6 membered heteroaryl, a partially unsaturated 4,5 or 6 membered heterocyclyl optionally substituted by oxo, a saturated 4,5 or 6 membered heterocyclyl substituted by oxo, or an unsubstituted saturated 5 or 6 membered heterocyclyl, wherein the heteroaryl or heterocyclyl comprises 1,2 or 3 heteroatoms independently selected from N, O and S; or an unsubstituted saturated 4-membered heterocyclyl, wherein the heterocyclyl contains 1,2 or 3 heteroatoms independently selected from O and S; and is

Preferably, the first and second electrodes are formed of a metal,

selected from:

more preferably still, the first and second liquid crystal compositions are,

selected from:

wherein from the ring

With C or N ring atoms extending therefrom

Denotes that the C or N atom is directly bonded to the B group from the ring

Extended out

Indicating ring

And

and bonding the groups.

In an embodiment of the compounds of the invention, each R is ² Independently selected from hydrogen and C _1-6 Alkyl (e.g. C) _1-4 Alkyl, especially C _1-3 Alkyl groups, such as methyl). In an embodiment of the compounds of the invention, each R is ³ Independently selected from hydrogen, halogen (e.g. fluorine, chlorine, bromine, iodine) and halo C _1-6 Alkyl (e.g. halo C) _1-3 Alkyl radicals, e.g. CF ₃ )。

In some embodiments, m, n are each independently 0, 1 or 2.

In some embodiments of the present invention, the substrate is,

is that

And R is ² Is hydrogen.

In some embodiments, X is N, and

is that

In some embodiments of the present invention, the substrate is,

is unsubstituted

And is

B is selected from: unsubstituted or independently selected from C _1-6 Alkyl (preferably C) _1-4 Alkyl, such as methyl, ethyl, propyl and isopropyl) phenyl, pyridyl and pyrazolyl substituted with 1,2 or 3 substituents;

more preferably, B is selected from: unsubstituted phenyl; an unsubstituted pyridyl group; and

pyrazolyl substituted by 1,2 or 3 methyl, ethyl, propyl or isopropyl groups, e.g.

In embodiments of the compounds of the invention, D is:

in an embodiment of the compounds of the invention, each Ra is independently selected from C _3-6 Cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.

In some embodiments of the compounds of the present invention, Z is

Preferably, Rb and Rc are each independently selected from hydrogen, halogen (e.g., F or Cl), halo C _1-6 Alkyl (e.g. CF) ₃ Or CHF ₂ ) Andhalogen substituted C _1-6 alkyl-O- (e.g. halo C) _1-3 alkyl-O-, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy). Preferably, W is CRc'. Preferably, Rc' is hydrogen.

In an embodiment of the compounds of the invention, Z is Rd. In some embodiments, Rd is selected from C optionally substituted with 1,2 or 3 Re _3-6 Cycloalkyl or C _5-11 A saturated bridge ring system, a saturated fused ring system, or a saturated spiro ring system. In other embodiments, Rd is selected from bicyclo [3.1.0] optionally substituted with 1,2, or 3 Re]Hexyl, spiro [2.3]]Hexyl, bicyclo [3.1.1]Heptyl, spiro [2.5 ]]Octyl, bicyclo [4.1.0]Heptyl, cyclopropyl, cyclohexyl, and cyclopentyl. In some embodiments, each Re is independently selected from hydrogen, halogen, hydroxy, CN, C _1-3 Alkyl, halo C _1-3 Alkyl radical, C _1-3 alkyl-O-, halo-C _1-3 alkyl-O-, C _3-6 Cycloalkyl, halo C _3-6 Cycloalkyl groups and phenyl groups. In other embodiments, Re is independently selected from hydrogen, C _1-3 Alkyl radical, C _3-6 Cycloalkyl (e.g., cyclopropyl) and phenyl.

In an embodiment of the compounds of the invention, the halogen is selected from F, Cl, Br and I, preferably F or Cl.

In an embodiment of the compounds of the invention, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic) or (Id) below:

wherein R is ¹ 、B、R ² 、n、X、R ³ M and D are as defined above.

Preferably, the compounds of general formula (I) of the present invention are selected from:

the compounds of the general formula (I) according to the invention may contain asymmetric or chiral centers and may thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers thereof, as well as mixtures thereof, e.g., racemic mixtures, are intended to form part of the present invention.

Furthermore, the present invention encompasses all diastereomers, including cis-trans (geometric) isomers and conformational isomers. For example, if the compounds of formula (I) contain double bonds or fused rings, the cis and trans forms as well as mixtures thereof are encompassed within the scope of the present invention. In the structures shown herein, all stereoisomers are considered and included as compounds of the present invention if the stereochemistry of any particular chiral atom is not specified. If stereochemistry is indicated with a solid or dashed wedge to indicate a particular configuration, the stereoisomer is so indicated and defined.

The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is intended to encompass both solvated and unsolvated forms.

The compounds of the invention may also exist in different tautomeric forms and all such forms are contemplated to be within the scope of the invention.

It is also to be understood that combinations of any two or more of the embodiments are also included within the scope of the present invention.

Pharmaceutical composition

Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound of general formula (I), or a stereoisomer, a tautomer, a polymorph, a solvate (e.g. a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, a chemically protected form thereof, or a prodrug thereof, according to the invention, as described above, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents, for example, additional therapeutic agents suitable for preventing or treating a disease or disorder mediated by FXR.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered with the active ingredient and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

Therapeutic uses

Another aspect of the invention provides therapeutic uses of the compounds and pharmaceutical compositions.

Thus, in some embodiments, the present invention relates to a method for the prevention or treatment of a disease or disorder mediated by FXR, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of general formula (I) of the present invention, a stereoisomer, a tautomer, a polymorph, a solvate (e.g., a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, a chemically protected form or a prodrug thereof, or a pharmaceutical composition of the present invention.

In other embodiments, the present invention relates to the use of at least one compound of general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, a chemically protected form or a prodrug thereof, or a pharmaceutical composition of the invention, for the preparation of a medicament for the prophylaxis or treatment of a disease or condition mediated by FXR.

Such diseases or conditions mediated by FXR include, but are not limited to:

chronic intrahepatic or certain forms of extrahepatic cholestatic conditions; liver fibrosis; obstructive or chronic inflammatory disorders of the liver; cirrhosis of the liver; fatty liver and complications; cholestatic and fibrotic effects associated with alcohol-induced cirrhosis or with viral infectious forms of hepatitis; liver failure or liver ischemia after partial hepatectomy; chemotherapy-associated steatohepatitis (CASH); acute liver failure;

inflammatory bowel disease, dyslipidemia, atherosclerosis, diabetes and related diseases; lipid and lipoprotein disorders; type II diabetes and clinical complications of type I and type II diabetes, including diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other observed effects of clinically significant long-term diabetes; disorders and diseases caused by chronic fatty and fibrotic properties due to forced lipid, particularly triglyceride, accumulation and subsequent activation of the pro-fibrotic pathways, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); obesity or metabolic syndrome (dyslipidemia, diabetes and the combined condition of abnormally high body mass index);

acute myocardial infarction, acute stroke, or thrombosis as a terminal point of chronic obstructive atherosclerosis; non-malignant hyperproliferative disorders and malignant hyperproliferative disorders, in particular hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, Batt's esophageal cancer and other forms of neoplastic diseases of the gastrointestinal tract and liver.

As used herein, unless otherwise indicated, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing the progression of, the indicated disease or disorder or one or more symptoms of such disease or disorder.

As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The term "therapeutically effective amount" as used herein refers to the amount of a compound that will achieve the above-mentioned therapeutic efficacy when administered.

The dosing regimen may be adjusted to provide the most desirable response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The amount or amount of a compound of the invention in the pharmaceutical composition may be from about 0.01mg to about 1000mg, suitably 0.1 to 500mg, preferably 0.5 to 300mg, more preferably 1 to 150mg, especially 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.

Combination therapy

The compounds of formula (I) may be used alone or in combination with one or more other therapeutic agents suitable for the prevention or treatment of diseases or conditions mediated by FXR. In some embodiments, the compounds of general formula (I) are combined with other therapeutic agents, e.g., having anti-hyperproliferative efficacy, in the pharmaceutical compositions or dosage regimens as a combination therapy. The other therapeutic agent may be, for example, a chemotherapeutic agent. The pharmaceutical composition or other therapeutic agent of the dosing regimen preferably has complementary activities to the compound of formula (I) such that they do not adversely affect each other. Such compounds are suitably present in combination in an amount effective for the intended purpose.

The combination therapy may be administered on a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. Combined administration includes simultaneous administration using separate pharmaceutical compositions or a single pharmaceutical composition comprising a compound of formula (I) and the other therapeutic agent, as well as sequential administration in any order, wherein preferably there is a period of time during which both (or all) active agents exert their biological activity simultaneously.

Suitable dosages for any of the above-mentioned concurrently administered agents are those currently used and may be reduced due to the combined (synergistic) action of the newly identified drug with other therapeutic agents or treatments.

Combination therapy may provide "synergy" and prove "synergistic," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced when the compounds are used separately. When the active ingredient: (1) when co-formulated and administered or delivered simultaneously in a combined unit dose formulation; (2) when delivered alternately or in parallel as separate formulations; or (3) by some other scheme, a synergistic effect may be achieved. When delivered in alternation therapy, a synergistic effect may be achieved when the compounds are administered or delivered sequentially, e.g., by separate injections in separate syringes, by separate pills or capsules, or by separate infusions. Generally in alternation therapy, an effective dose of each active ingredient is administered sequentially, i.e. consecutively, whereas in combination therapy, effective doses of two or more active ingredients are administered together.

In a particular embodiment of treatment, the compounds of general formula (I), stereoisomers, tautomers, polymorphs, solvates (e.g. hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof may be combined with other therapeutic agents such as those described herein, and may also be combined with surgical treatment and radiation therapy. Accordingly, the combination therapy of the present invention comprises the administration of at least one compound of general formula (I), its stereoisomers, tautomers, polymorphs, solvates (e.g. hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, as well as the use of at least one other therapeutic method. The amounts of the compound of formula (I) and the other therapeutic agent and the relative timing of administration are selected to achieve the desired combined therapeutic effect.

Metabolites of compounds of formula (I)

In vivo metabolites of the compounds of general formula (I) as described herein are also within the scope of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the present invention includes metabolites of compounds of formula (I), including compounds made by the process of contacting a compound of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The metabolites are typically produced by preparing the radioisotopes of the invention (e.g. ¹⁴ C or ³ H) Labeled compounds are identified by parenterally administering them to an animal such as rat, mouse, guinea pig, monkey, or human at a detectable dose (e.g., greater than about 0.5mg/kg), metabolizing for a sufficient time (typically about 30 seconds to 30 hours), and isolating their conversion products from urine, blood, or other biological samples. These products are easy to isolate as they are labelled (others are isolated by using antibodies capable of binding epitopes remaining in the metabolite). Metabolite structure is determined in conventional manner, e.g. by MS, LC/MS or NMR analysis. Analysis of the metabolites was performed in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Metabolites, as long as they are not found in vivo, can be used in diagnostic assays to therapeutically administer the compounds of the present invention.

Medicine box

In other embodiments of the invention, "kits" are provided that contain materials useful for treating the above-described diseases or conditions. The kit comprises a container containing a compound of general formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (e.g. a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, or a chemically protected form or prodrug thereof, as a first therapeutic agent, or a pharmaceutical composition of the invention as a first pharmaceutical composition. In some embodiments, the kit may further comprise a label or package insert on or with the container. The term "package insert" refers to instructions typically contained in commercial packages of therapeutic products that contain information regarding indications, usage, dosages, administration, contraindications and/or warnings associated with the use of the therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be made of various materials such as glass and plastic. The container may contain a compound of formula (I) or a formulation thereof effective to treat a condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is for use in treating a selected condition, such as cancer. In addition, the label or package insert can indicate that the patient to be treated is a patient suffering from a disease or condition such as cirrhosis, a hyperproliferative disorder, atherosclerosis, type I diabetes, and the like, and can also indicate that the composition can be used to treat other conditions. In other embodiments, the kit further comprises a second container comprising, as a second therapeutic agent, at least one other therapeutic agent suitable for preventing or treating a disease or condition mediated by FXR, or a pharmaceutical composition comprising the other therapeutic agent, as a second pharmaceutical composition. Thus, in some embodiments, the kit can include instructions for administering the first therapeutic agent or first pharmaceutical composition and the second therapeutic agent or second pharmaceutical composition (if present). For example, if the kit comprises a first composition comprising a compound of formula (I) and a second pharmaceutical composition comprising an additional therapeutic agent, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially or separately to a subject in need thereof. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. The kit may also include other materials desirable to the commercial and user, including other buffers, diluents, fillers, needles and syringes.

In other embodiments, the kit is suitable for delivering a solid oral form of a compound of formula (I), such as a tablet or capsule. Such kits preferably comprise a plurality of unit doses. Such kits may include cards with the dosage positioned for their intended use. One example of such a kit is a "blister pack". Blister packaging is well known in the packaging industry and is widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid may be provided in the form of a number, letter or other indicia or calendar insert, for example, specifying the day of administration in a treatment schedule.

