WO2018133730A1

WO2018133730A1 - Heterocyclic compound, preparation method and use therefor

Info

Publication number: WO2018133730A1
Application number: PCT/CN2018/072398
Authority: WO
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: 四川科伦博泰生物医药股份有限公司
Priority date: 2017-01-20
Filing date: 2018-01-12
Publication date: 2018-07-26
Also published as: CN109071468B; CN109071468A

Abstract

Disclosed in the present invention are a farnesoid X receptor (FXR) agonist compound and a preparation method and use therefor. Specifically, provided in the present invention are a heterocyclic FXR agonist compound, as well as stereoisomers, a tautomer, a polymorph, a solvate (e.g., a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite and an N-oxide thereof, and a chemically protected form and a prodrug of the foregoing. The present invention also provides a method for preparing the compound and a pharmaceutical composition and a kit which contain the compound, as well as a use therefor in the treatment of diseases or conditions which are mediated by FXR.

Description

Heterocyclic compound, preparation method and use thereof

Field of invention

The present invention relates to a heterocyclic compound for the treatment of a disease or condition mediated by a farnesoid X receptor (FXR), and more particularly to a FXR agonist compound, and stereoisomers, tautomers thereof Forms, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof. The invention further relates to a process for the preparation of said compounds, to pharmaceutical compositions and kits comprising said compounds, and to their therapeutic use.

Background of the invention

The farnesoid X receptor (FXR, NR1H4) is expressed in the liver, the entire gastrointestinal tract, kidney and adrenal glands including the esophagus, stomach, duodenum, small intestine, colon (Kuipers, F. et al, The Farnesoid X Receptor (FXR) as Modulator of Bile Acid Metabolism. Rev. Endocrine Metab. Disorders, 2004, 5: 319-326). FXR is a member of a transcription factor known to be a ligand for ligand activation of nuclear receptors. Bile acids such as chenodeoxycholic acid (CDCA) or its taurine or glycine amide conjugate are endogenous ligands for FXR. Bile acid binds to FXR and activates FXR, which controls the expression of multiple genes through heterodimeric complexes with retinoid X receptors (RXR), including bile acids, cholesterol, and triacids in the liver and circulation. Gene expression for glycerol, lipoprotein homeostasis (Kalaany, NY; Mangelsdorf, DJLXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu. Rev. Physiol., 2006, 68, 159-191). FXR also appears to be involved in paracrine and endocrine signaling by up-regulating fibroblast growth factor 15 (rodent) or fibroblast growth factor 19 (monkey, human) (T. Inagaki et al. Fibroblast growth factor 15 functions as an enterohepatic signal to Qualification bile acid homeostasis. Cell Metab., 2005, 2(4), 217-225).

Bile acids are amphiphilic molecules that form micelles and emulsifie lipids in the diet. If the bile acid concentration is too high, cytotoxicity is also produced, so there is a physiological mechanism for strictly controlling the concentration of bile acids. FXR plays a key role in controlling the steady state of bile acids (Makishima, M., Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors. J. Pharmacol. Sci., 2005, 97: 177 -183.).

In addition, FXR has been shown to regulate complex biological processes beyond metabolism, such as liver regeneration or intestinal barrier integrity. FXR also controls the immune system of the intestines and liver and has certain anti-inflammatory effects (Modica, S.; Gadaleta, RM; Moschetta, A.; Deciphering the nuclear bile acid receptor FXR paradigm. Nucl. Recept. Signal., 2010 , 8, e005.).

Obeticholic Acid (6-Et CDCA) is a FXR receptor agonist with higher endogenous ligand CDCA activity and has been shown in Phase IIa clinical studies of nonalcoholic fatty liver disease (NAFLD). Significant improvement in insulin sensitivity and other metabolic beneficial effects (Mudaliar, S.; Henry, RR; Sanyal, AJ et al., Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic Fatty liver disease. Gastroenterology, 2013, 145, 574-582.). Phase IIb studies of oleic acid showed that 72-week treatment was also beneficial for the histopathological improvement of nonalcoholic hepatitis (NASH). In a phase III study of primary biliary cirrhosis (PBC), liver function impairment is improved (Nevens, F., Andreone, P., Mazzella, G., et al. The first primary biliary cirrhosis (PBC) Phase 3trial in two decades-an international study of the FXR agonist obeticholic acid in PBC patients. J. Hepatol., 2014, 60, S525-S526).

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

Summary of invention

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

among them

R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, 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 , -ER ⁵ , -E-OR ⁵ , -E-CN, -E-NR ⁵ R ⁶ , C _3-10 cycloalkyl O-, -OC _1-6 alkyl-OR ⁵ , 3 to 10 membered heterocycloalkyl-O-, -EC(O)OR ⁵ , -EC(O)R ⁵ , -EC(O)NR ⁵ R ⁶ , -EC(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 a heterocycloalkyl group, and a 5, 6 or 7 membered monocyclic nitrogen-containing heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocycloalkyl group and heteroaryl group are unsubstituted or independently selected from halogen, CN, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy, oxo, C(O)OH, SO ₃ H, C _1-3 alkyl-O- and halogenated C _1-3 alkane Substituting 1, 2, 3 or 4 substituents of the radical -O-;

E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group;

R ⁴ , R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, C _1-6 alkyl, halo C _1-6 alkyl and C _3-6 cycloalkyl;

Each R ^{5 is} independently selected from the group consisting of hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, -C _1-6 alkyl-C _3-8 cycloalkyl, 3 To an 8-membered heterocycloalkyl group, a -C _1-6 alkyl-3 to 8 membered heterocycloalkyl group, a 5 or 6 membered heteroaryl group, and an aryl group; wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , 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, ₁ , ₂ , 3 or 4 substituents of C _1-3 alkyl-O-, halo C _1-3 alkyl-O- and -SO ₂ -C _1-3 alkyl;

p is 0, 1 or 2;

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

B is selected from a C _6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S; The or heteroaryl group 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, C _1-6 alkyl -O-, C _1-6 alkyl-OC _1-6 alkyl-O-, halogenated C _1-6 alkyl, halogenated C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN-C _1-6 alkyl, C _3-6 cycloalkyl and 3 to 6-membered heterocycloalkyl and C _1-6 comprising 1, 2 or 3 heteroatoms independently selected from N, O and S alkyl-S(O) _p -;

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl group or a saturated or partially unsaturated 3 to 10 membered heterocyclic group optionally substituted by oxo, wherein said heteroaryl or heterocyclic group comprises independently selected from 1, 2 or 3 heteroatoms of N, O and S;

Linking to a B group through a C ring atom or in the presence of an N ring atom through the N ring atom;

X is selected from N and CRc';

Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C ₁ - ₆ alkyl, C _1-6 alkyl-O- a halogenated C _1-6 alkyl-O-, C _3-8 cycloalkyl group and a halogenated C _3-8 cycloalkyl group;

Each R ^{3 is} independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C ₁ - ₆ alkyl, C _1-6 alkyl-O- , -O- halogenated C _1-6 alkyl, halo C _3-8 cycloalkyl and C _3-8 cycloalkyl;

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 a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _1-6 alkyl-O- group, a halogenated C _1-6 alkyl group, a halogenated C _3-8 cycloalkyl group, and Halogenated C _1-6 alkyl-O-;

Rb, Rc and Rc' are each independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _{1- 6} alkyl-O-, C _3-8 cycloalkyl, halogenated C _3-8 cycloalkyl, C _3-8 cycloalkyl-O- and halogenated C _3-8 cycloalkyl-O-;

Rd is selected from a C _3-10 cycloalkyl or C _5-14 bridged ring system, a fused ring system, or a spiro ring system; wherein the cycloalkyl, saturated bridged ring system, saturated fused ring system, or saturated spiro ring system is optional The ground is replaced by 1, 2 or 3 Re;

Each Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl-O a C _3-8 cycloalkyl group, a halogenated C _3-8 cycloalkyl group, and a C _6-10 monocyclic or bicyclic aryl group;

requirement is:

(1) and ring

Connected B groups do not

The groups are directly adjacent;

(2) When the ring

for

When R ² is not a hydroxyl group;

(3) When X is N, the ring

Not

Wherein from the ring

C or N ring atom extended

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

Outstretched

Ring

versus

Group bonding.

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

Not

Another aspect of the invention is a pharmaceutical composition comprising a compound of the formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), a pharmaceutically acceptable Accepted salts, esters, metabolites, chemically protected forms or prodrugs thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition may further comprise one or more additional 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 condition mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I), a stereoisomer thereof, Tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, chemically protected forms or prodrugs thereof or the pharmaceutical compositions.

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

a) a first container comprising, as a first therapeutic agent, at least one of the compounds of the formula (I), stereoisomers, tautomers, polymorphs, solvates thereof (eg hydrates) a pharmaceutically acceptable salt, ester, metabolite, chemically protected form or prodrug thereof or the pharmaceutical composition as a first pharmaceutical composition;

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

c) Optional package inserts.

The present invention also includes the compound of the formula (I), stereoisomers, tautomers, polymorphs, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, A chemically protected form or prodrug thereof or the pharmaceutical composition for use in preventing or treating a disease or condition mediated by FXR.

The present invention also includes the compound of the formula (I), stereoisomers, tautomers, polymorphs, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, A form of its chemically protected or prodrug or use of the pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR.

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

The compound of the formula (I) of the present invention has excellent in vivo or in vitro pharmacodynamic or pharmacokinetic properties, exhibits good FXR activating activity and activation, and excellent plasma drug exposure and bioavailability, thus Has good pharmaceutical activity and metabolic advantages in the body. In addition, the compounds of the invention also show better drug safety.

Detailed description of the invention

Certain embodiments of the invention are now described in detail, examples of which are illustrated in the accompanying structures and formula. While the invention has been described in connection with the embodiments illustrated, it is understood that the invention is not limited to those embodiments. Rather, the invention is to cover all alternatives, modifications, and equivalents, which are 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 invention. The invention is in no way limited to the methods and materials described. Where one or more of the cited documents, patents, and similar materials are different or contradictory to the present application (including but not limited to defined terms, term usage, techniques, etc.), this application is quasi.

definition

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

The terms "including", "comprising", "having", "containing" or "comprising" and their variants herein are inclusive or open and do not exclude other elements or method steps that are not listed. .

The term "alkyl" as used herein, refers to a saturated straight or branched chain hydrocarbon radical having from 1 to 12 carbon atoms (C _1-12 ), wherein the alkyl group may be optionally one or more (eg, 1 , 2, 3 or 4) substituted substituents. In some embodiments, an alkyl group has from 1 to 8 carbon atoms (C _1-8 ), especially from 1 to 6 carbon atoms (C _1-6 ). In other embodiments, the alkyl group has from 1 to 4 carbon atoms (C _1-4 ), especially from 1 to 3 carbon atoms (C _1-3 ) or from 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-propene Base (t-Bu or tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl , 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl and the like.

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

As used herein, the term "cycloalkyl" refers to having from 3 to 12 carbon atoms (C _3-12 ), especially from 3 to 10 carbon atoms (C _3-10 ) or from 3 to 8 carbon atoms ( C _3-8 ) a saturated carbon ring in the form of a single ring. In some embodiments, a cycloalkyl group has from 3 to 6 carbon atoms ( _C3-6 ), such as 3, 4, 5 or 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododeyl Alkyl and the like. The cycloalkyl group can 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 specifically defined, means a carbocyclic group having a bicyclic form of 5 to 14 ring carbon atoms (C _5-14 ), wherein two carbon rings share more than two (for example, 3) , 4 or 5) carbon atoms, the carbon chain formed by these common carbon atoms acts as a bridge, and the two carbon atoms at both ends of the bridge are called bridgehead carbon. Such bridged ring systems may have from 5 to 11 ring carbon atoms (C _5-11 ), especially from 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] 壬基. The bridged ring system can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

The term "fused ring system" as used herein, unless specifically defined, means a fused bicyclic form of a carbocyclic group having 5 to 14 ring carbon atoms (C _5-14 ), wherein the two carbon rings fused together share two Carbon atoms bonded to each other. Thus, the fused ring system is a fused bicyclic carbocyclic group that shares two carbon atoms bonded to each other. Such fused ring systems may have, for example, 5 to 10 ring carbon atoms (C _5-10 ), especially 7 to 10 ring carbon atoms (C _7-10 ). The two carbon rings of the C _7-10 fused ring system can be arranged into a 4-membered ring and a 5-membered ring (bicyclo[4,5] system), two 5-membered rings (bicyclo[5,5] system), 5 Yuan and 6-membered rings (bicyclo[5,6] systems), or two 6-membered rings (bicyclo[6,6] systems). 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] fluorenyl or bicyclo [4.4.0] fluorenyl. The fused ring system can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

The term "spirocyclic system" as used herein, unless specifically defined, means a bicyclic form of a carbocyclic group having 5 to 14 ring carbon atoms (C _5-14 ) wherein two carbon rings share one carbon atom (referred to as "Snail atom"). The spiro ring system may have, for example, 5 to 11 ring carbon atoms (C _5-11 ), particularly 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, Snail [3.5] thiol, snail [4.4] fluorenyl, snail [4.5] fluorenyl and spirulin [5.5] undecyl. The spiro ring system can be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.

The term "aryl" as used herein means a C _6-14 aromatic monocyclic or polycyclic (particularly bicyclic) group (C _6-14 aryl), suitably including a C _6-12 aryl group, more Suitably a C _6-10 monocyclic or bicyclic aryl group is included, preferably a C ₆ aryl group (ie, phenyl). The aryl group contains at least one aromatic ring (such as one ring or two rings), but may also contain additional rings that are non-aromatic. An example of a typical aryl group containing an aromatic ring is phenyl. An example of a typical aryl group containing two aromatic rings is a naphthyl group. A phenyl group (e.g., indane) fused to a C _5-8 carbocyclic group (suitably, a C _5-6 carbocyclic group) is also an example of an aryl group. The aryl group is optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

The terms "heterocycle" and "heterocyclyl" are used interchangeably herein and refer to have, for example, from 3 to 10 (suitably from 3 to 8, more suitably 3, 4, 5 or 6) a ring atom, wherein at least one of the ring atoms is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie one or more within the ring) Double bond and/or triple bond) cyclic group. For example, a "3 to 10 membered heterocyclic group" is a ring carbon atom having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) and independently selected from N, O, and S. One or more (eg, 1, 2, 3 or 4) saturated or partially unsaturated heterocyclic groups of heteroatoms. Examples of saturated heterocyclic groups (i.e., heterocycloalkyl groups) include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl. , pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithiatium Examples of trithianyl; partially unsaturated heterocyclic groups include, but are not limited to, dioxolinyl and pyrrolinyl. The heterocyclyl can be optionally substituted by one or more (e.g., 1, 2, 3 or 4) suitable substituents.

The term "heteroaryl" as used herein, refers to a monocyclic or polycyclic (eg bicyclic or tricyclic) aromatic ring system having from 5 to 14 ring atoms, for example 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and independently selected from N, O 1, 1, 2, 4 or 5 of the same or different heteroatoms of S. The heteroaryl group can be benzofused. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole , isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, quinolyl, anthracene , pyrrolopyridazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl , imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolyl, tetrahydroisoquinolinyl, benzimidazolyl, porphyrin, mesoindolyl, pyridazinyl, iso Mercapto, pteridinyl, fluorenyl, furyl, benzofurazinyl, quinoxalinyl, naphthyridyl or furopyridinyl. Preferably, the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzothiazolyl, benzo[d]isothiazolyl, imidazo[1,2 -a]pyridyl, quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-carbazolyl, benzo [d]oxazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazole And [1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl and 1H-[1,2,3]triazolo[4,5-b]pyridinyl. The heteroaryl group can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.

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

By way of example and not limitation, nitrogen-bonded heterocyclic or heteroaryl groups are bonded at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, Imidazolidin, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, hydrazine, porphyrin, 1H-carbazole Position 1, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 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, monosubstituted, disubstituted or trisubstituted, and the halogen atoms used for the substitution may be the same or different.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified The normal valence of an atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

The term "optionally substituted" refers to being optionally substituted with a particular group, radical or moiety.

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

The term "chiral" refers to molecules that have non-overlapping properties of mirrored pairs, while the term "achiral" refers to molecules that can overlap on their mirror image pairs.

The term "stereoisomer" refers to a compound having the same chemical composition but differing in the arrangement of atoms or groups in space.

"Diastereomer" refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. 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 non-superimposable mirror images of each other.

The stereochemical definitions and rules used herein generally follow SP 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 therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to their diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to constitute the invention. a part of. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In the expression of optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d and l or (+) and (-) are used to indicate the sign of the compound rotating the plane polarized light, where (-) or 1 means that the compound is left-handed. Compounds with the prefix (+) or d are dextrorotatory. These stereoisomers are identical for a particular chemical structure, except that they mirror each other. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur without a stereoselective or stereospecific nature of the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers which are not optically active. In one aspect, the stereoisomers of the invention may exist in a predominant form, 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.

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

The term "tautomer" or "tautomeric form" refers to structural isomers that differ in energy that can be converted into each other by a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversion by proton transfer, such as keto-enol and imine-enamine isomerization. Valence bond tautomers include mutual transformation by recombination of some bonding electrons.

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

It will be understood that certain compounds of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives. 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, Once the desired individual is administered, the compound of the invention or its metabolite or residue can be provided directly or indirectly.

Therefore, when reference is made herein to "a compound of the formula (I)", "a compound of the invention" or "a compound of the formula (I) of the invention", it is also intended to encompass the formula (I) Solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof.

The term "pharmaceutically acceptable salt" as used herein refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention. Exemplary salts include, but are not limited to, sulfates, acetates, chlorides, iodides, nitrates, hydrogen sulfates, acid phosphates, isonicotinic acid salts, salicylates, acid citrates, oils Acid salt, citrate, pantothenate, hydrogen tartrate, ascorbate, gentisate, gluconate, glucuronate, saccharide, formate, benzoate, glutamine Acid salt, and pamoate (i.e., 1,1 '-methylene-bis(2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts can include inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counter ion can be any organic or inorganic ion that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Where a plurality of charged atoms are part of a pharmaceutically acceptable salt, there may be multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.

If the compound of the present invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid. 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, pyranoside acid such as glucose Aldehydic acid or galacturonic acid, α-hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethyl sulfonate The acid is treated with a free base.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, with an inorganic or organic base such as an amine (primary, secondary or tertiary amine), an alkali metal hydroxide or The alkaline acid is treated with an alkaline earth metal hydroxide or 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 of 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 that make up the formulation and/or the mammals treated therewith.

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

The compounds of the invention may exist in the form of solvates (e.g., hydrates) wherein the compounds of the invention comprise a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.

A "metabolite" is a product produced by metabolism of a particular compound or salt thereof. Metabolites of the 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 be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a process comprising contacting a compound of formula (I) of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. The synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups. Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see for example: TLGilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; SVLey, Ed., Pergamon Press; Tisler and B. Stanovnik, Comprehensive Heterocyclic Chemistry, vol. 3, pp 18-20.

In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.