Process for preparing compounds

It is a further object of the present invention to provide a process for the preparation of compounds of the general formula (Ia), (Ib), (Ic) or (Id),

wherein R is ¹ 、B、R ² 、n、X、R ³ M and D are as defined above;

(i) the process for preparing formula (Ia) comprises:

wherein X' is a leaving group (e.g., Cl, Br, I, OMs or OTs); r ^1’ Represents a compound having a removable protecting group and which can be provided with R by removal of said protecting group ¹ A group of (1). In some embodiments, R ^1’ Is R '-OC (O) -, wherein R' is selected from C _1-6 Alkyl and benzyl, preferably C _1-4 Alkyl, in particular methyl, optionally substituted with one or more (e.g. 1,2,3 or 4) substituents independently selected from halogen (e.g. F, Cl, Br or I) and nitro; preferably, R ^1’ Is CH ₃ -OC (O) -. In said embodiment, R ¹ is-E-C (O) OR ⁵ E is a bond and R ⁵ Is hydrogen.

(1) Reacting compound IN-1 with compound IN-2 to give compound IN-3:

the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, dimethylsulfoxide, and any combination thereof, and is preferably dimethylformamide. The reaction is preferably carried out in the presence of a suitable base. The base may be an organic or inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, bicarbonate or acetate, for example lithium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and sodium acetate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably about 40 to 80 c, for example about 60 c. The reaction is preferably carried out for a suitable time (e.g. 8 to 24 hours, such as 10 to 20 hours or 12 to 18 hours) until the reaction is complete.

(2) Subjecting compound IN-3 to a Wittig reaction (Wittig reaction) to obtain compound IN-4:

in the presence of a strong organic base, e.g. an alkali metal hydrocarbyl radical (e.g. C) _1-4 Alkyl, such as butyl, or phenyl) derivatives, preferably n-butyllithium) with a phosphonium salt (e.g. MePh ₃ P ⁺ X” ^- Wherein X' is halogen, preferably Br or I) to give compound IN-4. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dimethylsulfoxide, and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out at a suitable temperature. The temperature is preferably room temperature (20 to 30 ℃). The reaction is preferably carried out for a suitable time (e.g. 1-3h, such as 2 or 2.5h) until the reaction is complete.

(3) Reacting compound IN-5 to give compound IN-6:

compound IN-5 is reacted with, for example, hydroxylamine hydrochloride to give compound IN-6. The reaction is preferably carried out in the presence of a suitable base. The base may be an organic or inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, bicarbonate or acetate, for example lithium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and sodium acetate, preferably sodium acetate. The reaction is preferably carried out in a suitable organic solvent, preferably an alcohol, such as methanol, ethanol or any combination thereof. The reaction is preferably carried out at a suitable temperature (e.g. room temperature). The reaction is preferably carried out for a suitable time until the reaction is complete.

(4) Reacting compound IN-6 to give compound IN-7:

compound IN-6 is reacted with a suitable chlorinating agent, such as N-chlorosuccinimide, to give compound IN-7. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, dimethyl sulfoxide, and any combination thereof, preferably dimethylformamide. The reaction is preferably carried out at a suitable temperature (e.g. room temperature). The reaction is preferably carried out for a suitable time (e.g. 8 to 18 hours or 10 to 12 hours) until the reaction is complete.

(5) Subjecting compound IN-7 to cyclization reaction with compound IN-4 to obtain compound IN-8:

the ring closure reaction is preferably carried out in the presence of a suitable base. Preferably, the base is an organic base, for example an organic amine such as triethylamine, N-diisopropylethylamine, or N-methylmorpholine or pyridine, preferably triethylamine. The reaction is preferably carried out at a suitable temperature (e.g. 0 ℃ or room temperature). The reaction is preferably carried out for a suitable time (e.g. 8 to 18 hours or 10 to 12 hours) until the reaction is complete.

And (6) reacting compound IN-8 to give the compound of formula (Ia):

at the time of removing R ^1’ Having a removable protecting group to provide R ¹ Under conditions such that compound IN-8 is reacted to give the compound of the general formula (Ia). For example, when R is ^1’ Is R '-OC (O) -and R' is as defined above (in this case, R ¹ is-E-C (O) OR ⁵ E is a bond and R ⁵ Is hydrogen), the reaction can be carried out by hydrolysis under acidic conditions or alcoholysis under basic conditions. Preferably, the reaction can be carried out by alcoholysis of the ester in the presence of an alcohol and a base. The alcohol may be, for example, methanol, ethanol, or any combination of the two. The base may be selected from alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dimethylsulfoxide, and any combination thereof, with tetrahydrofuran being preferred. The reaction is preferably carried out at a suitable temperature (e.g. room temperature to 80 ℃, such as 40 to 60 ℃). The reaction is preferably carried out for a suitable time (e.g. 2 to 6 hours, such as 3,4 or 5 hours) until the reaction is complete.

(ii) The process for preparing formula (Ib) comprises:

wherein, X' and R ^1’ As defined above in method (i); PG is a suitable hydroxy protecting group, e.g. C _1-6 Alkyl, benzyl or silyl radicals (e.g. Trimethylsilyl (TMS), Triethylsilyl (TES), tert-butyldimethylsilyl (TBS), Triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS)), especially C _1-4 An alkyl group;

(1) reacting compound IN-9 with compound IN-10 to give compound IN-11:

an azide of formula IN-9 is reacted with an alkyne of formula IN-10 by cycloaddition to produce a 1,2, 3-triazole compound of formula IN-11. Preferably, the reaction is carried out in the presence of a copper catalyst. The copper catalyst may be a cu (i) salt, such as cuprous iodide; or generated in situ from a system of a Cu (II) salt and a reducing agent or from a system of Cu (0) and an oxidizing agent. For example, the Cu (II) salt may be copper sulfate pentahydrate, copper acetate, and the reducing agent includes, but is not limited to, ascorbate salts (e.g., sodium ascorbate, potassium ascorbate), hydrazine hydrate, and Cu (0). Preferably, the reaction is carried out in a system of water and a hydrophilic organic solvent including, but not limited to, acetonitrile, alcohols (e.g., n-butanol, t-butanol, ethanol, and isopropanol), dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and any combination thereof. Preferably, the reaction is carried out at a suitable temperature (e.g. room temperature). The reaction is preferably carried out for a suitable time (e.g. 1 to 3 hours, such as 2 or 2.5 hours) until the reaction is complete.

(2) Deprotecting PG from Compound IN-11 to give Compound IN-12:

under conditions to remove the hydroxy protecting group PG, compound IN-11 is converted to compound IN-12. For example, compound IN-11 is reacted with boron tribromide to remove PG, to give compound IN-12. The reaction is preferably carried out in a suitable organic solvent which may be selected from benzene, toluene and xylene and any combination thereof, for example toluene. The reaction may be carried out at a suitable temperature (e.g. room temperature). The reaction is preferably carried out for a suitable time (e.g. 1 to 3 hours, such as 2 or 2.5 hours) until the reaction is complete.

(3) Reacting compound IN-12 with compound IN-2 to give compound IN-13:

the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, dimethyl sulfoxide, and any combination thereof, preferably dimethylformamide. The reaction is preferably carried out in the presence of a suitable base. The base may be an organic or inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, bicarbonate or acetate, for example lithium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and sodium acetate, preferably potassium carbonate. The reaction is preferably carried out at a suitable temperature, preferably about 40 to 80 c, for example about 60 c. The reaction is preferably carried out for a suitable time (e.g. 2 to 6 hours, such as 3,4 or 5 hours) until the reaction is complete.

And (4) reacting compound IN-13 to give the compound of formula (Ib);

the reaction was carried out as described IN step (6) of the above Process (i) except that the compound IN-13 was used IN place of the compound IN-8 to give the compound of the general formula (Ib).

(iii) The process for preparing formula (Ic) comprises:

wherein X' and R ^1’ As defined above in method (i);

(1) hydrazinolysis of compound IN-14 to give compound IN-15:

for example, compound IN-14 is reacted with hydrazine hydrate IN a suitable organic solvent to give compound IN-15. The organic solvent may be an alcohol, such as methanol, ethanol, or any combination thereof. Preferably, the reaction is carried out at a suitable temperature (e.g. 80 to 120 ℃, such as 90 to 110 ℃). The reaction is preferably carried out for a suitable time (e.g. 1 to 3 hours, such as 2 or 2.5 hours) until the reaction is complete.

(2) Acylating compound IN-15 with compound IN-16 to give compound IN-17:

the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of halogenated hydrocarbons (e.g., dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane), dimethylformamide, dimethylacetamide and any combination thereof, preferably dichloromethane. The reaction is preferably carried out in the presence of a suitable base. Preferably, the base is an organic base, for example an organic amine such as triethylamine, N-diisopropylethylamine, or N-methylmorpholine or pyridine, preferably N, N-diisopropylethylamine. The reaction is preferably carried out at a suitable temperature (e.g. room temperature). The reaction is preferably carried out for a suitable time (e.g., 10 to 24 hours or 12 to 20 hours) until the reaction is complete.

(3) Subjecting compound IN-17 to a cyclization reaction to give compound IN-18:

compound IN-17 is subjected to a cyclization reaction with a suitable dehydrating agent (e.g., phosphorus oxychloride) to give compound IN-18. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from acetonitrile, alcohols (e.g., n-butanol, t-butanol, ethanol, and isopropanol), dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and any combination thereof. The reaction is preferably carried out at a suitable temperature. The reaction is preferably carried out for a suitable time (e.g. 2 to 6 hours, such as 3,4 or 5 hours) until the reaction is complete.

(4) Reacting compound IN-18 with compound IN-2 to give compound IN-19:

the reaction was carried out as described IN step (3) of the above Process (ii) except that the compound IN-18 was used IN place of the compound IN-12 to give the compound IN-19.

And (5) reacting compound IN-19 to give said compound of general formula (Ic):

the reaction was carried out as described IN step (6) of Process (i) above, except that Compound IN-19 was used instead of Compound IN-8, to give the compound of the general formula (Ic).

(iv) The process for preparing the general formula (Id) comprises:

wherein R is ^1’ And X' is as defined in method (i) above and PG is as defined in method (ii) above;

(1) subjecting compound IN-7 to a ring-closing reaction with compound IN-10 to give compound IN-20:

In some cases, the protecting group PG (e.g., a silane group) may be removed during the ring closing reaction.

(2) Reacting compound IN-20 with compound IN-2 to give compound IN-21:

the reaction was carried out as described IN step (3) of the above method (ii) except that the compound IN-12 was replaced with the compound IN-20 to give the compound IN-21.

And (3) reacting compound IN-21 to give the compound of the general formula (Id).

The reaction was carried out as described IN step (6) of Process (i) above except that Compound IN-21 was used instead of Compound IN-8 to give the compound of the general formula (Id).

The term "suitable" as used herein means that the selection of a particular compound or condition will depend on the particular synthetic procedure to be performed and the identity of the molecule or molecules to be transformed, but is within the ability of one skilled in the art. All process/method steps described herein are performed under conditions sufficient to provide the indicated products. Those skilled in the art will appreciate that all reaction conditions (including, for example, reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.) can be varied to optimize the yield of the desired product, and that such variations are within the ability of those skilled in the art.

The examples provide exemplary methods of preparing compounds of formula (I). One skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of formula (I). Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be substituted to provide various derivatives and/or reaction conditions. In addition, many of the example compounds produced by the methods described herein may be further modified using conventional chemistry well known to those skilled in the art, with reference to this disclosure.

In preparing the compounds of formula (I), it may be desirable to protect the remote functional groups (e.g., carboxyl or amino groups) of the intermediates. The need for such protection may vary with the nature of the distal functional group and the conditions of the preparation method. The necessity of such protection is readily determined by the person skilled in the art. For a summary of protecting Groups and their use, see t.w. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

The structure of the compound is determined by nuclear magnetic resonance ¹ H-NMR) or Mass Spectrometry (MS). ¹ The H-NMR shifts (. delta.) are given in parts per million (ppm). Chemical shift is at 10 ^-6 (ppm) is given as a unit.

MS was determined using an Agilent (ESI) mass spectrometer.

Preparation of high performance liquid phase a shimadzu preparative high performance liquid chromatograph was used.

Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and GF 254 (0.4-0.5 mm) was used for separation and purification by thin layer chromatography.

The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS using a developing system of: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, and volume ratio of solvent is regulated according to different polarities of the compounds or by adding triethylamine and the like.

Use of microwave reaction

Initiator + (400W, RT-300 ℃) microwave reactor.

The column chromatography generally uses 200-300 mesh silica gel as a carrier. The system of eluents comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of triethylamine can be added for adjustment.

Unless otherwise specified, the reaction temperatures of the examples are room temperature (20 ℃ C. to 30 ℃ C.).