The invention further includes within its scope prodrugs of the compounds of the invention. Typically such prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Thus, in these instances, the term "administering" for use in the methods of treatment of the invention shall include the treatment of various diseases or conditions with a prodrug form of one or more of the claimed compounds, but The prodrug form is converted to the above compound in vivo after administration to the individual. For example, in "Design of Prodrug", ed. H. Bundgaard, Elsevier, 1985, a conventional method of selecting and preparing suitable prodrug derivatives is described.

Any formula or structure shown herein, including compounds of formula (I), is also intended to mean both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure shown by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes which may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H (氘, D), ³ H (氚), 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 containing radioisotopes such as ³ H, ¹³ C and ¹⁴ C are included. Such isotopically labeled compounds can be used 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. Determination, or for radiotherapy of a patient. The guanidine-labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements. ¹⁸ F-labeled compounds can be used in PET or SPECT studies. The isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent by the methods disclosed in the Schemes or Examples and the preparation methods described below. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It will be understood that in this case hydrazine is considered to be a substituent in the compound of formula (I). The concentration of such heavier isotopes, particularly ruthenium, can be defined by isotopic enrichment factors. In the compounds of the invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is explicitly indicated by "H" or "hydrogen", it is understood to mean hydrogen having a natural abundance isotopic composition at that position. Thus, in the compounds of the invention, any atom clearly indicating 氘(D) is intended to mean 氘.

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

Compound

The present invention provides a compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite, N-oxidation And the form and prodrug of its chemical protection.

The compound of the formula (I) has the following structure:

among them

R ^{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C _1-6 alkyl, 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 , -ER ⁵ , -E-OR ⁵ , -E-CN, -E-NR ⁵ R ^6, C _3-10 cycloalkyl, -O -, - OC _1-6 alkyl group -OR ^5, 3 to 10-membered heterocyclic group -O -, - EC (O) OR 5, -EC (O R ⁵ , -EC(O)NR ⁵ R ⁶ , -EC(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 a 10-membered heterocycloalkyl group, and a 5, 6 or 7 membered monocyclic nitrogen-containing heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group and heteroaryl group are unsubstituted or independently selected from Halogen, CN, C _1-3 alkyl, halogenated C _1-3 alkyl, hydroxy, oxo, C(O)OH, SO ₃ H, C _1-3 alkyl-O- and halogenated C _{1- 1} , 2, 3 or 4 substituents of ₃ alkyl-O-;

E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group;

p is 0, 1 or 2;

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

B is selected from a C _6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, wherein said aryl The or heteroaryl group 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 (eg methyl, ethyl) , isopropyl or tert-butyl), C _1-6 alkyl-O-, C _1-6 alkyl-OC _1-6 alkyl-O-, halogenated C _1-6 alkyl (eg CHF ₂ ) Halogenated C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN-C _1-6 alkyl, C _3-6 cycloalkyl, and 1 independently selected from N, O and S a 2 to 6 membered heterocycloalkyl group of 2 or 3 heteroatoms and a C _1-6 alkyl-S(O) _p -;

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl group or a saturated or partially unsaturated 3 to 10 membered heterocyclic group optionally substituted by oxo; wherein said heteroaryl or heterocyclic group comprises independently selected from 1, 2 or 3 heteroatoms of N, O and S;

X is selected from N and CRc';

Each R ^{2 is} independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C ₁ - ₆ alkyl, C _1-6 alkyl-O- , -O- halogenated C _1-6 alkyl, halo C _3-8 cycloalkyl and C _3-8 cycloalkyl;

Each R ^{3 is} independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C _1-6 alkyl, halo C _1-6 alkyl, hydroxy C ₁ - ₆ alkyl, C _1-6 alkyl-O- a halogenated C _1-6 alkyl-O-, C _3-8 cycloalkyl group and a halogenated C _3-8 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 Re is independently selected from hydrogen, halogen, hydroxy, the CN, C _1-6 alkyl, halo C _1-6 alkyl, -O- C _1-6 alkyl, halo C _1-6 alkyl -O a C _3-8 cycloalkyl group, a halogenated C _3-8 cycloalkyl group, and a C _6-10 monocyclic or bicyclic aryl group;

requirement is:

(1) and ring

Connected B groups do not

The groups are directly adjacent;

(2) When the ring

for

or

When R ² is not a hydroxyl group;

(3) When X is N, the ring

Not

Wherein from the ring

C or N ring atom extended

Outstretched

Ring

versus

Group bonding.

In some embodiments, R ^{1 is} selected from the group consisting of: -EC(O)OR ⁵ and -EC(O)NR ⁵ R ⁶ ; more preferably, R ¹ is -EC(O)OR ⁵ .

In a preferred embodiment, E is a bond.

In some embodiments, R ⁴ , R ⁶ and R ⁷ are each independently selected from hydrogen, C _1-3 alkyl, halo C _1-3 alkyl, and cyclopropyl; preferably, R ⁴ , R ⁶ and R ^{7 is} each independently hydrogen.

In some embodiments, each R ^{5 is} independently selected from hydrogen and C _1-6 alkyl (eg, C _1-4 alkyl, particularly C _1-3 alkyl); more preferably, R ^{5 is} 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 -EC(O)OR ⁵ , E is a bond, and R ^{5 is} selected from hydrogen and C _1-6 alkyl (preferably C _1-4 alkyl). More preferably, R ^{1 is} selected from the group consisting of 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 members comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Monocyclic heteroaryl; in particular, the aryl group is selected from phenyl; the heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furan , pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl and furazolyl, more particularly The heteroaryl group is selected from the group consisting of pyridyl and pyrazolyl. The aryl or heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of C _1-6 alkyl, for example C _1-3 alkyl, preferably methyl , ethyl or isopropyl; halo C _1-6 alkyl, such as halo C _1-3 alkyl, preferably CHF ₂ ; and comprising 1, 2 or 3, independently selected from N, O and S a 3- to 6-membered heterocycloalkyl group of an atom, such as an oxiranyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an aziridine group, an azetidinyl group, and a pyrrolidinyl group, particularly Ethylene oxide, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, preferably oxetanyl.

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

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

It may be attached to the B group through the C ring atom or in the presence of an N ring atom through the N ring atom.

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

Not

or

ring

Yes:

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

Preferably,

From:

More preferably,

From:

Wherein from the ring

C or N ring atom extended

Outstretched

Ring

versus

Group bonding.

In an embodiment of the compounds of the invention, each R ^{2 is} independently selected from hydrogen and C _1-6 alkyl (eg, C _1-4 alkyl, especially C _1-3 alkyl, eg, methyl). In an embodiment of the compounds of the invention, each R ^{3 is} independently selected from the group consisting of hydrogen, halogen (eg, fluoro, chloro, bromo, iodo) and halo C _1-6 alkyl (eg, halo C _1-3 alkyl, For example CF ₃ ).

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

In some embodiments,

Yes

And R ² is hydrogen.

In some embodiments, X is N, and

Yes

In some embodiments,

Is unsubstituted

and

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

More preferably, B is selected from the group consisting of: an unsubstituted phenyl group; an unsubstituted pyridyl group;

Pyrazolyl substituted with 1, 2 or 3 methyl, ethyl, propyl or isopropyl groups, for example

In an embodiment of the compounds of the invention, D is:

In an embodiment of the compounds of the invention, each Ra is independently selected from _C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopropyl.

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

Preferably, Rb and Rc are each independently selected from hydrogen, halo (e.g. F or Cl), halo-C _1-6 alkyl (e.g. CF ₃ or CHF _2), and halogenated C _1-6 alkyl -O- ( For example, 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 a C _3-6 cycloalkyl group or a C _5-11 saturated bridged ring system, a saturated fused ring system, or a saturated spiro ring system, optionally substituted with 1, 2, or 3 Re. In other embodiments, Rd is selected from bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[2.5] optionally substituted with 1, 2 or 3 Re. Octyl, bicyclo[4.1.0]heptyl, cyclopropyl, cyclohexyl and cyclopentyl. In some embodiments, each Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkyl-O-, halo C _{1 -3} alkyl-O-, C _3-6 cycloalkyl, halogenated C _3-6 cycloalkyl, and phenyl. In other embodiments, Re is independently selected from the group consisting of hydrogen, _C1-3 alkyl, _C3-6 cycloalkyl (such as cyclopropyl), and phenyl.

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

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

Wherein R ¹ , B, R ² , n, X, R ³ , m and D are as defined above.

Preferably, the compound of formula (I) of the invention is selected from the group consisting of:

The compounds of the formula (I) according to the invention may comprise asymmetric centers or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to, their diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to constitute the present invention. portion.

Furthermore, the invention encompasses all diastereomers, including cis-trans (geometric) isomers and conformational isomers. For example, if the compound of formula (I) comprises a double bond or a fused ring, the cis and trans forms, as well as mixtures thereof, are intended to be encompassed within the scope of the invention. In the structures shown herein, all stereoisomers are considered and included as a compound of the invention if the stereochemistry of any particular chiral atom is not indicated. If stereochemistry is indicated by a solid or dashed line indicating a particular configuration, the stereoisomer is thus indicated and defined.

The compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the 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 embraced 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 invention.

Pharmaceutical composition

According to a further aspect of the invention there is provided a pharmaceutical composition comprising at least one of the compounds of the formula (I), stereoisomers, tautomers, polymorphs, solvates thereof of the invention as described above ( For example, a hydrate, a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, a chemically protected form or prodrug thereof, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents suitable for preventing or treating a disease or condition mediated by FXR.

"Pharmaceutically acceptable carrier" in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered, and which is suitable for contacting humans and/or others within the scope of sound medical judgment. Animal tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications that correspond to a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used 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, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).

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

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

The dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.

Use for treatment

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

Accordingly, in some embodiments, the invention relates to a method of preventing or treating a disease or condition mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one formula of the invention ( Compounds of I), stereoisomers, tautomers, polymorphs, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected thereof Form or prodrug, or administration of a pharmaceutical composition of the invention.