The reagents used in the present invention are commercially available from Acros Organics, Aldrich Chemical Company, Shanghai Teber Chemical science and technology, Inc., and the like.

In the conventional syntheses as well as in the examples and intermediate syntheses, the abbreviations have the following meanings.

Meaning of abbreviations

DIPEA N, N-diisopropylethylamine

TLC thin layer chromatography

DMF N, N-dimethylformamide

NCS N-chlorosuccinimide

RT (or RT) Room temperature

Preparation of intermediates

Intermediate preparation example 1: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldehyde

2-chloro-4-hydroxybenzaldehyde (2.5g,15.9mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (4.8g,15.9mmol) were dissolved in DMF (50mL), potassium carbonate (6.6g,47.7mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried, and concentrated to obtain the title compound of this step (6g, yield: 89.3%).

The second step is that: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

Methyltriphenylphosphonium bromide (7.7g,23.8mmol) was dissolved in tetrahydrofuran (150mL), n-butyllithium (9.5mL,23.8mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (4.58g,10.8mmol) obtained in the first step in tetrahydrofuran (50mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (4.2g, yield: 92.4%).

Intermediate preparation example 2: preparation of methyl 4- (chloro (hydroxyimino) methyl) benzoate

The first step is as follows: preparation of methyl 4- ((hydroxyimino) methyl) benzoate

Methyl 4-formylbenzoate (10g,59.2mmol), hydroxylamine hydrochloride (6.5g,94.7mmol) and sodium acetate (9.7g,118.4mmol) were added to methanol (100mL) and stirred at room temperature overnight. The reaction solution was poured into water and filtered to obtain the title compound of this step (10g, yield: 94.4%).

The second step: preparation of methyl 4- (chloro (hydroxyimino) methyl) benzoate

The compound (3g,16.8mmol) obtained in the first step was dissolved in DMF (20mL), NCS (2.3g,16.8mmol) was added and stirred at room temperature overnight. Then, the reaction solution was poured into water and filtered to obtain the title compound (2.9g, yield: 81%).

Intermediate preparation example 3: preparation of methyl 3- (chloro (hydroxyimino) methyl) benzoate

The title compound (3.1g, yield: 86.3%) was obtained according to the procedure described in intermediate preparation example 2 using methyl 3-formylbenzoate (10g,59.2mmol) in place of methyl 4-formylbenzoate.

Intermediate preparation example 4: preparation of methyl 6- (chloro (hydroxyimino) methyl) nicotinate

The title compound (95mg, yield: 78.6%) was obtained in a similar manner to the intermediate preparation example 2 except that methyl 6-formylnicotinate (2g,12.1mmol) was used instead of methyl 4-formylbenzoate.

Intermediate preparation example 5: preparation of methyl 2- (chloro (hydroxyimino) methyl) isonicotinate

The title compound (95mg, yield: 78.6%) was obtained in a similar manner to the intermediate preparation example 2 except that methyl 2-formylisonicotinate (2g,12.1mmol) was used instead of methyl 4-formylbenzoate.

Intermediate preparation example 6: preparation of methyl 5- (chloro (hydroxyimino) methyl) nicotinate

The title compound (573mg, yield: 86.9%) was obtained in a similar manner to the intermediate preparation example 2 except that methyl 5-formylnicotinate (500mg,3.03mmol) was used instead of methyl 4-formylbenzoate.

Intermediate preparation example 7: preparation of methyl 5- (chloro (hydroxyimino) methyl) nicotinate

The title compound (810mg, yield: 62.3%) was obtained in a similar manner to the intermediate preparation example 2 using methyl 5-formylpyridine-2-carboxylate (1g,6.06mmol) in place of methyl 4-formylbenzoate.

Intermediate preparation example 8: preparation of 5- (chloro (hydroxyamine) methyl) -1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

The first step is as follows: preparation of 1-isopropyl-1H-pyrazole-3, 5-dicarboxylic acid methyl ester

Methyl 1H-pyrazole-3, 5-dicarboxylate (10.0g,54.3mmol) was dissolved in DMF (50mL), and sodium hydride (3.6g,90mmol) was added portionwise at 0 ℃ and stirred at 0 ℃ for 30 minutes. Then, a solution of isopropyl bromide (10.5g,85.2mmol) in DMF (20mL) was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried and concentrated to obtain the title compound of this step (7.4g, yield: 60.2%).

The second step is that: preparation of 1-isopropyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carboxylic acid

The compound (5.8g,25.6mmol) obtained in the first step was dissolved in methanol (50mL), and a saturated potassium hydroxide solution in methanol (25mL) was added dropwise at 0 ℃ to keep it at 0 ℃ for 4 hours. Then, the reaction solution was adjusted to pH 4 with 2N hydrochloric acid and then terminated. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound of this step (3.8g, yield: 70.4%).

The third step: preparation of 1-isopropyl-3-methyl formate-1H-pyrazole-5-methanol

The compound obtained in the second step (1.7g,8.0mmol) was dissolved in tetrahydrofuran (30mL), borane dimethyl sulfide (20mL) was added in portions, and the reaction was allowed to proceed overnight at room temperature. Then, methanol (10mL) was added to terminate the reaction, and the reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound of this step (1.3g, yield: 81.8%).

The fourth step: preparation of 1-isopropyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carbaldehyde

The compound (3.9g,19.7mmol) obtained in the third step was dissolved in tetrahydrofuran (50mL), and activated manganese dioxide (17.1g,197mmol) was added to the solution to react at 60 ℃ overnight. The reaction solution was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (1.6g, yield: 41.0%).

The fifth step: preparation of 5- (hydroxyaminomethyl) -1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound (800mg,4.08mmol) obtained in the fourth step was dissolved in anhydrous ethanol (20mL), and sodium acetate (463.5mg,5.65mmol) and hydroxylamine hydrochloride (565.6mg,8.14mmol) were added and left overnight at room temperature. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (860mg, yield: 99.8%).

And a sixth step: preparation of 5- (chloro (hydroxyamine) methyl) -1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound (300mg,1.42mmol) obtained in the fifth step was dissolved in DMF (10mL), NCS (208mg,1.55mmol) was added dropwise at 0 ℃ and stirred at room temperature for 6 hours, after which time water was added to terminate the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to give the title compound of this step (320mg, yield: 91.7%).

Intermediate preparation example 9: preparation of methyl 5- (chloro (hydroxyaminomethyl) -1-methyl-1H-pyrazole-3-carboxylate

The first step is as follows: preparation of 1-methyl-1H-pyrazole-3, 5-dicarboxylic acid methyl ester

Methyl 1H-pyrazole-3, 5-dicarboxylate (3.0g,16.3mmol) was dissolved in DMF (50mL), and sodium hydride (1.1g,27.7mmol) was added portionwise at 0 ℃ and stirred at 0 ℃ for 30 minutes. Then, a solution of iodomethane (2.3g,16.3mmol) in DMF (20mL) was added and stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried, and concentrated to obtain the title compound of this step (1.6g, yield: 50.0%).

The second step is that: preparation of 1-methyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carboxylic acid

The compound (1.8g,9.1mmol) obtained in the first step was dissolved in methanol (50mL), and a saturated potassium hydroxide solution in methanol (25mL) was added dropwise at 0 ℃ to keep it at 0 ℃ for 4 hours. Then, the reaction solution was adjusted to pH 4 with 2N hydrochloric acid and then terminated. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound of this step (1.2g, yield: 70.6%).

The third step: preparation of 1-methyl-3-carboxylic acid methyl ester-1H-pyrazole-5-methanol

The compound obtained in the second step (1.7g,9.2mmol) was dissolved in tetrahydrofuran (30mL), borane dimethyl sulfide (20mL) was added in portions, and the reaction was allowed to proceed overnight at room temperature. Then, methanol (10mL) was added to terminate the reaction, and the reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound (177mg, yield: 11.1%) of this step.

The fourth step: preparation of 1-methyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carbaldehyde

The compound (100mg,0.59mmol) obtained in the third step was dissolved in tetrahydrofuran (50mL), and activated manganese dioxide (510.8mg,5.9mmol) was added to the solution, followed by reaction at 60 ℃ overnight. The reaction solution was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (70mg, yield: 70.7%).

The fifth step: preparation of methyl 5- ((hydroxyaminomethyl) -1-methyl-1H-pyrazole-3-carboxylate

The compound (800mg,4.76mmol) obtained in the fourth step was dissolved in anhydrous ethanol (20mL), and sodium acetate (463.0mg,5.64mmol) and hydroxylamine hydrochloride (566.0mg,8.14mmol) were added and left overnight at room temperature. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (860mg, yield: 98.6%).

And a sixth step: preparation of methyl 5- (chloro (hydroxyaminomethyl) -1-methyl-1H-pyrazole-3-carboxylate

The compound (300mg,1.64mmol) obtained in the fifth step was dissolved in DMF (10mL), NCS (207.0mg,1.55mmol) was added dropwise at 0 ℃ and stirred at room temperature for 6 hours, after which time water was added to terminate the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to give the title compound (290mg, yield: 81.2%).

Intermediate preparation example 10: preparation of methyl 5- (chloro (hydroxyamine) methyl) -1-ethyl-1H-pyrazole-3-carboxylate

The first step is as follows: preparation of 1-ethyl-1H-pyrazole-3, 5-dicarboxylic acid methyl ester

Methyl 1H-pyrazole-3, 5-dicarboxylate (4.0g,21.7mmol) was dissolved in DMF (50mL), and sodium hydride (2.5g,62.5mmol) was added in portions at 0 ℃ and stirred at 0 ℃ for 30 min. Then, a solution of bromoethane (2.6g,24.3mmol) in DMF (20mL) was added and stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried and concentrated to obtain the title compound of this step (1.1g, yield: 23.9%).

The second step is that: preparation of 1-ethyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carboxylic acid

The compound (1.8g,8.5mmol) obtained in the first step was dissolved in methanol (50mL), and a saturated potassium hydroxide solution in methanol (25mL) was added dropwise at 0 ℃ to keep it at 0 ℃ for 4 hours. Then, the reaction solution was adjusted to pH 4 with 2N hydrochloric acid and then terminated. The reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound of this step (1.2g, yield: 71.4%).

The third step: preparation of 1-ethyl-3-carboxylic acid methyl ester-1H-pyrazole-5-methanol

The compound obtained in the second step (1.7g,8.6mmol) was dissolved in tetrahydrofuran (30mL), borane dimethyl sulfide (20mL) was added in portions, and the reaction was allowed to proceed overnight at room temperature. Then, methanol (10mL) was added to terminate the reaction, and the reaction mixture was extracted with dichloromethane, washed with saturated brine, dried and concentrated to obtain the title compound (179mg, yield: 11.3%) of this step.

The fourth step: preparation of 1-ethyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carbaldehyde

The compound (0.1g,0.54mmol) obtained in the third step was dissolved in tetrahydrofuran (50mL), and activated manganese dioxide (443.0mg,5.4mmol) was added to the solution, followed by reaction at 60 ℃ overnight. The reaction solution was filtered, the filtrate was collected, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (70mg, yield: 70.8%).

The fifth step: preparation of methyl 5- ((hydroxylamine) methyl) -1-ethyl-1H-pyrazole-3-carboxylate

The compound (800mg,4.39mmol) obtained in the fourth step was dissolved in anhydrous ethanol (20mL), and sodium acetate (463mg,5.65mmol) and hydroxylamine hydrochloride (566mg,8.14mmol) were added and left overnight at room temperature. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (860mg, yield: 99.3%).

And a sixth step: preparation of methyl 5- (chloro (hydroxyamine) methyl) -1-ethyl-1H-pyrazole-3-carboxylate

The compound (300mg,1.52mmol) obtained in the fifth step was dissolved in DMF (10mL), NCS (207mg,1.55mmol) was added dropwise at 0 ℃ and stirred at room temperature for 6 hours, after which time water was added to terminate the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to give the title compound (320mg, yield: 90.9%).

Intermediate preparation example 11: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldoxime chloride

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldehyde oxime

2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldehyde (200mg,0.47mmol) was dissolved in absolute ethanol (10mL), and sodium acetate (50.9mg,0.62mmol) and hydroxylamine hydrochloride (66.0mg,0.95mmol) were added and left overnight at room temperature. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried, and concentrated to obtain the title compound of this step (200mg, yield: 97.1%).

The second step is that: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldoxime chloride

The compound (200mg, 0.46mmol) obtained in the first step was dissolved in DMF (10mL), NCS (80mg,0.60mmol) was added dropwise at 0 ℃ and stirred at room temperature for 6 hours, after which time water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to give the title compound (200mg, yield: 92.2%).

Intermediate preparation example 12: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazol-4-yl) methoxy) benzaldehyde

2-chloro-4-hydroxybenzaldehyde (2g,12.8mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazole (3.5g,12.8mmol) were dissolved in DMF (50mL), potassium carbonate (3.1g,22.3mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (2.5g, yield: 50.0%).

The second step is that: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazole

Methyltriphenylphosphonium bromide (4.2g,11.8mmol) was dissolved in tetrahydrofuran (25mL), n-butyllithium (5.9mL,11.8mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (2.5g,6.4mmol) obtained in the first step in tetrahydrofuran (50mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.1g, yield: 84.0%).

Intermediate preparation example 13: preparation of 4- ((3-chloro-4- (prop-1-en-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

The first step is as follows: preparation of 1- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazol-4-yl) methoxy) phenyl) ethanone

2-chloro-4-hydroxyacetophenone (1g,5.9mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazole (1.8g,5.9mmol) were dissolved in DMF (50mL), potassium carbonate (2.4g,17.6mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (2.1g, yield: 80.8%).

The second step is that: preparation of 4- ((3-chloro-4- (prop-1-en-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

Methyltriphenylphosphonium bromide (4.3g,12.0mmol) was dissolved in tetrahydrofuran (60mL), n-butyllithium (6.0mL,12.0mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (2.6g,5.9mmol) obtained in the first step in tetrahydrofuran (25mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.1g, yield: 80.8%).

Intermediate preparation example 14: preparation of 5-cyclopropyl-3- (2, 6-dichlorophenyl) -4- (((6- (trifluoromethyl) -5-vinylpyridin-2-yl) oxy) methyl) isoxazole

The first step is as follows: preparation of ethyl 6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) nicotinate

Ethyl 6-hydroxy-2-trifluoromethylnicotinate (1g,4.3mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (1.3g,4.3mmol) were dissolved in DMF (50mL), potassium carbonate (3.1g,22.3mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (1.1g, yield: 50.0%).

The second step is that: preparation of (6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) methanol

Lithium aluminum hydride (90.0mg,2.7mmol) was dissolved in anhydrous tetrahydrofuran (10mL) and stirred at 0 ℃ for 15 minutes. Then, a solution of the compound (1.1g,2.2mmol) obtained in the first step in anhydrous tetrahydrofuran (10mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of methanol to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (1.0g, yield: 100%).

The third step: preparation of 6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) nicotinaldehyde

The compound (1.1g,2.4mmol) obtained in the second step was added to anhydrous tetrahydrofuran (20mL), activated manganese dioxide (2.0g,23.0mmol) was added, and after stirring at 60 ℃ for 8 hours, the mixture was filtered, and the filtrate was collected and concentrated to obtain the title compound (1.0g, yield: 99.0%) of this step.

The fourth step: preparation of 5-cyclopropyl-3- (2, 6-dichlorophenyl) -4- (((6- (trifluoromethyl) -5-vinylpyridin-2-yl) oxy) methyl) isoxazole

Methyltriphenylphosphonium bromide (0.86g,2.4mmol) was dissolved in tetrahydrofuran (16mL), n-butyllithium (1.2mL,2.4mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (1.0g,2.2mmol) obtained in the third step in tetrahydrofuran (4mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (0.6g, yield: 60.0%).

Intermediate preparation example 15: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazole

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) benzaldehyde

2-chloro-4-hydroxybenzaldehyde (0.5g,3.2mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazole (1.0g,3.2mmol) were dissolved in DMF (50mL), potassium carbonate (3.1g,22.3mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (1.4g, yield: 100%).

The second step is that: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazole

Methyltriphenylphosphonium bromide (4.2g,11.8mmol) was dissolved in tetrahydrofuran (25mL), n-butyllithium (5.9mL,11.8mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (2.5g,5.9mmol) obtained in the first step in tetrahydrofuran (50mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.1g, yield: 84%).

Intermediate preparation example 16: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) benzaldehyde

2-chloro-4-hydroxybenzaldehyde (0.5g,3.2mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (1.0g,3.2mmol) were dissolved in DMF (50mL), potassium carbonate (3.1g,22.3mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (1.2g, yield: 85.7%).

The second step is that: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole

Methyltriphenylphosphonium bromide (4.2g,11.8mmol) was dissolved in tetrahydrofuran (25mL), n-butyllithium (5.9mL,11.8mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (2.5g,5.7mmol) obtained in the first step in tetrahydrofuran (50mL) was added, and the mixture was stirred at room temperature for 2 hours and then quenched by addition of water. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.1g, yield: 84.0%).

Intermediate preparation example 17: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole

The first step is as follows: preparation of 2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) benzaldehyde

2-chloro-4-hydroxybenzaldehyde (0.5g,3.2mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole (1.0g,3.2mmol) were dissolved in DMF (50mL), potassium carbonate (3.1g,22.3mmol) was added and heated at 60 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, dried and concentrated to obtain the title compound of this step (1.2g, yield: 92.3%).

The second step is that: preparation of 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole

Methyltriphenylphosphonium bromide (4.2g,11.8mmol) was dissolved in tetrahydrofuran (25mL), n-butyllithium (5.9mL,11.8mmol) was added dropwise at-78 deg.C and stirred at that temperature for 1 hour. Then, a solution of the compound (2.5g,5.9mmol) obtained in the first step in tetrahydrofuran (50mL) was added, and the mixture was stirred at room temperature for 2 hours, followed by addition of water to terminate the reaction. The reaction solution was extracted with ethyl acetate, the organic phase was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (2.1g, yield: 84.0%).

Preparation of the Compounds of the invention

Example 1: preparation of 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 1)

The first step is as follows: preparation of methyl 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoate (compound 29)

The compound (300.0mg,1.40mmol) obtained in intermediate preparation 2 and the compound (589.0mg,1.40mmol) obtained in intermediate preparation 1 were added to triethylamine (5mL) and reacted at room temperature for 12 hours. The reaction was poured into water (60mL) and extracted with dichloromethane (40 mL. times.4). The organic phase was washed with saturated brine solution (40 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound of this step (400mg, yield: 47.9%).

MS m/z(ESI):597.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.12(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.40-7.29(m,4H),6.84(d,J＝2.4Hz,1H),6.73-6.70(m,1H),6.02-5.98(m,1H),4.79(s,2H),3.92-3.86(m,4H),3.22-3.16(m,1H),2.16-2.11(m,1H),1.30-1.25(m,2H),1.17-1.12(m,2H)。

The second step is that: preparation of 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 1)

The compound (100.0mg,0.17mmol) obtained in the first step was dissolved in a mixed system of tetrahydrofuran (4mL) and methanol (2mL), and a saturated aqueous solution of potassium hydroxide (1mL) was added to conduct a reaction at 40 ℃ for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate, concentration of the organic phase and purification by preparative thin layer chromatography to give the title compound (60mg, yield: 58.8%).

MS m/z(ESI):583.2[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.12(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),7.40-7.29(m,4H),6.84(d,J＝2.4Hz,1H),6.73-6.70(m,1H),6.02-5.98(m,1H),4.79(s,2H),3.92-3.86(m,1H),3.22-3.16(m,1H),2.16-2.11(m,1H),1.30-1.25(m,2H),1.17-1.12(m,2H)。

Example 2: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 2)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoate (compound 30)

The compound (300.0mg,1.40mmol) obtained in intermediate preparation example 3 and the compound (589.0mg,1.40mmol) obtained in intermediate preparation example 1 were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, the reaction solution was poured into water (60mL), extracted with dichloromethane (40mL x4), and the organic phase was washed with a saturated aqueous saline solution (40mL x 2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to give the title compound of this step (500mg, yield: 60%).

MS m/z(ESI):597.2[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.28-8.27(m,1H),8.16-8.13(m,1H),8.04-8.02(m,1H),7.55-7.51(m,1H),7.40-7.29(m,4H),6.84(d,J＝2.4Hz,1H),6.73-6.70(m,1H),6.02-5.97(m,1H),4.79(s,2H),3.95-3.88(m,4H),3.25-3.19(m,1H),2.18-2.11(m,1H),1.30-1.21(m,2H),1.17-1.12(m,2H)。

The second step is that: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 2)

The compound (100.0mg,0.17mmol) obtained in the first step was dissolved in a mixed system of tetrahydrofuran (4mL) and methanol (2mL), and a saturated aqueous solution of potassium hydroxide (1mL) was added to conduct a reaction at 40 ℃ for 2 hours. Then, the organic solvent was removed, the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (60mg, yield: 58.8%).

MS m/z(ESI):583.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.28-8.27(m,1H),8.16-8.13(m,1H),8.04-8.02(m,1H),7.55-7.51(m,1H),7.40-7.29(m,4H),6.84(d,J＝2.4Hz,1H),6.73-6.70(m,1H),6.02-5.97(m,1H),4.79(s,2H),3.95-3.88(m,1H),3.25-3.19(m,1H),2.18-2.11(m,1H),1.30-1.21(m,2H),1.17-1.12(m,2H)。

Example 3: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 3)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 31)

Methyl 5- (chloro (hydroxyamine) methyl) -1-isopropyl-1H-pyrazole-3-carboxylate (300.0mg,1.22mmol), 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (515.0mg,1.22mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, the reaction solution was poured into water (60mL), extracted with dichloromethane (40mL x4), and the organic phase was washed with a saturated aqueous saline solution (40mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to give the title compound of this step (400mg, yield: 44.7%).

MS m/z(ESI):629.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.62(d,J＝1.6Hz,1H),7.60(s,1H),7.55-7.51(m,1H),7.32(d,J＝8.4Hz,1H),7.04(s,1H),6.99(d,J＝2.4Hz,1H),6.82-6.79(m,1H),5.88-5.83(m,1H),5.35-5.29(m,1H),4.92(s,2H),3.89(s,3H),3.41-3.23(m,1H),2.48-2.42(m,1H),1.43(d,J＝6.4Hz,6H),1.23-1.10(m,5H),

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 3)

The compound (100.0mg,0.16mmol) obtained in the first step was dissolved in a mixed system of tetrahydrofuran (4mL) and methanol (2mL), and a saturated aqueous solution of potassium hydroxide (1mL) was added to conduct a reaction at 40 ℃ for 2 hours. Then, the reaction solution was poured into water (20mL), extracted with dichloromethane (40mL x5), and the organic phase was washed with a saturated aqueous saline solution (40mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (60mg, yield: 61.2%).

MS m/z(ESI):615.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.62(d,J＝1.6Hz,1H),7.60(s,1H),7.55-7.51(m,1H),7.32(d,J＝8.4Hz,1H),7.04(s,1H),6.99(d,J＝2.4Hz,1H),6.82-6.79(m,1H),5.88-5.83(m,1H),5.35-5.29(m,1H),4.92(s,2H),3.41-3.23(m,1H),2.48-2.42(m,1H),1.43(d,J＝6.4Hz,6H),1.23-1.10(m,5H),

Example 4: preparation of 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (compound 4)

The first step is as follows: preparation of 4- (2-chloro-4-methoxyphenyl) -2-methylbut-3-yn-2-ol

Bis (cyanophenyl) palladium dichloride (150mg,0.39mmol) and cuprous iodide (51.6mg,0.27mmol) were added to the reactor, dioxane (20mL) was added, tri-tert-butylphosphine (0.2mL,0.85mmol) and diisopropylamine (2.1mL,14.9mmol) were added under nitrogen, and the compounds 1-bromo-2-chloro-4-methoxybenzene (3g,13.6mmol) and 2-methylbut-3-yn-2-ol (1.56mL,16.1mmol) were added. The mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (2.5g, yield: 83.3%).

The second step is that: preparation of 2-chloro-1-ethynyl-4-methoxybenzene

The compound (2.0g,8.92mmol) obtained in the first step was dissolved in toluene (40mL), and sodium hydroxide (360mg,9.0mmol) was added and heated under reflux for 3 hours under nitrogen. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried, concentrated, and the residue was purified by silica gel column chromatography to give the title compound of this step (1.2g, yield: 81.1%).

The third step: preparation of 3-azido methyl benzoate

Methyl 3-aminobenzoate (2.0g,13.23mmol) was dissolved in water (27mL), concentrated hydrochloric acid (4.5mL) was added, then an aqueous solution (5mL) of sodium nitrite (910mg,13.10mmol) was added, the mixture was stirred for 10 minutes, and an aqueous solution (5mL) of sodium azide (0.95g,14.55mmol) was added. The mixture was stirred at 0 ℃ until TLC showed the starting material reaction was complete. Ethyl acetate was added, and the ethyl acetate layer was washed with water, then dried and concentrated to give the title compound of this step (2g, yield: 98.0%).

The fourth step: preparation of methyl 3- (4- (2-chloro-4-methoxyphenyl) -1H-1,2, 3-triazol-1-yl) benzoate

The compound (319.8mg,1.8mmol) obtained in the third step, 2-chloro-1-ethynyl-4-methoxybenzene (300mg,1.8mmol) and copper sulfate pentahydrate (28.7mg,0.18mmol) were dissolved in water (8mL) and acetonitrile (4mL), followed by addition of hydrazine hydrate (87.5. mu.L, 1.8mmol), and the reaction was stirred at room temperature for 2 hours. The solid was filtered, washed with water, and dried to give the title compound of this step (100mg, yield: 0.16%).