In other embodiments, the invention relates to at least one compound of the formula (I), stereoisomers, tautomers, polymorphs, solvates (eg, hydrates thereof), pharmacy of the invention An acceptable salt, ester, metabolite, N-oxide, chemically protected form or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR use.

The FXR mediated disease or condition includes, but is not limited to:

Chronic intrahepatic or some form of extrahepatic cholestasis; liver fibrosis; obstructive or chronic inflammatory conditions of the liver; cirrhosis; fatty liver and complications; and cirrhosis or viral infectious forms caused by alcohol Hepatic-related cholestatic and fibrotic effects; liver failure or hepatic ischemia after partial hepatectomy; chemotherapy-related steatohepatitis (CASH); acute liver failure;

Inflammatory bowel disease, dyslipidemia, atherosclerosis, diabetes and related diseases; lipid and lipoprotein disorders; clinical complications of type 2 diabetes and type I and type II diabetes, including diabetic nephropathy, diabetic neuropathy Other observed effects of diabetic retinopathy, and clinically significant long-term diabetes; chronic fatty and fibrotic degeneration due to forced lipids, particularly triglyceride accumulation and subsequent activation of the pro-fibrotic pathway Caused diseases and diseases, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); obesity or metabolic syndrome (dyslipidemia, diabetes, and a combination of abnormally high body mass index);

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

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of a disease or condition indicated or one or more symptoms of such a disease or condition, or preventing such disease or condition or such One or more symptoms of a disease or condition.

"Individual" as used herein includes human or non-human animals. Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, 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 therapeutic efficacy described above after administration.

The dosage regimen can 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 urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.

The amount of the compound of the invention administered will depend on the severity of the individual, condition or condition being treated, the rate of administration, the handling of the compound, and the judgment of the prescribing physician. Generally, an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day. In some cases, a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.

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

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 a disease or condition mediated by FXR. In some embodiments, the compound of formula (I) is combined with, for example, other therapeutic agents having anti-hyperproliferative efficacy in the pharmaceutical composition or as a combination therapy. The additional therapeutic agent can be, for example, a chemotherapeutic agent. The pharmaceutical compositions or other therapeutic agents of the dosing regimen preferably have complementary activities to the compounds of formula (I) such that they do not adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose.

Combination therapies can be administered in a regimen of simultaneous or sequential administration. When administered sequentially, the combination can be administered in two or more administrations. Combination administration includes simultaneous administration using separate pharmaceutical compositions or a single pharmaceutical composition comprising a compound of formula (I) and other therapeutic agents, and sequential administration in any order, wherein preferably two (or all) are present The period of time during which the active agents simultaneously exert their biological activity.

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

Combination therapies provide "synergistic effects" and prove to be "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) is co-formulated in a combined unit dose formulation and administered or delivered simultaneously; (2) when delivered as separate formulations, alternately or in parallel; or (3) by some other regimen, A synergistic effect can be achieved. When delivered in alternation therapy, a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by separate injections in separate syringes, by separate pills or capsules, or by separate infusions. Typically, in alternation therapy, an effective amount of each active ingredient is administered sequentially, i.e., continuously, and in combination therapy, an effective amount of two or more active ingredients are administered together.

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

Metabolite of a compound of formula (I)

In vivo metabolites of the compounds of formula (I) described herein are also within the scope of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of formula (I), including those prepared by contacting a compound of the invention with a mammal for a time sufficient to produce its metabolites.

Metabolites are typically prepared by the preparation of a radioisotope (e.g., ¹⁴ C or ³ H) labeled compound of the invention at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as a rat, mouse, guinea pig, monkey. Or parenteral administration, metabolizing for a sufficient period of time (usually about 30 seconds to 30 hours), and then separating the transformed product from urine, blood or other biological samples for identification. These products are easy to isolate because they are labeled (others are isolated by the use of antibodies that bind to the remaining epitopes in the metabolite). The metabolite structure is determined by conventional methods, for example by MS, LC/MS or NMR. Analysis of the metabolites was performed in the same manner as 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 invention.

Pill box

In other embodiments of the invention, a "kit" comprising a material for treating the above mentioned diseases or conditions is provided. The kit includes a container comprising a compound of the formula (I), a stereoisomer, a tautomer, a polymorph, a solvate (such as a hydrate), as a first therapeutic agent, A pharmaceutically acceptable salt, ester, metabolite, N-oxide, or chemically protected form or prodrug thereof, or a pharmaceutical composition of the invention as a first pharmaceutical composition. In some embodiments, the kit may also include a label or package insert on or associated with the container. The term "package insert" refers to instructions typically included in commercial packages of therapeutic products that contain information on the indications, usage, dosage, administration, contraindications, and/or warnings associated with the use of the therapeutic product. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container can be made of various materials such as glass and plastic. The container may contain a compound of formula (I) or a formulation thereof effective for treating a condition, and may have a sterile inlet (eg, the container may be an intravenous solution bag or have a piercable needle that can be pierced by a hypodermic needle) Cork of the cork). The label or package insert indicates that the composition is used to treat a condition of choice, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient label or package insert having a disease or condition such as cirrhosis, hyperproliferative disorder, atherosclerosis, type I diabetes or may also indicate the composition It 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 additional therapeutic agent suitable for preventing or treating a disease or condition mediated by FXR, or as a second A pharmaceutical composition comprising the other therapeutic agent of a 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 any. For example, if the kit comprises a first composition comprising a compound of formula (I) and a second pharmaceutical composition comprising another therapeutic agent, the kit may further comprise simultaneous, sequential or sequential to the individual in need thereof Instructions for the first pharmaceutical composition and the second pharmaceutical composition are administered separately. 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 that are desirable for both the commercial and the user, including other buffers, diluents, fillers, injection needles, and syringes.

In other embodiments, the kit is suitable for delivery of a solid oral form of a compound of formula (I), such as a tablet or capsule. Such a kit preferably comprises a plurality of unit doses. Such kits can include cards having doses that are positioned for their intended use. An example of such a kit is a "blister pack." Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example, in the form of a number, letter or other indicia or calendar insert specifying the date on which the treatment schedule can be administered.

Method for preparing a compound

A further object of the present invention is to provide a process for the preparation of a compound of the following formula (Ia), (Ib), (Ic) or (Id),

Wherein R ¹ , B, R ² , n, X, R ³ , m and D are as defined above;

(i) A method of preparing the formula (Ia) includes:

Wherein X' is a leaving group (for example, Cl, Br, I, OMs or OTs); R ¹ ' represents a group having a removable protecting group and which can provide R ¹ by removing the protecting group. 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, especially methyl, optionally The ground is substituted with one or more (eg 1, 2, 3 or 4) substituents independently selected from halogen (eg F, Cl, Br or I) and nitro; preferably, R ¹ 'is CH ₃ - OC(O)-. In the embodiment, R ¹ is -EC(O)OR ⁵ , E is a bond and R ⁵ is hydrogen.

(1) reacting compound IN-1 with compound IN-2 to obtain 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 (such as diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, and dimethylene. Sulfone 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 base or an inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, hydrogencarbonate or acetate, such as lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, Potassium hydrogencarbonate, 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 period of time (for example 8 to 24 hours, such as 10 to 20 hours or 12 to 18 hours) until the reaction is complete.

(2) The Wittig reaction of the compound IN-3 is carried out to obtain the compound IN-4:

Compound IN-3 and a phosphonium salt are present in the presence of a strong organic base such as an alkali metal hydrocarbyl group (e.g., a C _1-4 alkyl group such as butyl or phenyl) derivative, preferably n-butyl lithium (e.g., MePh ₃ P ⁺ X" ^- , wherein X" is a halogen, preferably Br or I), undergoes a Wittig reaction to give compound IN-4. The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, and dimethylene. Sulfone 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 ° C). The reaction is preferably carried out for a suitable period of time (for example 1-3 h, for example 2 or 2.5 h) 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 base or an inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, hydrogencarbonate or acetate, such as lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, Potassium hydrogencarbonate, 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 (for example room temperature). The reaction is preferably carried out for a suitable period of 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 (such as diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, and dimethylene. Sulfone and any combination thereof, preferably dimethylformamide. The reaction is preferably carried out at a suitable temperature (for example room temperature). The reaction is preferably carried out for a suitable period of time (for example 8 to 18 hours or 10 to 12 hours) until the reaction is complete.

(5) A compound IN-7 is compounded with compound IN-4 to give a compound IN-8:

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

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

The compound IN-8 is reacted to obtain the compound of the formula (Ia) under conditions capable of removing the removable protecting group possessed by R ¹ ' to provide R ¹ . For example, when R ¹ 'is R"-OC(O)- and R" is as defined above (in this case, R ¹ is -EC(O)OR ⁵ , E is a bond and R ⁵ is hydrogen), This reaction can be carried out by hydrolysis under acidic conditions or by alcoholysis under basic conditions. Preferably, the reaction can be carried out by an alcoholysis reaction of an ester in the presence of an alcohol and a base. The alcohol can 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 the group consisting of tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dimethyl Sulfone and any combination thereof, preferably tetrahydrofuran. The reaction is preferably carried out at a suitable temperature (for example, room temperature to 80 ° C, such as 40 to 60 ° C). The reaction is preferably carried out for a suitable period of time (for example 2 to 6 hours, such as 3, 4 or 5 hours) until the reaction is complete.