The fifth step: preparation of methyl 3- (4- (2-chloro-4-hydroxyphenyl) -1H-1,2, 3-triazol-1-yl) benzoate

The compound (100mg,0.29mmol) obtained in the fourth step was dissolved in toluene (2mL), and boron tribromide (145mg,0.58mmol) was added dropwise over an ice bath. The mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried, concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (50mg, yield: 83.3%).

And a sixth step: preparation of methyl 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1H-1,2, 3-triazol-1-yl) benzoate (compound 32)

The compound (50mg,0.15mmol) obtained in the fifth step was dissolved in DMF (2mL), potassium carbonate (61.8mg,0.45mmol) was added, followed by 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (45mg,0.15 mmol). The mixture was stirred at 60 ℃ for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried and concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (70mg, yield: 78.3%).

MS m/z(ESI):595.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.58(s,1H),8.46(s,1H),8.20-8.14(m,3H),7.71-7.67(m,1H),7.43-7.41(m,2H),7.36-7.32(m,1H),6.93(m,1H),6.88-6.85(m,1H),4.86(s,2H),3.91(s,3H),1.33-1.15(m,5H)。

The seventh step: preparation of 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1H-1,2, 3-triazol-1-yl) benzoic acid (compound 4)

The compound (70mg,0.12mmol) obtained in the sixth step was dissolved in tetrahydrofuran (2mL) and methanol (1mL), followed by addition of potassium hydroxide (33mg,0.59 mmol). The mixture was stirred at 60 ℃ for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried and concentrated, and the residue was purified by preparation of a thin layer chromatography plate to give the title compound (30mg, yield: 43.0%).

MS m/z(ESI):581.0[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.58(s,1H),8.46(s,1H),8.20-8.14(m,3H),7.71-7.67(m,1H),7.43-7.41(m,2H),7.36-7.32(m,1H),6.93(m,1H),6.88-6.85(m,1H),4.86(s,2H),1.33-1.15(m,5H)。

Example 5: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) benzoic acid (compound 5)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4-hydroxyphenyl) isoxazol-3-yl) benzoate

(3-chloro-4-ethynylphenoxy) tert-butyldimethylsilane (200mg,0.75mmol) and methyl 3- (chloro (hydroxyimino) methyl) benzoate (256mg,1.2mmol) were dissolved in dichloromethane (20mL), triethylamine (303mg,3mmol) was added, and the mixture was stirred at room temperature for 4 hours. Then, the reaction solution was evaporated to dryness and purified by preparation of a thin layer chromatography plate to obtain the title compound of this step (224mg, yield: 90.7%).

The second step is that: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) benzoate (compound 33)

The compound (224mg,0.68mmol) obtained in the first step and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (206mg,0.68mmol) were dissolved in DMF (20mL), and potassium carbonate (282mg,2.04mmol) was added and heated at 60 ℃ overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, then dried, concentrated, and then purified by preparative thin layer chromatography to give the title compound of this step (95mg, yield: 23.5%).

MS m/z(ESI):595.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.47(s,1H),8.15-8.07(m,2H),7.83(d,J＝8.8Hz,1H),7.65-7.53(m,5H),7.17(d,J＝2.4Hz,1H),7.00-6.97(m,1H),5.04(s,2H),3.88(s,3H),2.55-2.52(m,1H),1.23-1.15(m,4H)。

The third step: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) benzoic acid (compound 5)

The compound (95mg,0.16mmol) obtained in the second step was dissolved in methanol (10mL), and a saturated aqueous solution (1mL) of potassium hydroxide was added to react at 40 ℃ for 2 hours. Then, the organic solvent was removed, the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (44mg, yield: 50%).

MS m/z(ESI):581.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.47(s,1H),8.15-8.07(m,2H),7.83(d,J＝8.8Hz,1H),7.65-7.53(m,5H),7.17(d,J＝2.4Hz,1H),7.00-6.97(m,1H),5.04(s,2H),2.55-2.52(m,1H),1.23-1.15(m,4H)。

Example 6: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,3, 4-oxadiazol-2-yl) benzoic acid (compound 6)

The first step is as follows: preparation of 2-chloro-4-hydroxybenzoyl hydrazine

Methyl 2-chloro-4-hydroxybenzoate (2g,10.8mmol) was dissolved in methanol (15mL), followed by hydrazine hydrate (5 mL). The mixture was stirred at 90 ℃ for 2 hours. After concentration, the title compound of this step was obtained (2g, yield: 100.0%).

The second step is that: preparation of methyl 3- (2- (2-chloro-4-hydroxybenzoyl) hydrazinocarbonyl) benzoate

The compound (200mg,1.1mmol) obtained in the first step was dissolved in dichloromethane (4mL), DIPEA (283.8mg,2.2mmol) was added, and then a solution of methyl 3- (chlorocarbonyl) benzoate (200mg,1.1mmol) in dichloromethane (2mL) was added dropwise. The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the mixture, and the dichloromethane layer was washed with water, then dried, concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (300mg, yield: 78.5%).

The third step: preparation of methyl 3- (5- (2-chloro-4-hydroxyphenyl) -1,3, 4-oxadiazol-2-yl) benzoate

The compound obtained in the second step (50mg,0.14mmol) was dissolved in acetonitrile (3mL), followed by addition of phosphorus oxychloride (1 mL). The mixture was heated to reflux for 4 hours. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried, concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (10mg, yield: 22%).

The fourth step: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,3, 4-oxadiazol-2-yl) benzoate (Compound 34)

The compound (10mg,0.03mmol) obtained in the third step was dissolved in DMF (2mL), potassium carbonate (8.16mg,0.06mmol) was added, followed by 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (9.5mg,0.03 mmol). The mixture was stirred at 60 ℃ for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried and concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (15mg, yield: 84%).

MS m/z(ESI):596.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.82(s,1H),8.41-8.39(m,1H),8.30-8.28(m,1H),8.01-7.98(m,1H),7.69-7.66(m,1H),7.43-7.41(m,2H),7.37-7.33(m,1H),6.99(m,1H),6.88-6.84(m,1H),4.90(s,2H),3.90(s,3H),1.33-1.18(m,5H)。

The fifth step: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,3, 4-oxadiazol-2-yl) benzoic acid (compound 6)

The compound (15mg,0.025mmol) obtained in the fourth step was dissolved in tetrahydrofuran (2mL) and methanol (1mL), followed by addition of potassium hydroxide (4.8mg,0.086 mmol). The mixture was stirred at 60 ℃ for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with water, then dried and concentrated, and the residue was purified by preparation of a thin layer chromatography plate to give the title compound (10mg, yield: 43.0%).

MS m/z(ESI):582.0[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.82(s,1H),8.41-8.39(m,1H),8.30-8.28(m,1H),8.01-7.98(m,1H),7.69-7.66(m,1H),7.43-7.41(m,2H),7.37-7.33(m,1H),6.99(m,1H),6.88-6.84(m,1H),4.90(s,2H),1.33-1.18(m,5H)。

Example 7: preparation of 6- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) nicotinic acid (compound 7)

The first step is as follows: preparation of methyl 6- (5- (2-chloro-4-hydroxyphenyl) isoxazol-3-yl) nicotinate

(3-chloro-4-ethynylphenoxy) tert-butyldimethylsilane (66mg,0.41mmol) and the compound obtained in intermediate preparation example 4 (166mg,0.81mmol) were dissolved in dichloromethane (5mL), triethylamine (124mg,1.23mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was then evaporated to dryness and purified by preparation of a thin layer chromatography plate to obtain the title compound of this step (60mg, yield: 43.9%).

The second step is that: preparation of methyl 6- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) nicotinate (compound 35)

The compound obtained in the first step (60mg,0.18mmol) and 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (67mg,0.22mmol) were dissolved in DMF (5mL), potassium carbonate (50mg,0.36mmol) was added and heated at 60 ℃ overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, then dried, concentrated, and purified by preparative thin layer chromatography to give the title compound of this step (27mg, yield: 27.8%).

MS m/z(ESI):596.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:9.21(m,1H),8.46-8.44(m,1H),8.22(d,J＝8.0Hz,1H),7.87(d,J＝8.8Hz,1H),7.65-7.49(m,4H),7.19(d,J＝2.4Hz,1H),7.01-6.98(m,1H),5.04(s,2H),3.87(s,3H),2.53-2.51(m,1H),1.23-1.13(m,4H)。

The third step: preparation of 6- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) isoxazol-3-yl) nicotinic acid (compound 7)

The compound (27mg,0.05mmol) obtained in the second step was dissolved in methanol (5mL), and a saturated aqueous solution of potassium hydroxide (0.5mL) was added to react at 40 ℃ for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (19mg, yield: 60%).

MS m/z(ESI):582.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:13.61(s,1H),9.21(m,1H),8.46-8.44(m,1H),8.22(d,J＝8.0Hz,1H),7.87(d,J＝8.8Hz,1H),7.65-7.49(m,4H),7.19(d,J＝2.4Hz,1H),7.01-6.98(m,1H),5.04(s,2H),2.53-2.51(m,1H),1.23-1.13(m,4H)。

Example 8: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) nicotinic acid (compound 8)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) nicotinate (compound 36)

The compound (50mg,0.23mmol) obtained in intermediate preparation example 6 and the compound (63mg,0.15mmol) obtained in intermediate preparation example 1 were added to triethylamine (5mL) and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound of this step (96mg, yield: 71.1%).

MS m/z(ESI):598.0[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.81(d,J＝8.0Hz,1H),8.32(s,1H),7.87-7.86(m,1H),7.61-7.51(m,3H),7.33(d,J＝8.0Hz,1H),7.00(d,J＝4.0Hz,1H),6.82-6.79(m,1H),6.00-5.95(m,1H),4.93(s,2H),4.02-3.95(m,1H),3.89(s,3H),3.38-3.32(m,1H),2.48-2.44(m,1H),1.21-1.10(m,4H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) nicotinic acid (compound 8)

The compound (96mg,0.16mmol) obtained in the first step was dissolved in a mixed solvent of methanol (4mL) and tetrahydrofuran (2mL), and a saturated aqueous solution of sodium hydroxide (1mL) was added to react at 60 ℃ for 2 hours. Then, the organic solvent was distilled off, the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (73mg, yield: 77.8%).

MS m/z(ESI):584.2[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:14.00(s,1H),8.81(d,J＝8.0Hz,1H),8.32(s,1H),7.87-7.86(m,1H),7.61-7.51(m,3H),7.33(d,J＝8.0Hz,1H),7.00(d,J＝4.0Hz,1H),6.82-6.79(m,1H),6.00-5.95(m,1H),4.93(s,2H),4.02-3.95(m,1H),3.38-3.32(m,1H),2.48-2.44(m,1H),1.21-1.10(m,4H)。

Example 9: preparation of 2- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) isonicotinic acid (compound 9)

The first step is as follows: preparation of methyl 2- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) isonicotinate (compound 37)

The compound (50mg,0.23mmol) obtained in intermediate preparation example 5 and the compound (63mg,0.15mmol) obtained in intermediate preparation example 1 were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, the reaction solution was concentrated under reduced pressure and purified by preparative thin layer chromatography to give the title compound of this step (54mg, yield: 23.7%).

MS m/z(ESI):598.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:9.04(s,1H),8.87(s,1H),8.43(s,1H),7.61-7.51(m,3H),7.34(d,J＝8.0Hz,1H),7.03-7.01(m,1H),6.82-6.79(m,1H),5.95-5.90(m,1H),4.92(s,2H),4.02-3.95(m,1H),3.89(s,3H),3.44-3.38(m,1H),2.50-2.44(m,1H),1.25-1.10(m,4H)。

The second step is that: preparation of 2- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) isonicotinic acid (compound 9)

The compound (54mg,0.09mmol) obtained in the first step was dissolved in a mixed solvent of methanol (2mL) and tetrahydrofuran (1mL), and a saturated aqueous solution of sodium hydroxide (0.5mL) was added to conduct a reaction at 60 ℃ for 2 hours. Then, the organic solvent was distilled off, the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (37mg, yield: 66.7%).

MS m/z(ESI):584.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:9.04(s,1H),8.87(s,1H),8.43(s,1H),7.61-7.51(m,3H),7.34(d,J＝8.0Hz,1H),7.01-7.03(m,1H),6.82-6.79(m,1H),5.95-5.90(m,1H),4.92(s,2H),4.02-3.95(m,1H),3.44-3.38(m,1H),2.50-2.44(m,1H),1.25-1.10(m,4H)。

Example 10: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 10)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 56)

4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole (108mg,0.26mmol) and methyl 5- (chloro (hydroxyamino) methyl) -1-isopropyl-1H-pyrazole-3-carboxylate (100mg,0.40mmol) were dissolved in dichloromethane (3mL), triethylamine (3mL) was added, and the reaction was carried out at room temperature for 12 hours. Then, the reaction solution was poured into water (60mL), extracted with dichloromethane (40mL x4), and the organic phase was washed with a saturated aqueous saline solution (40mL x 2), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo to give the title compound of this step (30mg, yield: 12.5%).

MS m/z(ESI):627.0[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:7.52-7.46(m,2H),7.36-7.26(m,3H),6.91(s,1H),6.86(d,J＝4.0Hz,1H),6.75-6.73(m,1H),6.62-6.26(m,1H),5.95-5.90(m,1H),5.55-5.48(m,1H),4.88(s,2H),3.90-3.83(m,1H),3.80(s,3H),3.21-3.15(m,1H),2.16-2.09(m,1H),1.57(s,3H),1.55(s,3H),1.26-1.22(m,2H),1.15-1.10(m,2H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 10)

The compound (30mg,0.05mmol) obtained in the first step was dissolved in methanol (5mL), and a saturated aqueous solution (1mL) of sodium hydroxide was added to the solution to react at 60 ℃ for 2 hours. Then, the organic solvent was distilled off, the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, extracted with ethyl acetate, and the organic phase was concentrated and purified by preparation of thin layer chromatography to give the title compound (7mg, yield: 20%).

MS m/z(ESI):613.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:7.52-7.46(m,2H),7.36-7.26(m,3H),6.91(s,1H),6.86(d,J＝4.0Hz,1H),6.75-6.73(m,1H),6.62-6.26(m,1H),5.95-5.90(m,1H),5.55-5.48(m,1H),4.88(s,2H),3.90-3.83(m,1H),3.21-3.15(m,1H),2.16-2.09(m,1H),1.57(s,3H),1.55(s,3H),1.26-1.22(m,2H),1.15-1.10(m,2H)。

Example 11: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,2, 4-oxadiazol-3-yl) benzoic acid (compound 57)

The first step is as follows: preparation of methyl 3- (N-hydroxycarbamimidoyl) benzoate

Methyl 3-cyanobenzoate (3g,18.6mmol) and hydroxylamine hydrochloride (1.5g,22.3mmol) were dissolved in ethanol (50mL), and potassium hydroxide (1.2g,22.3mmol) was added to react at 90 ℃ for 2 hours. The filtrate was evaporated to dryness while it was still hot, and purified by preparative high performance liquid chromatography to give the title compound of this step (2.8g, yield: 77.8%).

The second step is that: preparation of methyl 3- (5- (2-chloro-4-hydroxyphenyl) -1,2, 4-oxadiazol-3-yl) benzoate

The compound (113mg,0.58mmol) obtained in the first step and 2-chloro-4-hydroxybenzoyl chloride (222mg,1.16mmol) were dissolved in pyridine (5mL) and heated at 90 ℃ overnight. The reaction solution was cooled, diluted with ethyl acetate, and washed with dilute hydrochloric acid. The organic phase was concentrated, and the residue was purified by preparative thin layer chromatography to give the title compound of this step (90mg, yield: 46.6%).

The third step: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,2, 4-oxadiazol-3-yl) benzoate (Compound 65)

The compound obtained in the second step (90mg,0.27mmol), 4- (chloromethyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (97mg,0.32mmol) and potassium carbonate (75mg,0.54mmol) were added to DMF (5mL) and heated at 60 ℃ overnight. The reaction solution was extracted with water and ethyl acetate, the organic phase was washed with water and then concentrated, the solvent was distilled off, and the obtained residue was purified by preparative thin layer chromatography to give the title compound of this step (140mg, yield: 87%).

MS m/z(ESI):596.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.62(s,1H),8.24-8.11(m,3H),7.70-7.54(m,4H),7.24(s,1H),7.05-7.02(m,1H),5.09(s,2H),3.89(s,3H),2.53-2.51(m,1H),1.24-1.16(m,4H)。

The fourth step: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -1,2, 4-oxadiazol-3-yl) benzoic acid (compound 57)

The compound (140mg,0.23mmol) obtained in the third step was dissolved in methanol (4mL) and tetrahydrofuran (2mL), and an aqueous solution of sodium hydroxide (18mg,0.46mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (80mg, yield: 59.7%).

MS m/z(ESI):582.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.02(s,1H),8.62(s,1H),8.24-8.11(m,3H),7.70-7.54(m,4H),7.24(s,1H),7.05-7.02(m,1H),5.09(s,2H),2.53-2.51(m,1H),1.24-1.16(m,4H)。

Example 12: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-methyl-1H-pyrazole-3-carboxylic acid (compound 20)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-methyl-1H-pyrazole-3-carboxylate (compound 47)

Methyl 5- (chloro (hydroxyimino) methyl) -1-methyl-1H-pyrazole-3-carboxylate (0.7g,3.2mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (1.1g,2.6mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (0.5g, yield: 32.1%).

MS m/z(ESI):601.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.61-7.30(m,4H),6.98(s,1H),6.81-6.78(m,2H),5.87-5.82(m,1H),5.55-5.48(m,1H),5.33-5.31(m,1H),4.92(s,2H),4.06(s,3H),3.89(s,3H),2.03-1.96(m,1H),1.19-1.03(m,4H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-methyl-1H-pyrazole-3-carboxylic acid (compound 20)

The compound (0.3g,0.5mmol) obtained in the first step was dissolved in methanol (2mL) and tetrahydrofuran (4mL), and an aqueous solution of sodium hydroxide (40mg,1mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound of this step (58mg, yield: 19.7%).

MS m/z(ESI):587.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.01(s,1H),7.61-7.30(m,4H),6.98(s,1H),6.81-6.78(m,2H),5.87-5.82(m,1H),5.55-5.48(m,1H),5.33-5.31(m,1H),4.92(s,2H),4.06(s,3H),2.03-1.96(m,1H),1.19-1.03(m,4H)。

Example 13: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl)) methoxy) phenyl) 4, 5-dihydroisoxazol-3-yl) -picolinic acid (compound 21)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -picolinate (compound 48)

Methyl 5- (chloro (hydroxyimino) methyl) picolinate (200mg,0.93mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (310mg,0.74mmol) were added to triethylamine (15mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (200mg, yield: 45.1%).

MS m/z(ESI):598.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.77(s,1H),8.01-6.99(m,7H),6.82-6.79(m,1H),5.56-5.53(m,1H),4.92(s,2H),3.87(s,3H),3.44-3.38(m,1H),3.38-3.08(m,1H),1.26-1.10(m,5H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -picolinic acid (compound 21)

The compound (200mg,0.33mmol) obtained in the first step was dissolved in methanol (2mL) and tetrahydrofuran (4mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound of this step (170mg, yield: 88.1%).

MS m/z(ESI):584.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.77(s,1H),8.01-6.99(m,7H),6.82-6.79(m,1H),5.56-5.53(m,1H),4.92(s,2H),3.44-3.38(m,1H),3.38-3.08(m,1H),1.26-1.10(m,5H)。

Example 14: preparation of 3- (3- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl)) methoxy) phenyl) -4, 5-dihydroisoxazol-5-yl) benzoic acid (compound 22)

3-vinyl benzoic acid (100mg,0.67mmol) and 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -N-chlorobenzeneoxime chloride (300mg,0.64mmol) were added to triethylamine (10mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (50mg, yield: 13.4%).

MS m/z(ESI):583.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.97-7.89(m,2H),7.63-7.48(m,6H),7.04(s,1H),6.87-6.84(m,1H),5.82-5.78(m,1H),4.98(s,2H),3.95-3.88(m,1H),3.43-3.36(m,1H),1.29-1.12(m,5H)。

Example 15: preparation of 3- (5- (6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 24)

The first step is as follows: preparation of methyl 3- (5- (6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) -4, 5-dihydroisoxazol-3-yl) benzoate (Compound 51)

Methyl 3- (chloro (hydroxyimino) methyl) benzoate (150mg,0.70mmol) and 5-cyclopropyl-3- (2, 6-dichlorophenyl) -4- (((6- (trifluoromethyl) -5-vinylpyridin-2-yl) oxy) methyl) isoxazole (300mg,0.66mmol) were added to triethylamine (10mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (300mg, yield: 71.9%).

MS m/z(ESI):632.4[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.24(s,1H),8.01-7.36(m,7H),6.95-6.93(m,1H),5.94(t,J＝9.2Hz,1H),5.30(s,2H),4.01-3.94(m,1H),3.89(s,3H),3.41-3.35(m,1H),1.36-1.07(m,5H)。

The second step is that: preparation of 3- (5- (6- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 24)

The compound (300mg,0.47mmol) obtained in the first step was dissolved in methanol (3mL) and tetrahydrofuran (6mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (200mg, yield: 68.8%).

MS m/z(ESI):618.4[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.02(s,1H),8.24(s,1H),8.01-7.36(m,7H),6.95-6.93(m,1H),5.94(t,J＝9.2Hz,1H),5.30(s,2H),4.01-3.94(m,1H),3.41-3.35(m,1H),1.36-1.07(m,5H)。

Example 16: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 25)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoate (compound 52)

Methyl 3- (chloro (hydroxyamino) methyl) benzoate (52mg,0.24mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole (100mg,0.24mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (130mg, yield: 91%).

MS m/z(ESI):595.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),7.93-7.91(m,1H),7.62-6.82(m,10H),5.90-5.85(m,1H),4.96(s,2H),3.98-3.91(m,1H),3.87(s,3H),3.32-3.26(m,1H),1.17-1.06(m,5H)。

The second step is that: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 25)

The compound (130mg,0.22mmol) obtained in the first step was dissolved in methanol (3mL) and tetrahydrofuran (6mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (50mg, yield: 39.1%).

MS m/z(ESI):581.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),7.93-7.91(m,1H),7.62-6.82(m,10H),5.90-5.85(m,1H),4.96(s,2H),3.98-3.91(m,1H),3.32-3.26(m,1H),1.17-1.06(m,5H)。

Example 17: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-ethyl-1H-pyrazole-3-carboxylic acid (compound 27)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-ethyl-1H-pyrazole-3-carboxylate (compound 54)

Methyl 5- (chloro (hydroxyimino) methyl) -1-ethyl-1H-pyrazole-3-carboxylate (1.4g,6.1mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (2.2g,5.2mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (1.0g, yield: 31.3%).

MS m/z(ESI):615.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.61-7.51(m,3H),7.31(d,J＝8.4Hz,1H),6.99-6.79(m,3H),5.88-5.84(m,1H),4.92(s,2H),4.48(t,J＝6.4Hz,2H),3.89(s,3H),3.95-3.88(m,1H),2.48-2.41(m,1H),1.33-1.10(m,8H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-ethyl-1H-pyrazole-3-carboxylic acid (compound 27)

The compound (0.6g,0.97mmol) obtained in the first step was dissolved in methanol (2mL) and tetrahydrofuran (4mL), and an aqueous solution of sodium hydroxide (40mg,1mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (58mg, yield: 100%).

MS m/z(ESI):601.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.01(s,1H),7.61-7.51(m,3H),7.31(d,J＝8.4Hz,1H),6.99-6.79(m,3H),5.88-5.84(m,1H),4.92(s,2H),4.48(t,J＝6.4Hz,2H),3.95-3.88(m,1H),2.48-2.41(m,1H),1.33-1.10(m,8H)。

Example 18: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 58)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoate (compound 66)

Methyl 3- (chloro (hydroxyimino) methyl) benzoate (200mg,0.94mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (400mg,0.92mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (180mg, yield: 32%).

MS m/z(ESI):613.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),7.92-7.90(m,1H),7.67-7.49(m,5H),7.36-7.32(m,2H),7.03(d,J＝2.4Hz,1H),6.87-6.84(m,1H),5.90-5.86(m,1H),4.95(s,2H),3.99-3.92(m,1H),3.89(s,3H),3.33-3.26(m,1H),1.25-1.07(m,5H)。

The second step is that: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 58)

The compound (180mg,0.29mmol) obtained in the first step was dissolved in methanol (3mL) and tetrahydrofuran (6mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (100mg, yield: 56.9%).

MS m/z(ESI):599.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.03(s,1H),8.15(s,1H),7.92-7.90(m,1H),7.67-7.49(m,5H),7.36-7.32(m,2H),7.03(d,J＝2.4Hz,1H),6.87-6.84(m,1H),5.90-5.86(m,1H),4.95(s,2H),3.99-3.92(m,1H),3.33-3.26(m,1H),1.25-1.07(m,5H)。

Example 19: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 59)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoate (compound 67)

Methyl 3- (chloro (hydroxyimino) methyl) benzoate (200mg,0.94mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (395mg,0.94mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (200mg, yield: 35.7%).

MS m/z(ESI):597.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.18(s,1H),7.95-7.87(m,2H),7.78-7.55(m,4H),7.37-7.31(m,2H),7.02(d,J＝2.4Hz,1H),6.85-6.83(m,1H),5.89-5.85(m,1H),4.88(s,2H),3.98-3.91(m,1H),3.89(s,3H),3.33-3.25(m,1H),1.19-1.11(m,5H)。

The second step: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 59)

The compound (200mg,0.34mmol) obtained in the first step was dissolved in methanol (3mL) and tetrahydrofuran (6mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (100mg, yield: 50.5%).