(ii) A method of preparing the general formula (Ib) includes:

Wherein X' and R ¹ ' are as defined in the above method (i); PG is a suitable hydroxy protecting group such as a C _1-6 alkyl group, a benzyl group or a silane group (for example, trimethylsilyl (TMS), Triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) or tert-butyldiphenylsilyl (TBDPS), especially C _1-4 alkyl;

(1) The compound IN-9 is reacted with the compound IN-10 to give the compound IN-11:

The azide of formula IN-9 is reacted with an alkyne of formula IN-10 by cycloaddition to form 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 may be formed in situ from a system of Cu(II) salts 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 (such as 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 (eg, n-butanol, tert-butanol, ethanol, and isopropanol), Dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and any combination thereof. Preferably, the reaction is carried out at a suitable temperature, such as room temperature. The reaction is preferably carried out for a suitable period of time (for example 1-3 hours, for example 2 or 2.5 hours) until the reaction is complete.

(2) The compound IN-11 is deprotected to give the compound IN-12:

Compound IN-11 was converted to compound IN-12 under conditions in which the hydroxy protecting group PG was removed. 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 the group consisting of benzene, toluene and xylene, and any combination thereof, such as toluene. The reaction can be carried out at a suitable temperature (for example, room temperature). The reaction is preferably carried out for a suitable period of time (for example 1-3 hours, for example 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 (such as diethyl ether, ethylene glycol dimethyl ether, etc.), N-methylpyrrolidone, dioxane, and dimethylene. Sulfone 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 base or an inorganic base, preferably a basic inorganic or organic salt, especially an alkali metal carbonate, hydrogencarbonate or acetate, such as lithium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, Potassium hydrogencarbonate, 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 period of time (for example 2 to 6 hours, such as 3, 4 or 5 hours) until the reaction is complete.

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

The compound of the formula (Ib) is obtained by carrying out the reaction as described in the step (6) of the above method (i), except that the compound IN-8 is replaced by the compound IN-13.

(iii) A method of preparing the formula (Ic) includes:

Wherein X' and R ¹ ' are as defined in method (i) above;

(1) The compound IN-14 is subjected to a hydrazino reaction to obtain a 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 can 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 ° C, such as 90 to 110 ° C). The reaction is preferably carried out for a suitable period of time (for example 1-3 hours, for example 2 or 2.5 hours) until the reaction is complete.

(2) An acylation reaction of 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 halogenated hydrocarbons (for example, dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane), dimethylformamide, dimethylacetamide, and any combination thereof. Preferably, dichloromethane is used. The reaction is preferably carried out in the presence of a suitable base. Preferably, the base is an organic base such as an organic amine such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine or pyridine, preferably N,N-diisopropyl B. amine. The reaction is preferably carried out at a suitable temperature (for example room temperature). The reaction is preferably carried out for a suitable period of time (for example 10 to 24 hours or 12 to 20 hours) until the reaction is complete.

(3) The compound IN-17 is subjected to a ring-closing reaction to obtain a compound IN-18:

Compound IN-17 is subjected to a ring-closing reaction with a suitable dehydrating agent such as 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 the group consisting of acetonitrile, alcohols (eg, n-butanol, tert-butanol, ethanol, and isopropanol), dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetamide, acetone, and random combination. The reaction is preferably carried out at a suitable temperature. The reaction is preferably carried out for a suitable period of time (for example 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 in accordance with the step (3) of the above method (ii) to give the compound IN-19, except that the compound IN-12 was used instead of the compound IN-12.

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

The compound of the formula (Ic) is obtained by carrying out the reaction as described in the step (6) of the above method (i), except that the compound IN-9 is used instead of the compound IN-8.

(iv) A method of preparing the formula (Id) includes:

Wherein R ¹ 'and X' are as defined in method (i) above and PG is as defined in method (ii) above;

(1) A compound IN-7 is compounded with compound IN-10 to give a compound IN-20:

In some cases, the protecting group PG (eg, a silane group) will 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 in accordance with the step (3) of the above method (ii), except that the compound IN-20 was used instead of the compound IN-12 to give the compound IN-21.

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

The compound of the formula (Id) is obtained by carrying out the reaction as described in the step (6) of the above method (i), except that the compound IN-21 is used instead of the compound IN-8.

The term "suitable" as used herein means that the choice of a particular compound or condition will depend on the particular synthetic operation being performed and the characteristics of the molecule or molecules to be transformed, but such selection is within the skill of the art. . All of the processes/methods described herein are carried out under conditions sufficient to provide the product shown. 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 these Variations are within the abilities of those skilled in the art.

The examples provide exemplary methods of preparing compounds of formula (I). Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of formula (I). While specific 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 prepared by the methods can be further modified with reference to the present disclosure using conventional chemistry well known to those skilled in the art.

In the preparation of compounds of formula (I), it may be desirable to protect the distal functional groups of the intermediate (e.g., carboxyl or amino groups). The need for such protection can vary with the nature of the remote functional groups and the conditions of the method of preparation. Those skilled in the art will readily determine the need for such protection. For an overview of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Example

The invention is further described in the following examples, but these examples 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). ^{The 1} H-NMR shift (δ) is given in parts per million (ppm). Chemical shifts are given in units of 10 ^-6 (ppm).

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

Preparation of high performance liquid phase using Shimadzu preparative high performance liquid chromatography.

Thin layer chromatography silica gel plates (TLC) were prepared using an aluminum plate (20 x 20 cm) manufactured by Merck, and separated by thin layer chromatography using GF 254 (0.4 to 0.5 mm).

The reaction was monitored by thin layer chromatography (TLC) or LC-MS. The developing solvent system used was: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio. The adjustment is carried out depending on the polarity of the compound or by adding triethylamine or the like.

Microwave reaction

Initiator + (400 W, RT ~ 300 ° C) microwave reactor.

Column chromatography generally uses 200 to 300 mesh silica gel as a carrier. The system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.

The reaction temperature of the examples is room temperature (20 ° C to 30 ° C) unless otherwise specified.

The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., and the like.

In the conventional synthesis method and the synthesis examples of the examples and the intermediates, each abbreviation has the following meaning.

Abbreviation

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

First step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (2.5 g, 15.9 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (4.8 g , 15.9 mmol) was dissolved in DMF (50 mL). EtOAc (EtOAc,EtOAc. Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: Preparation of 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

Methyltriphenylphosphonium bromide (7.7 g, 23.8 mmol) was dissolved in tetrahydrofuran (150 mL), n-butyllithium (9.5 mL, 23.8 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the first step (4.58 g, 10.8 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 2: Preparation of methyl 4-(chloro(hydroxyimino)methyl)benzoate

First step: Preparation of methyl 4-((hydroxyimino)methyl)benzoate

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

Second step: Preparation of methyl 4-(chloro(hydroxyimino)methyl)benzoate

The compound obtained in the first step (3 g, 16.8 mmol) was dissolved in DMF (20 mL). Then, the reaction liquid was poured into water and filtered to give the title compound (2.9 g, yield: 81%).

Intermediate Preparation Example 3: Preparation of methyl 3-(chloro(hydroxyimino)methyl)benzoate

Substituting methyl 3-formylbenzoate (10 g, 59.2 mmol) for methyl 4-formylbenzoate, the title compound (3.1 g, yield: 86.3%).

Intermediate Preparation Example 4: Preparation of 6-(chloro(hydroxyimino)methyl)nicotinic acid methyl ester

The title compound (95 mg, yield: 78.6%) was obtained from the title compound (yield: 78.6%).

Intermediate Preparation Example 5: Preparation of 2-(Chloro(hydroxyimino)methyl)isonicotinate

Intermediate Preparation Example 6 Preparation of 5-(Chloro(hydroxyimino)methyl)nicotinate

The title compound (573 mg, yield: 86.9%) was obtained from the title compound (yield: 86.9%).

Intermediate Preparation Example 7: Preparation of 5-(chloro(hydroxyimino)methyl)nicotinic acid methyl ester

The methyl 4-formylpyridine-2-carboxylate (1 g, 6.06 mmol) was used instead of methyl 4-formylbenzoate to give the title compound (810 mg, yield: 62.3%). ).

Intermediate Preparation Example 8 Preparation of 5-(Chloro(hydroxylamine)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

First step: Preparation of methyl 1-isopropyl-1H-pyrazole-3,5-dicarboxylate

Methyl 1H-pyrazole-3,5-dicarboxylate (10.0 g, 54.3 mmol) was dissolved in DMF (50 mL), and sodium hydride (3.6 g, 90 mmol) was added portionwise at 0 ° C and stirred at 0 ° C 30 minute. Then, isopropyl bromide (10.5 g, 85.2 mmol) in DMF (20 mL) was added and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of EtOAc. EtOAc (EtOAc)

Second step: Preparation of 1-isopropyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carboxylic acid

The compound obtained in the first step (5.8 g, 25.6 mmol) was dissolved in methanol (50 mL), and a saturated aqueous solution of potassium hydroxide (25 mL) was added dropwise at 0 ° C, and the mixture was reacted at 0 ° C for 4 hours. Then, the pH of the reaction mixture was adjusted to 4 with 2N hydrochloric acid and then quenched. The reaction mixture was extracted with EtOAc (EtOAc m.

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

The compound obtained in the second step (1.7 g, 8.0 mmol) was dissolved in tetrahydrofuran (30 mL). The reaction was quenched with EtOAc (3 mL).

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

The compound obtained in the third step (3.9 g, 19.7 mmol) was dissolved in tetrahydrofuran (50 mL), and activated manganese dioxide (17.1 g, 197 mmol) was added and reacted at 60 ° C overnight. The reaction mixture was filtered, and the filtrate was evaporated.

Step 5: Preparation of methyl 5-(hydroxylaminemethyl)-1-isopropyl-1H-pyrazole-3-carboxylate

The compound obtained in the fourth step (800 mg, 4.08 mmol) was dissolved in anhydrous ethanol (20 mL), and sodium acetate (463.5 mg, 5.65 mmol) and hydroxylamine hydrochloride (565.6 mg, 8.14 mmol) were added and allowed to stand overnight at room temperature. Then, the reaction mixture was poured into water, EtOAc (EtOAc)

Step 6: Preparation of 5-(chloro(hydroxylamine)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound obtained in the fifth step (300 mg, 1.42 mmol) was dissolved in DMF (10 mL). The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation 9: Preparation of 5-(Chloro(hydroxylamine)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester

First step: Preparation of methyl 1-methyl-1H-pyrazole-3,5-dicarboxylate

Methyl 1H-pyrazole-3,5-dicarboxylate (3.0 g, 16.3 mmol) was dissolved in DMF (50 mL), and sodium hydride (1.1 g, 27.7 mmol) was added portionwise at 0 ° C and then stirred at 0 ° C 30 minutes. Then, methyl iodide (2.3 g, 16.3 mmol) in DMF (20 mL) was added and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of EtOAc. EtOAc (EtOAc)

The second step: preparation of methyl 1-methyl-3-carboxylate-1H-pyrazole-5-carboxylic acid

The compound obtained in the first step (1.8 g, 9.1 mmol) was dissolved in methanol (50 mL), and a saturated aqueous solution of potassium hydroxide (25 mL) was added dropwise at 0 ° C, and the mixture was reacted at 0 ° C for 4 hours. Then, the pH of the reaction mixture was adjusted to 4 with 2N hydrochloric acid and then quenched. The reaction mixture was extracted with EtOAc (EtOAc m.

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

The compound obtained in the second step (1.7 g, 9.2 mmol) was dissolved in tetrahydrofuran (30 mL). The reaction was then quenched with EtOAc (EtOAc)EtOAc.

The fourth step: preparation of methyl 1-methyl-3-carboxylate-1H-pyrazole-5-formaldehyde

The compound obtained in the third step (100 mg, 0.59 mmol) was dissolved in tetrahydrofuran (50 mL), and activated manganese dioxide (510.8 mg, 5.9 mmol) was added and reacted at 60 ° C overnight. The reaction mixture was filtered, and the filtrate was evaporated.

Step 5: Preparation of methyl 5-((hydroxylamine)methyl)-1-methyl-1H-pyrazole-3-carboxylate

The compound obtained in the fourth step (800 mg, 4.76 mmol) was dissolved in anhydrous ethanol (20 mL), and sodium acetate (463.0 mg, 5.64 mmol) and hydroxylamine hydrochloride (566.0 mg, 8.14 mmol) were added and allowed to stand overnight at room temperature. Then, the reaction mixture was poured into water, EtOAc (EtOAc)

Step 6: Preparation of 5-(chloro(hydroxylamine)methyl)-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound obtained in the fifth step (300 mg, 1.64 mmol) was dissolved in DMF (10 mL), and the mixture was stirred at 0 ° C, NCS (207.0 mg, 1.55 mmol) and stirred at room temperature for 6 hr. The reaction mixture was extracted with EtOAc.

Intermediate Preparation Example 10: Preparation of 5-(Chloro(hydroxylamine)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid methyl ester

First step: Preparation of methyl 1-ethyl-1H-pyrazole-3,5-dicarboxylate

The 1H-pyrazole-3,5-dicarboxylic acid methyl ester (4.0 g, 21.7 mmol) was dissolved in DMF (50 mL), and sodium hydride (2.5 g, 62.5 mmol) was added portionwise at 0 ° C and then stirred at 0 ° C 30 minutes. Then, a solution of bromoethane (2.6 g, 24.3 mmol) in DMF (20 mL) was added and stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous solution of EtOAc. EtOAc (EtOAc)

Step 2: Preparation of 1-ethyl-3-carboxylic acid methyl ester-1H-pyrazole-5-carboxylic acid

The compound obtained in the first step (1.8 g, 8.5 mmol) was dissolved in methanol (50 mL), and a saturated aqueous solution of potassium hydroxide (25 mL) was added dropwise at 0 ° C, and the mixture was reacted at 0 ° C for 4 hours. Then, the pH of the reaction mixture was adjusted to 4 with 2N hydrochloric acid and then quenched. The reaction mixture was extracted with EtOAc (EtOAc m.

The third step: preparation of methyl 1-ethyl-3-carboxylate-1H-pyrazole-5-methanol

The compound obtained in the second step (1.7 g, 8.6 mmol) was dissolved in tetrahydrofuran (30 mL). Then, the reaction was quenched with MeOH (10 mL).

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

The compound obtained in the third step (0.1 g, 0.54 mmol) was dissolved in tetrahydrofuran (50 mL), and activated manganese dioxide (443.0 mg, 5.4 mmol) was added and reacted at 60 ° C overnight. The reaction mixture was filtered, and the filtrate was evaporated.

Step 5: Preparation of 5-((hydroxylamine)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound obtained in the fourth step (800 mg, 4.39 mmol) was dissolved in anhydrous ethanol (20 mL), and sodium acetate (463 mg, 5.65 mmol) and hydroxylamine hydrochloride (566 mg, 8.14 mmol) were added and allowed to stand overnight at room temperature. Then, the reaction mixture was poured into water, EtOAc (EtOAc)

Step 6: Preparation of 5-(chloro(hydroxylamine)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid methyl ester

The compound obtained in the fifth step (300 mg, 1.52 mmol) was dissolved in DMF (10 mL), and the mixture was stirred at 0 ° C, NCS (207 mg, 1.55 mmol) and stirred at room temperature for 6 hr. The reaction mixture was extracted with EtOAc.

Intermediate Preparation Example 11: 2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde hydrazide preparation

First step: 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 (200 mg, 0.47 mmol) was dissolved in Sodium acetate (50.9 mg, 0.62 mmol) and hydroxylamine hydrochloride (66.0 mg, 0.95 mmol) were added to water ethanol (10 mL) and the mixture was stirred at room temperature overnight. Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)chlorobenzaldehyde oxime

The compound obtained in the first step (200 mg, 0.46 mmol) was dissolved in DMF (10 mL), and NCS (80 mg, 0.60 mmol) was added dropwise at 0 ° C and stirred at room temperature for 6 hr. The reaction mixture was extracted with EtOAc EtOAc.

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

First step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (2 g, 12.8 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole (3.5 g, 12.8 mmol) was dissolved in DMF (50 mL). EtOAc (EtOAc,EtOAc. Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: Preparation of 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole

Methyltriphenylphosphonium bromide (4.2 g, 11.8 mmol) was dissolved in tetrahydrofuran (25 mL), n-butyllithium (5.9 mL, 11.8 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the first step (2.5 g, 6.4 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 13: 4-((3-Chloro-4-(prop-1-en-2-yl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichloro Preparation of phenyl)isoxazole

First step: 1-(2-chloro-4-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)phenyl)ethanone Preparation

2-Chloro-4-hydroxyacetophenone (1 g, 5.9 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole (1.8 g 5.9 mmol) was dissolved in DMF (50 mL). Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: 4-((3-chloro-4-(prop-1-en-2-yl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl Preparation of isoxazole

Methyltriphenylphosphonium bromide (4.3 g, 12.0 mmol) was dissolved in tetrahydrofuran (60 mL), n-butyllithium (6.0 mL, 12.0 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the first step (2.6 g, 5.9 mmol) in tetrahydrofuran (25 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 14: 5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-(((6-(trifluoromethyl)-5-vinylpyridin-2-yl)oxy) Preparation of methyl)isoxazole

First step: 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)nicotinic acid Preparation of ester

Ethyl 6-hydroxy-2-trifluoromethylnicotinate (1 g, 4.3 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) isomer The azole (1.3 g, 4.3 mmol) was dissolved in DMF (50 mL). Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: (6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)pyridine- Preparation of 3-base)methanol

Lithium aluminum hydride (90.0 mg, 2.7 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and stirred at 0 ° C for 15 min. Then, a solution of the compound obtained in the first step (1.1 g, 2.2 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred and stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc. EtOAc m.

Third step: 6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)nitroal preparation

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

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

Methyltriphenylphosphonium bromide (0.86 g, 2.4 mmol) was dissolved in tetrahydrofuran (16 mL), n-butyllithium (1.2 mL, 2.4 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the third step (1.0 g, 2.2 mmol) in tetrahydrofuran (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 15: 4-((3-Chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole preparation

First step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (0.5 g, 3.2 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole ( 1.0 g, 3.2 mmol) was dissolved in DMF (50 mL) EtOAc. Then, the reaction mixture was poured into water, EtOAc (EtOAc)

Second step: Preparation of 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole

Methyltriphenylphosphonium bromide (4.2 g, 11.8 mmol) was dissolved in tetrahydrofuran (25 mL), n-butyllithium (5.9 mL, 11.8 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the first step (2.5 g, 5.9 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 16: 4-((3-Chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole Preparation

First step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (0.5 g, 3.2 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (1.0 g, 3.2 mmol) was dissolved in DMF (50 mL)EtOAc. Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: Preparation of 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole

Methyltriphenylphosphonium bromide (4.2 g, 11.8 mmol) was dissolved in tetrahydrofuran (25 mL), n-butyllithium (5.9 mL, 11.8 mmol) was added dropwise at -78 ° C and stirred at this temperature for 1 hour. . Then, a solution of the compound obtained in the first step (2.5 g, 5.7 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was extracted with EtOAc EtOAc.

Intermediate Preparation Example 17: 4-((3-Chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole Preparation

First step: Preparation of 2-chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (0.5 g, 3.2 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole (1.0 g, 3.2 mmol) was dissolved in DMF (50 mL)EtOAc. Then, the reaction mixture was poured into EtOAc (EtOAc m.