MS m/z(ESI):583.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:8.18(s,1H),7.95-7.87(m,2H),7.78-7.55(m,4H),7.37-7.31(m,2H),7.02(d,J＝2.4Hz,1H),6.85-6.83(m,1H),5.89-5.85(m,1H),4.88(s,2H),3.98-3.91(m,1H),3.33-3.25(m,1H),1.19-1.11(m,5H)。

Example 20: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 60)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 68)

Methyl 5- (chloro (hydroxyimino) methyl) -1-methyl-1H-pyrazole-3-carboxylate (200mg,0.81mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole (301mg,0.69mmol) were added to triethylamine (15mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (300mg, yield: 67.4%).

MS m/z(ESI):645.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.68-7.50(m,4H),7.35(d,J＝4.4Hz,1H),7.06(s,1H),7.05(s,1H),6.89-6.85(m,1H),5.90-5.85(m,1H),5.34-5.31(m,1H),4.96(s,2H),3.97-3.90(m,1H),3.89(s,3H),2.44-2.40(m,1H),1.42(d,J＝6.8Hz,6H),1.18-1.08(m,5H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 60)

The compound (300mg,0.47mmol) obtained in the first step was dissolved in methanol (4mL) and tetrahydrofuran (8mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (240mg, yield: 81%).

MS m/z(ESI):631.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.03(s,1H),7.68-7.50(m,4H),7.35(d,J＝4.4Hz,1H),7.06(s,1H),7.05(s,1H),6.89-6.85(m,1H),5.90-5.85(m,1H),5.34-5.31(m,1H),4.96(s,2H),3.97-3.90(m,1H),2.44-2.40(m,1H),1.42(d,J＝6.8Hz,6H),1.18-1.08(m,5H)。

Example 21: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 61)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 69)

Methyl 5- (chloro (hydroxyimino) methyl) -1-methyl-1H-pyrazole-3-carboxylate (250mg,1.02mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazole (400mg,0.95mmol) were added to triethylamine (15mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (300mg, yield: 50.2%).

MS m/z(ESI):629.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.90-7.56(m,4H),7.56(d,J＝4.0Hz,1H),7.04(s,1H),7.00(s,1H),6.87-6.84(m,1H),5.88-5.83(m,1H),5.33-5.28(m,1H),4.89(s,2H),3.96-3.89(m,1H),3.88(s,3H),2.47-2.40(m,1H),1.42(d,J＝6.8Hz,6H),1.19-1.08(m,5H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 61)

The compound (300mg,0.48mmol) obtained in the first step was dissolved in methanol (4mL) and tetrahydrofuran (8mL), and an aqueous solution of sodium hydroxide (32.0mg,0.80mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (260mg, yield: 88.1%).

MS m/z(ESI):615.0[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.01(s,1H),7.90-7.56(m,4H),7.56(d,J＝4.0Hz,1H),7.04(s,1H),7.00(s,1H),6.87-6.84(m,1H),5.88-5.83(m,1H),5.33-5.28(m,1H),4.89(s,2H),3.96-3.89(m,1H),2.47-2.40(m,1H),1.42(d,J＝6.8Hz,6H),1.19-1.08(m,5H)。

Example 22: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 62)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 70)

Methyl 5- (chloro (hydroxyimino) methyl) -1-isopropyl-1H-pyrazole-3-carboxylate (230mg,0.94mmol) and 4- ((3-chloro-4- (prop-1-en-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (407mg,0.94mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (60mg, yield: 9.9%).

MS m/z(ESI):643.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.62-7.52(m,4H),7.04(s,2H),6.97(s,1H),5.33-5.26(m,1H),4.92(s,2H),3.89(s,3H),3.77-3.51(m,2H),1.72(s,3H),1.44-1.36(m,6H),1.19-1.10(m,5H)。

The second step: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 62)

The compound (50mg,0.08mmol) obtained in the first step was dissolved in methanol (1mL) and tetrahydrofuran (2mL), and an aqueous solution of sodium hydroxide (6.4mg,0.16mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (30mg, yield: 60%).

MS m/z(ESI):629.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:12.02(s,1H),7.62-7.52(m,4H),7.04(s,2H),6.97(s,1H),5.33-5.26(m,1H),4.92(s,2H),3.77-3.51(m,2H),1.72(s,3H),1.44-1.36(m,6H),1.19-1.10(m,5H)。

Example 23: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 16)

The first step is as follows: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoate (Compound 43)

Methyl 3- (chloro (hydroxyimino) methyl) benzoate (200mg,0.94mmol) and 4- ((3-chloro-4- (prop-1-en-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (407mg,0.94mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (50mg, yield: 8.7%).

MS m/z(ESI):611.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.98-7.96(m,2H),7.78-7.76(m,2H),7.61-7.59(m,2H),7.54-7.50(m,2H),6.97-6.96(m,1H),6.82-6.79(m,1H),4.91(s,2H),3.87(s,3H),3.78-3.60(m,2H),2.47-2.43(m,1H),1.72(s,3H),1.23-1.15(m,2H),1.14-1.12(m,2H)。

The second step is that: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 16)

The compound (50mg,0.08mmol) obtained in the first step was dissolved in methanol (2mL) and tetrahydrofuran (1mL), and an aqueous solution of sodium hydroxide (6.4mg,0.16mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (30mg, yield: 62.8%).

MS m/z(ESI):597.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.98-7.96(m,2H),7.78-7.76(m,2H),7.61-7.59(m,2H),7.54-7.50(m,2H),6.97-6.96(m,1H),6.82-6.79(m,1H),4.91(s,2H),3.78-3.60(m,2H),2.47-2.43(m,1H),1.72(s,3H),1.23-1.15(m,2H),1.14-1.12(m,2H)。

Example 24: preparation of 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 63)

The first step is as follows: preparation of methyl 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoate (Compound 71)

Methyl 4- (chloro (hydroxyimino) methyl) benzoate (200mg,0.94mmol) and 4- ((3-chloro-4- (prop-1-en-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole (407mg,0.94mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (50mg, yield: 8.7%).

MS m/z(ESI):611.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.97-7.50(m,8H),6.97(m,1H),6.82-6.79(m,1H),4.91(s,2H),3.89(s,3H),3.76-3.59(m,2H),1.72(s,3H),1.23-1.10(m,5H)。

The second step is that: preparation of 4- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -5-methyl-4, 5-dihydroisoxazol-3-yl) benzoic acid (compound 63)

The compound (50mg,0.08mmol) obtained in the first step was dissolved in methanol (1mL) and tetrahydrofuran (2mL), and an aqueous solution of sodium hydroxide (6.4mg,0.16mmol) was added and reacted at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to acidic pH with 2N hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (30mg, yield: 62.8%).

MS m/z(ESI):597.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.50-7.97(m,8H),6.97(m,1H),6.79-6.82(m,1H),4.91(s,2H),3.59-3.76(m,2H),1.72(s,3H),1.10-1.23(m,5H)。

Example 25: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 64)

The first step is as follows: preparation of methyl 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylate (compound 72)

Methyl 5- (chloro (hydroxyimino) methyl) -1-isopropyl-1H-pyrazole-3-carboxylate (0.7g,2.8mmol) and 4- ((3-chloro-4-vinylphenoxy) methyl) -5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazole (1.1g,2.8mmol) were added to triethylamine (5mL) and reacted at room temperature for 12 hours. Then, water was added, and extraction was performed 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound of this step (0.5g, yield: 29.9%).

MS m/z(ESI):597.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.65-7.61(m,1H),7.34-7.25(m,3H),7.08-7.01(m,2H),6.84-6.81(m,1H),5.89-5.84(m,1H),5.34-5.31(m,1H),5.00(s,2H),3.97-3.90(m,1H),3.89(s,3H),2.46-2.42(m,1H),1.43(d,J＝6.8Hz,6H),1.19-1.15(m,3H),1.13-1.09(m,2H)。

The second step is that: preparation of 5- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-difluorophenyl) isoxazol-4-yl) methoxy) phenyl) -4, 5-dihydroisoxazol-3-yl) -1-isopropyl-1H-pyrazole-3-carboxylic acid (compound 64)

The compound (0.3g,0.5mmol) obtained in the first step was dissolved in methanol (4mL) and tetrahydrofuran (2mL), and an aqueous solution of sodium hydroxide (40mg,1mmol) was added and reacted at room temperature. The organic phase was concentrated and purified by preparative thin layer chromatography to give the title compound (60mg, yield: 20.6%).

MS m/z(ESI):583.2[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.65-7.61(m,1H),7.34-7.25(m,3H),7.08-7.01(m,2H),6.84-6.81(m,1H),5.89-5.84(m,1H),5.34-5.31(m,1H),5.00(s,2H),3.97-3.90(m,1H),2.46-2.42(m,1H),1.43(d,J＝6.8Hz,6H),1.19-1.15(m,3H),1.13-1.09(m,2H)。

Example 26: preparation of 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxopyrrolidin-1-yl) benzoic acid (Compound 18)

The first step is as follows: preparation of diethyl 2- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzylidene) malonate

2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldehyde (200mg,0.47mmol) was added to toluene (10mL), piperidine (81.6mg,0.96mmol) and diethyl malonate (80mg,0.5mmol) were added and heated at 110 ℃ overnight. Then, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with water, followed by drying and concentration to obtain the title compound of this step (200mg, yield: 75.5%).

The second step is that: preparation of diethyl 2- (1- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-nitroethyl) malonate

Nitromethane (54mg,0.89mmol) was added to anhydrous tetrahydrofuran (5mL), sodium hydride (36.8mg,0.92mmol) was added under nitrogen, and the mixture was stirred at room temperature for 20 minutes, then a solution of the compound obtained in the first step (100mg,0.18mmol) in tetrahydrofuran (3mL) was added and the reaction was allowed to proceed at room temperature for 2 hours. Then, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with water, then dried and concentrated to obtain the title compound of this step (80mg, yield: 71%).

The third step: preparation of ethyl 4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxopyrrolidine-3-carboxylate

The compound (500mg,0.80mmol) obtained in the second step was added to a mixed solvent of glacial acetic acid (20mL) and methanol (5mL), and after adding zinc powder (130mg,2.0mmol), the mixture was reacted with room temperature overnight. The reaction mixture was concentrated in vacuo, and methylene chloride (20mL) was added to the mixture, followed by addition of a saturated sodium bicarbonate solution (5mL) and reaction at room temperature for 2 hours. Then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was washed with water, dried, concentrated and then purified by preparative thin layer chromatography to give the title compound of this step (200mg, yield: 45.5%).

The fourth step: preparation of 4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxopyrrolidine-3-carboxylic acid

The compound (200mg,0.36mmol) obtained in the third step was added to a mixed solvent of tetrahydrofuran (20mL) and methanol (10mL), and a saturated aqueous solution (2mL) of sodium hydroxide was added to conduct a reaction at room temperature for 2 hours. Then, the reaction solution was adjusted to pH 2 with 2N hydrochloric acid, poured into water, and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the title compound of this step (160mg, yield: 85.2%).

The fifth step: preparation of 4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) pyrrolidin-2-one

The compound (160mg,0.31mmol) obtained in the fourth step was added to DMSO (20mL) and reacted at 130 ℃ for 4 hours. The reaction solution was then poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the title compound of this step (120mg, yield: 81.1%).

And a sixth step: preparation of methyl 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxopyrrolidin-1-yl) benzoate (Compound 45)

Adding the compound (120mg,0.25mmol) obtained in the fifth step to dioxane (20mL), adding methyl 3-iodobenzoate (84mg,0.32mmol), Xantphos (40mg,0.07mmol), Pd ₂ (dba) ₃ (60mg,0.07mmol) and sodium t-butoxide (40mg,0.42mmol), 3 times with nitrogen substitution, and reacted at 90 ℃ for 4 hours in a microwave reactor. The reaction solution was then concentrated, and purification by preparative high performance liquid chromatography gave the title compound of this step (20mg, yield: 13.1%).

MS m/z(ESI):611.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:7.68-7.65(m,2H),7.39-7.32(m,4H),7.16-7.14(m,2H),6.86-6.84(m,1H),6.78-6.75(m,1H),4.92(s,2H),4.19-3.78(m,6H),2.63-2.62(m,2H),1.35-1.19(m,5H)。

The seventh step: preparation of 3- (4- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxopyrrolidin-1-yl) benzoic acid (Compound 18)

The compound (20mg,0.03mmol) obtained in the sixth step was added to a mixed solvent of tetrahydrofuran (5mL) and methanol (2mL), and a saturated aqueous solution (0.5mL) of sodium hydroxide was added to conduct a reaction at room temperature for 2 hours. Then, the reaction solution was adjusted to pH 2 with 2N hydrochloric acid, poured into water, and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated to give the title compound (10mg, yield: 55.9%).