Second step: Preparation of 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole

Preparation of the compounds of the invention

Example 1: 4-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 1)

First step: 4-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)benzoate (Compound 29)

The compound obtained in Intermediate Preparation Example 2 (300.0 mg, 1.40 mmol) and the compound obtained in Intermediate Preparation Example 1 (589.0 mg, 1.40 mmol) were added to triethylamine (5 mL) and allowed to react at room temperature for 12 hours. Then, the reaction solution was poured into water (60 mL) and extracted with dichloromethane (40 mL, 4). The organic phase was washed with aq. EtOAc (EtOAc m.

MS m/z (ESI): 597.1 [M+H] ⁺

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.12 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.40-7.29 (m, 4H), 6.84 (d, J) =2.4 Hz, 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), 1.7-1.12 (m, 2H).

Second step: 4-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 1)

The compound obtained in the first step (100.0 mg, 0.17 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL), and a saturated aqueous solution of potassium hydroxide (1 mL) was added and reacted at 40 ° C for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N aqueous hydrochloric acid, and then ethyl acetate was evaporated. ).

MS m/z (ESI): 583.2 [M+H] ⁺

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.12 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.40-7.29 (m, 4H), 6.84 (d, J) =2.4 Hz, 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), 1.7-1.12 (m, 2H).

Example 2: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 2)

First step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)benzoate (Compound 30)

The compound obtained in Intermediate Preparation Example 3 (300.0 mg, 1.40 mmol) and the compound obtained in Intermediate Preparation Example 1 (589.0 mg, 1.40 mmol) were added to triethylamine (5 mL), and reacted at room temperature for 12 hours. The reaction mixture was poured into water (60 mL), EtOAc (EtOAc) The title compound (500 mg, yield: 60%) of this step was obtained.

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 = 2.4 Hz, 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).

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 2)

The compound obtained in the first step (100.0 mg, 0.17 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL), and a saturated aqueous solution of potassium hydroxide (1 mL) was added and reacted at 40 ° C for 2 hours. Then, the organic solvent was removed, and the aqueous layer was adjusted to pH with EtOAc (EtOAc) (EtOAc) .

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 = 2.4 Hz, 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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 3)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (Compound 31)

Methyl 5-(chloro(hydroxylamine)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (300.0 mg, 1.22 mmol), 4-((3-chloro-4-vinylphenoxy) Methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (515.0 mg, 1.22 mmol) was added to triethylamine (5 mL) and allowed to react at room temperature for 12 hours. . Then, the reaction mixture was poured into water (60 mL), EtOAc (EtOAc m. The title compound of this step (400 mg, 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 = 2.4 Hz, 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 = 6.4 Hz, 6H), 1.23-1.10 (m, 5H) ),

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 3)

The compound obtained in the first step (100.0 mg, 0.16 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL) and methanol (2 mL), and a saturated aqueous solution of potassium hydroxide (1 mL) was added and reacted at 40 ° C for 2 hours. Then, the reaction mixture was poured into water (20 mL), EtOAc (EtOAc m. The title compound (60 mg, 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 = 2.4 Hz, 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 = 6.4 Hz, 6H), 1.23-1.10 (m, 5H),

Example 4: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -1H-1,2,3-triazol-1-yl)benzoic acid (Compound 4)

First step: Preparation of 4-(2-chloro-4-methoxyphenyl)-2-methylbut-3-yn-2-ol

Add bis(cyanobenzene)palladium dichloride (150 mg, 0.39 mmol) and cuprous iodide (51.6 mg, 0.27 mmol) to the reactor, add dioxane (20 mL), and add three under nitrogen. tert-Butylphosphine (0.2 mL, 0.85 mmol) and diisopropylamine (2.1 mL, 14.9 mmol) followed by the compound 1-bromo-2-chloro-4-methoxybenzene (3 g, 13.6 mmol) and 2- Chitin-3-yn-2-ol (1.56 mL, 16.1 mmol). 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 EtOAc.

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

The compound obtained in the first step (2.0 g, 8.92 mmol) was dissolved in toluene (40 mL), and sodium hydroxide (360 mg, 9.0 mmol) was added and heated under reflux for 3 hours under nitrogen atmosphere. Water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with EtOAc.

The third step: preparation of methyl 3-azidobenzoate

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

Fourth step: Preparation of methyl 3-(4-(2-chloro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)benzoate

The compound obtained in the third step (319.8 mg, 1.8 mmol), 2-chloro-1-ethynyl-4-methoxybenzene (300 mg, 1.8 mmol) and copper sulfate pentahydrate (28.7 mg, 0.18 mmol) were dissolved. Water (8 mL) and acetonitrile (4 mL) were added to hydrazine hydrate (87.5 μL, 1.8 mmol), and the mixture was stirred at room temperature for 2 hours. The solid was filtered, washed with water and dried then evaporated

Step 5: Preparation of methyl 3-(4-(2-chloro-4-hydroxyphenyl)-1H-1,2,3-triazol-1-yl)benzoate

The compound obtained in the fourth step (100 mg, 0.29 mmol) was dissolved in toluene (2 mL), and boron tribromide (145 mg, 0.58 mmol) was added dropwise on 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 EtOAc.

Step 6: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-1H-1,2,3-triazol-1-yl)benzoate (Compound 32)

The compound obtained in the fifth step (50 mg, 0.15 mmol) was dissolved in DMF (2 mL), potassium carbonate (61.8 mg, 0.45 mmol), then 4-(chloromethyl)-5-cyclopropyl-3- ( 2,6-Dichlorophenyl)isoxazole (45 mg, 0.15 mmol). The mixture was stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with EtOAc. .

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) .

Step 7: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -1H-1,2,3-triazol-1-yl)benzoic acid (Compound 4)

The compound obtained in the sixth step (70 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2mL) and methanol (1mL), then potassium hydroxide (33mg, 0.59mmol). The mixture was stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with EtOAc.

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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of isoxazol-3-yl)benzoic acid (Compound 5)

First step: Preparation of methyl 3-(5-(2-chloro-4-hydroxyphenyl)isoxazol-3-yl)benzoate

(3-Chloro-4-ethynylphenoxy)tert-butyldimethylsilane (200 mg, 0.75 mmol) and methyl 3-(chloro(hydroxyimino)methyl)benzoate (256 mg, 1.2 mmol) Dissolved in dichloromethane (20 mL), added triethylamine (303 mg, 3 mmol). Then, the reaction mixture was evaporated to dryness crystals crystals

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl isoxazol-3-yl)benzoate (compound 33)

The compound obtained in the first step (224 mg, 0.68 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (206 mg, 0.68 mmol) were dissolved. Potassium carbonate (282 mg, 2.04 mmol) was added to DMF (20 mL). The reaction mixture was poured into water, and the mixture was evaporated, evaporated, evaporated, evaporated

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 = 2.4 Hz, 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: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of isoxazol-3-yl)benzoic acid (Compound 5)

The compound obtained in the second step (95 mg, 0.16 mmol) was dissolved in methanol (10 mL), and a saturated aqueous solution of potassium hydroxide (1 mL) was added and reacted at 40 ° C for 2 hours. Then, the organic solvent was removed, and the aqueous layer was adjusted to EtOAc (EtOAc) (EtOAc) .

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 = 2.4 Hz, 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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-1,3,4-oxadiazol-2-yl)benzoic acid (Compound 6)

First step: Preparation of 2-chloro-4-hydroxybenzoyl hydrazide

Methyl 2-chloro-4-hydroxybenzoate (2 g, 10.8 mmol) was dissolved in methanol (15 mL) then EtOAc (5 mL). The mixture was stirred at 90 ° C for 2 hours. After concentration, the title compound (2 g, yield: 100.0%) was obtained.

Second step: Preparation of methyl 3-(2-(2-chloro-4-hydroxybenzoyl)hydrazinecarbonyl)benzoate

The compound obtained in the first step (200 mg, 1.1 mmol) was dissolved in dichloromethane (4mL), then DIPEA (283.8mg, 2.2mmol), then 3-(chlorocarbonyl)benzoic acid methyl ester (200mg, 1.1mmol) A solution of dichloromethane (2 mL). The mixture was stirred at room temperature overnight. Water and methylene chloride were added to the mixture, and the methylene chloride layer was washed with EtOAc.

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 (50 mg, 0.14 mmol) was dissolved in acetonitrile (3 mL) and then EtOAc (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 EtOAc.

Step 4: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-1,3,4-oxadiazol-2-yl)benzoate (compound 34)

The compound obtained in the third step (10 mg, 0.03 mmol) was dissolved in DMF (2 mL), potassium carbonate (8.16 mg, 0.06 mmol), and then 4-(chloromethyl)-5-cyclopropyl-3- ( 2,6-Dichlorophenyl)isoxazole (9.5 mg, 0.03 mmol). The mixture was stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with EtOAc. .

MS m/z (ESI): 596.1 [M+H] ⁺

^{1 H-NMR (400MHz, CDCl3} ) 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).

Step 5: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-1,3,4-oxadiazol-2-yl)benzoic acid (Compound 6)

The compound obtained in the fourth step (15 mg, 0.025 mmol) was dissolved in tetrahydrofuran (2mL) and methanol (1mL), then potassium hydroxide (4.8mg, 0.086mmol). The mixture was stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the ethyl acetate layer was washed with EtOAc.

MS m/z (ESI): 582.0 [M+H] ⁺

^{1 H-NMR (400MHz, CDCl3} ) 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: 6-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of isoxazolyl-3-yl)nicotinic acid (compound 7)

First step: Preparation of 6-(5-(2-chloro-4-hydroxyphenyl)isoxazol-3-yl)methyl nicotinate

(3-Chloro-4-ethynylphenoxy)-tert-butyldimethylsilane (66 mg, 0.41 mmol) and the compound obtained in Intermediate Preparation 4 (166 mg, 0.81 mmol) were dissolved in dichloromethane (5mL) Triethylamine (124 mg, 1.23 mmol) was added and stirred at room temperature overnight. Then, the reaction mixture was evaporated to dryness crystals crystals crystals

Second step: 6-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of isoxazolyl-3-yl)methylnicotinate (Compound 35)

The compound obtained in the first step (60 mg, 0.18 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (67 mg, 0.22 mmol) were dissolved. Potassium carbonate (50 mg, 0.36 mmol) was added to DMF (5 mL). The reaction mixture was poured into water, and the mixture was evaporated.