MS m/z(ESI):597.1[M+H] ⁺

¹ H-NMR(400MHz,DMSO-d6)δ:9.88(s,1H),7.68-7.65(m,2H),7.39-7.32(m,4H),7.16-7.14(m,2H),6.86-6.84(m,1H),6.78-6.75(m,1H),4.92(s,2H),4.19-3.78(m,3H),2.63-2.62(m,2H),1.35-1.19(m,5H)。

Example 27: preparation of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxooxazolidin-3-yl) benzoic acid (compound 23)

The first step is as follows: preparation of 4- ((3-chloro-4- (oxiran-2-yl) phenoxy) methyl) -5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazole

Trimethylsulfonium iodide (0.65g,3.2mmol) was dissolved in DMSO (20mL), sodium hydride (0.16g,4.0mmol) was added, and 2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) benzaldehyde (1.2g,2.8mmol) was further added and reacted at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (20mL) was added to the reaction solution to quench the reaction. The reaction solution was extracted with dichloromethane (30 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE: EA ═ 4:1) to give the title compound of this step (1.2g, yield: 100%).

The second step is that: preparation of methyl 3- ((2- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-hydroxyethyl) amino) benzoate

The compound obtained in the first step (1.21g,2.80mmol) was added to methyl 3-aminobenzoate (0.44g,2.80mmol) at room temperature, lithium bromide (12mg,0.5mmol) was added, and the reaction was stirred without solvent overnight until the starting material was reacted completely. Water (20mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE: EA ═ 3:1) to give the title compound of this step (512mg, yield: 31.1%).

The third step: preparation of methyl 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxooxazolidin-3-yl) benzoate (Compound 50)

The compound obtained in the second step (512mg,0.87mmol) was added to dichloromethane (10mL) at room temperature, cooled to 0 deg.C and triethylamine (204mg,2.0mmol) was added. After the addition was completed, the mixture was stirred at 0 ℃ for 30 minutes, then triphosgene (300mg,1.0mmol) was added and reacted at 45 ℃ for 2 hours, then diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE: EA ═ 4:1) to give the title compound of this step (314mg, yield: 58.8%).

MS m/z(ESI):613.1[M+H] ⁺ 。

The fourth step: synthesis of 3- (5- (2-chloro-4- ((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) phenyl) -2-oxooxazolidin-3-yl) benzoic acid (Compound 23)

The compound (314mg,0.51mmol) obtained in the third step was added to methanol (10mL) at room temperature, and water (2.0mL) and lithium hydroxide (14mg,0.51mmol) were added. The mixture was reacted at room temperature overnight and then purified by preparative high performance liquid chromatography to give the title compound (50mg, yield: 16.3%).

MS m/z(ESI):599.1[M+H] ⁺

¹ H-NMR(400MHz,CDCl ₃ )δ:8.23-8.08(m,1H),7.77(d,J＝8.0Hz,1H),7.60(t,J＝8.0Hz,1H),7.47-7.40(m,2H),7.38-7.28(m,3H),6.93(d,J＝2.8Hz,1H),6.78(dd,J＝8.8,2.8Hz,1H),5.77(t,J＝8.0Hz,1H),4.82(s,2H),4.33(t,J＝8.8Hz,1H),3.88(dd,J＝8.8,7.6Hz,1H),1.36-1.28(m,3H),1.19(ddd,J＝11.6,7.2,4.4Hz,2H)。

In a manner analogous to that described above for examples 1-27, the following compounds in Table 1 were prepared:

table 1.

Biological assay

EXAMPLE 1 bile acid receptor FXR coactivator binding assay

1. Test method

Invitrogen LanthaScreen was used ^TM The TR-FRET Farnesoid X Receptor activator Assay kit measures the FXR activation effect of a compound.

After the compound with the agonistic effect is combined with the FXR receptor, the short peptide of the coactivator is recruited to be further combined to form a complex. According to the principle, terbium-labeled antibody capable of recognizing FXR receptor and fluorescence-labeled short coactivator peptide are respectively designed. When the FXR receptor is activated and fluorescence labeling of the short peptide of the co-activation factor is recruited to form a complex, the antibody is added to be combined with the FXR receptor, so that terbium labeling groups and fluorescence groups labeled on the short peptide of the co-activation factor can reach FRET generating conditions, and after the FXR receptor is incubated with compounds with different concentrations at room temperature, FRET signal magnitude is tested, and the agonism of the compounds on the FXR receptor can be reflected. Calculating the activating activity EC of the compound on FXR by taking receptor-free proteome as a blank ₅₀ And a maximum activation effect signal value Max (Max value in the following equation):

y＝min+(max-min)/(1+(x/EC ₅₀ )^(-Hillslope))

where y is the FRET binding signal, max and min are the maximum and minimum values of the fitted curve, respectively, x is the log concentration of the compound, and Hillslope is the slope of the curve.

In addition, the relative activation effect of the compounds of the present invention was calculated by the following formula using chenodeoxycholic acid (i.e., CDCA) as a positive control:

relative activation effect (%) - (Max/Max') x 100%

Where Max represents the maximum activation effect signal value for the compound of the invention and Max' represents the maximum activation effect signal value for CDCA, both calculated by the formula shown above.

2. Test results

TABLE 2-1 EC of FXR for Compounds of the invention ₅₀

As can be seen from Table 2-1, the compounds of the present invention have lower EC relative to the positive control CDCA ₅₀ The value is obtained.

TABLE 2-2 relative activating Effect of the Compounds of the invention on FXR

Test compounds	Relative activation effect
		CDCA	100％
Compound 3	139％
		Compound 4	111％
Compound 5	160％
		Compound 7	117％

As can be seen from tables 2-2, compound 3, compound 4, compound 5 and compound 7 of the present invention have a significantly superior maximum activation effect over CDCA. The remaining compounds of the invention also have a better maximum activation effect.

EXAMPLE 2 luciferase reporter Gene detection assay

1. Test method

Human embryonic kidney cells HEK293 were cultured in DMEM medium containing 10% FBS. And co-transfecting the plasmid to ensure that the plasmid highly expresses the FXR and the human BSEP luciferase reporter gene. Transfected cells were digested, resuspended, counted, and then plated in multi-well plates. mu.L of each test compound was added to a multiwell plate to give final concentrations of 64. mu.M, 16. mu.M, 4. mu.M, 1. mu.M, 0.25. mu.M, 0.0625. mu.M, 0.0156. mu.M, 0.0039. mu.M, 0.000977. mu.M, 0. mu.M, and DMSO to give a final concentration of 0.5%. After the test compound is incubated with the cells for 18h, Brigh-Glo is added ^TM And (3) detecting a chemiluminescence unit value (RLU) by using a multifunctional full-automatic enzyme standard instrument, and calculating the relative signal percentage (%) at each compound concentration by taking the signal value of a blank hole (without a compound) as 100%. Fitting of Compound EC with SigmaPlut 10 software Using a four parameter model ₅₀ And maximum activation effect (relative signal percentage).

2. Test results

The results of the measurement are shown in Table 3 below.

TABLE 3

Test compounds	Maximum activation effect
		Obeticholic acid	217％
Compound 1	313％
		Compound 2	388％
Compound 3	420％
		Compound 4	493％
Compound 5	445％

The results show that the EC of obeticholic acid is relative to the positive control ₅₀ The value 0.59. + -. 0.20. mu.M, the compounds of the invention have a lower EC ₅₀ Values, for example, for compound 1 at 0.26. + -. 0.04. mu.M and for compound 3 at 0.08. + -. 0.02. mu.M. At the same time, the compounds of the invention show a better maximal FXR activation effect in vitro cellular assays.

EXAMPLE 3 Biochemical hERG assay

Test method

This experiment uses a biochemical hERG assay kit (semer feishel) based on fluorescence polarization technology to assess the potential of compounds to induce prolongation of cardiac QT interval. Adding a compound to be detected into a microplate containing an hERG cell membrane, adding a tracer with high hERG affinity, incubating the microplate at 25 ℃ for 2 hours, detecting the change of fluorescence polarization value by using a BMG PHARESTar multifunctional microplate reader, finally calculating the percentage inhibition rate (%) of the compound to hERG under different concentrations, and judging the half maximum Inhibition Concentration (IC) of the compound ₅₀ ) The range of (1).

The results of the assay show that IC of compound 2 on hERG ₅₀ The value is greater than 30. mu.M. IC of hERG by the remaining Compounds of the invention ₅₀ Are all more than 30 mu M, showing that the medicine has better safety. The test shows that the compound of the invention has no obvious hERG toxicity.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R ¹ Is C (O) OH;

b is selected from unsubstituted or independently selected from C _1-6 Phenyl, pyridine or pyrazolyl substituted with 1,2 or 3 substituents of alkyl;

selected from:

wherein from the ring

With C or N ring atoms extending therefrom

Denotes that the C or N atom is directly bonded to the B group from the ring

Extended out

Indicating ring

And

bonding of groups;

x is selected from N and CH;

each R is ² Independently selected from hydrogen and C _1-6 An alkyl group;

each R is ³ Independently selected from hydrogen, halogen and halogeno C _1-6 An alkyl group;

m, n are each independently 0, 1 or 2;

d is:

z is:

w is selected from CH;

ra is selected from C _3-8 A cycloalkyl group;

rb and Rc are independently selected from hydrogen, halogen and halogenated C _1-6 Alkyl and halo C _1-6 alkyl-O-.

2. The compound of claim 1, wherein B is selected from the group consisting of unsubstituted phenyl, unsubstituted pyridyl, and pyrazolyl substituted with 1,2, or 3 methyl, ethyl, propyl, or isopropyl groups.

3. The compound of claim 2, wherein B is selected from the group consisting of unsubstituted phenyl, unsubstituted pyridyl,

4. The compound of claim 1, wherein each R is ³ Independently selected from hydrogen, fluorine, chlorine, bromine, iodine and CF ₃ 。

5. The compound of claim 1, wherein each Ra is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

6. The compound of claim 5, wherein each Ra is independently cyclopropyl.

7. The compound of claim 1, wherein Rb and Rc are each independently selected from hydrogen, F, Cl, CF ₃ 、CHF ₂ Fluoromethoxy, difluoromethoxy and trifluoromethoxy.

8. The compound of claim 7, wherein Rb and Rc are each independently selected from hydrogen, Cl, CF ₃ Difluoromethoxy and trifluoromethoxy.

9. The compound of any one of claims 1-8, wherein X is N, and

is that

10. The compound of any one of claims 1-8, wherein

Is unsubstituted

And is

B is selected from: unsubstituted or independently selected from C _1-6 Phenyl, pyridyl and pyrazolyl substituted with 1,2 or 3 substituents of alkyl.

11. The compound of claim 10, wherein

Is unsubstituted

And is

B is selected from: unsubstituted or independently selected from C _1-4 Phenyl, pyridyl and pyrazolyl substituted with 1,2 or 3 substituents of alkyl.

12. The compound of claim 11, wherein

Is unsubstituted

And is

B is selected from: phenyl, pyridyl and pyrazolyl unsubstituted or substituted with 1,2 or 3 substituents independently selected from methyl, ethyl, propyl and isopropyl.

13. The compound of claim 12, wherein B is selected from: unsubstituted phenyl; an unsubstituted pyridyl group; and

pyrazolyl substituted by 1,2 or 3 methyl, ethyl, propyl or isopropyl groups.

14. The compound of claim 13, wherein B is selected from:

15. the compound of claim 1, wherein the compound is of formula (Ia) or (Id):

wherein R is ¹ 、B、R ² 、n、X、R ³ M and D are as defined in claim 1.

16. The compound of claim 1, wherein the compound is selected from the group consisting of:

17. a pharmaceutical composition comprising at least one compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

18. The pharmaceutical composition of claim 17, in a form selected from the group consisting of: tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

19. A kit, comprising:

a) a first container comprising as a first therapeutic agent at least one compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof, or as a first pharmaceutical composition a pharmaceutical composition of claim 17 or 18;

b) optionally, packaging instructions.

20. Use of a compound of any one of claims 1-16, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 17 or 18 in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by a farnesoid X receptor.

21. A process for the preparation of a compound of the following general formula (Ia) or (Id),

wherein R is ¹ 、B、R ² 、n、X、R ³ M and D are as defined in claim 1;

(i) the process for preparing formula (Ia) comprises:

wherein X' is a leaving group selected from Cl, Br, I, OMs or OTs; r ^1’ Represents a compound having a removable protecting group and which can be provided with R by removal of said protecting group ¹ A group of (a);

(1) reacting compound IN-1 with compound IN-2 to obtain IN-3;

(2) subjecting compound IN-3 to a Wittig reaction (Wittig reaction) to obtain compound IN-4;

(3) reacting compound IN-5 to give compound IN-6;

(4) reacting compound IN-6 to give compound IN-7;

(5) subjecting compound IN-7 to cyclization reaction with compound IN-4 to obtain compound IN-8; and

(6) reacting compound IN-8 to obtain said compound of formula (Ia);

(ii) the process for preparing the formula (Id) comprises:

wherein R is ^1’ And X' is as defined in method (i) above and PG is a suitable hydroxy protecting group;

(1) subjecting compound IN-7 to a ring-closing reaction with compound IN-10 to obtain compound IN-20, wherein PG is removed during said ring-closing reaction;

(2) reacting compound IN-20 with compound IN-2 to give compound IN-21: and

(3) reacting compound IN-21 to obtain the compound of formula (Id).