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 = 2.4 Hz, 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: 6-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of isoxazolyl-3-yl)nicotinic acid (compound 7)

The compound obtained in the second step (27 mg, 0.05 mmol) was dissolved in methanol (5 mL). Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N aqueous hydrochloric acid, and ethyl acetate was evaporated. ).

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 = 8.8 Hz, 1H), 7.65-7.49 (m, 4H), 7.19 (d, J = 2.4 Hz, 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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazole-3-yl)nicotinic acid (Compound 8)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazole-3-yl)nicotinate (compound 36)

The compound obtained in Intermediate Preparation Example 6 (50 mg, 0.23 mmol) and the compound obtained in Intermediate Preparation Example 1 (63 mg, 0.15 mmol) were added to triethylamine (5 mL), and reacted at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure.

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=8.0 Hz, 1H), 7.00 (d, J=4.0 Hz, 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).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of -4,5-dihydroisoxazole-3-yl)nicotinic acid (Compound 8)

The compound obtained in the first step (96 mg, 0.16 mmol) was dissolved in a mixed solvent of methanol (4 mL) and tetrahydrofuran (2 mL), and a saturated aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at 60 ° C for 2 hours. Then, the organic solvent was evaporated, and the obtained aqueous layer was evaporated to ethyl acetate (yield: EtOAc) ).

MS m / z (ESI): 584.2 [M + H] +

¹ H-NMR (400MHz, CDCl ₃ ) δ: 14.00 (s, 1H), 8.81 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.87-7.86 (m, 1H), 7.61-7.51 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 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: 2-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)isonicotinic acid (Compound 9)

First step: 2-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)isonicotinate (Compound 37)

The compound obtained in Intermediate Preparation Example 5 (50 mg, 0.23 mmol) and the compound obtained in Intermediate Preparation Example 1 (63 mg, 0.15 mmol) were added to triethylamine (5 mL) and allowed to react at room temperature for 12 hours. Then, the reaction mixture was concentrated under reduced pressure.

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).

Second step: 2-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)isonicotinic acid (Compound 9)

The compound obtained by the first step (54 mg, 0.09 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (1 mL), and a saturated aqueous sodium hydroxide solution (0.5 mL) was added and the mixture was reacted at 60 ° C for 2 hours. Then, the organic solvent was evaporated, and the aqueous layer was evaporated to ethyl acetate. EtOAcjjjjjjjjjjjj ).

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 10)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl 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 (108 mg, 0.26 mmol) And 5-(chloro(hydroxylamine)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.40 mmol) was dissolved in dichloromethane (3 mL). 3 mL), reacted at room temperature for 12 hours. The reaction mixture was poured into water (60 mL), EtOAc (EtOAc) The title compound (30 mg, yield: 12.5%) of this step was obtained.

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).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 10)

The compound obtained in the first step (30 mg, 0.05 mmol) was dissolved in methanol (5 mL), and a saturated aqueous sodium hydroxide (1 mL) was added and the mixture was reacted at 60 ° C for 2 hours. Then, the organic solvent was evaporated, and the aqueous layer was evaporated to ethyl acetate (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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-1,2,4-oxadiazol-3-yl)benzoic acid (Compound 57)

First step: Preparation of methyl 3-(N-hydroxymethylindenyl)benzoate

Methyl 3-cyanobenzoate (3 g, 18.6 mmol) and hydroxylamine hydrochloride (1.5 g, 22.3 mmol) were dissolved in ethanol (50 mL), and potassium hydroxide (1.2 g, 22.3 mmol) was added and reacted at 90 ° C for 2 hours. . The title compound (2.8 g, yield: 77.8%) was obtained.

Second step: Preparation of methyl 3-(5-(2-chloro-4-hydroxyphenyl)-1,2,4-oxadiazol-3-yl)benzoate

The compound obtained in the first step (113 mg, 0.58 mmol) and 2-chloro-4-hydroxybenzoyl chloride (222 mg, 1.16 mmol) was dissolved in pyridine (5 mL) The reaction solution was cooled, diluted with ethyl acetate and washed with diluted hydrochloric. The organic phase was concentrated, and the residue was crystallijjjjjj

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

The compound obtained in the second step (90 mg, 0.27 mmol), 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (97 mg, 0.32 mmol) Potassium carbonate (75 mg, 0.54 mmol) was added to DMF (5 mL). The reaction mixture was extracted with water and ethyl acetate. EtOAc was evaporated. .

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).

Step 4: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-1,2,4-oxadiazol-3-yl)benzoic acid (Compound 57)

The compound obtained in the third step (140 mg, 0.23 mmol) was dissolved in methanol (4 mL) and THF (2 mL), and aqueous sodium hydroxide (18 mg, 0.46 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography chromatography

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (Compound 20)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)-1-methyl-1H-pyrazole-3-carboxylate (Compound 47)

Methyl 5-(chloro(hydroxyimino)methyl)-1-methyl-1H-pyrazole-3-carboxylate (0.7 g, 3.2 mmol) and 4-((3-chloro-4-vinylbenzene) Oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.1 g, 2.6 mmol) was added to triethylamine (5 mL) and reacted at room temperature 12 hour. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-methyl-1H-pyrazole-3-carboxylic acid (Compound 20)

The compound obtained in the first step (0.3 g, 0.5 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (4 mL), and aqueous sodium hydroxide (40 mg, 1 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by EtOAcqqqqqq

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)) methoxy)benzene Preparation of 4,5-dihydroisoxazole-3-yl)-picolinic acid (Compound 21)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)-picolinate (Compound 48)

Methyl 5-(chloro(hydroxyimino)methyl)pyridinecarboxylate (200 mg, 0.93 mmol) and 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl- 3-(2,6-Dichlorophenyl)isoxazole (310 mg, 0.74 mmol) was added to triethylamine (15 mL) and was allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-picolinic acid (Compound 21)

The compound obtained in the first step (200 mg, 0.33 mmol) was dissolved in methanol (2mL) and THF (4mL), and aqueous sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by EtOAc (EtOAc)

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: 3-(3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)) methoxy)benzene Preparation of 4,5-dihydroisoxazole-5-yl)benzoic acid (Compound 22)

3-vinylbenzoic acid (100 mg, 0.67 mmol) and 2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy Base-N-benzyl benzamidine chloride (300 mg, 0.64 mmol) was added to triethylamine (10 mL) and allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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: 3-(5-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoro) Preparation of methyl)pyridin-3-yl)-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 24)

First step: 3-(5-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoro) Preparation of methyl methyl)pyridin-3-yl)-4,5-dihydroisoxazol-3-yl)benzoate (Compound 51)

Methyl 3-(chloro(hydroxyimino)methyl)benzoate (150 mg, 0.70 mmol) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((6-(6-) (Trifluoromethyl)-5-vinylpyridin-2-yl)oxy)methyl)isoxazole (300 mg, 0.66 mmol) was added to triethylamine (10 mL) and allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 3-(5-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoro) Preparation of methyl)pyridin-3-yl)-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 24)

The compound obtained in the first step (300 mg, 0.47 mmol) was dissolved in methanol (3 mL) and THF (6 mL), and aqueous sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography.

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 = 9.2 Hz, 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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 25)

First step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl phenyl)-4,5-dihydroisoxazol-3-yl)benzoate (Compound 52)

Methyl 3-(chloro(hydroxylamine)methyl)benzoate (52 mg, 0.24 mmol) and 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl-3- (2-(Difluoromethoxy)phenyl)isoxazole (100 mg, 0.24 mmol) was added to triethylamine (5 mL) and was allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 25)

The compound obtained in the first step (130 mg, 0.22 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (6 mL), and aqueous solution of sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography chromatography

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-ethyl-1H-pyrazole-3-carboxylic acid (Compound 27)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)-1-ethyl-1H-pyrazole-3-carboxylate (Compound 54)

Methyl 5-(chloro(hydroxyimino)methyl)-1-ethyl-1H-pyrazole-3-carboxylate (1.4 g, 6.1 mmol) and 4-((3-chloro-4-vinylbenzene) Oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (2.2 g, 5.2 mmol) was added to triethylamine (5 mL) and reacted at room temperature 12 hour. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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 = 6.4 Hz, 2H), 3.89 (s, 3H), 3.95-3.88 (m, 1H), 2.48-2.41 (m, 1H), 1.33-1.10 ( m, 8H).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-ethyl-1H-pyrazole-3-carboxylic acid (Compound 27)

The compound obtained in the first step (0.6 g, 0.97 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (4 mL), and aqueous solution of sodium hydroxide (40 mg, 1 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography.

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 = 6.4 Hz, 2H), 3.95-3.88 (m, 1H), 2.48-2.41 (m, 1H), 1.33-1.10 ( m, 8H).

Example 18: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 58)

First step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl phenyl)-4,5-dihydroisoxazol-3-yl)benzoate (compound 66)

Methyl 3-(chloro(hydroxyimino)methyl)benzoate (200 mg, 0.94 mmol) and 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl- 3-(2-(Trifluoromethoxy)phenyl)isoxazole (400 mg, 0.92 mmol) was added to triethylamine (5 mL) and was allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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=2.4 Hz, 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).

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Of phenyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 58)

The compound obtained in the first step (180 mg, 0.29 mmol) was dissolved in methanol (3 mL) and tetrahydrofuran (6 mL), and aqueous solution of sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography.

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 = 2.4 Hz, 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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 59)

First step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl phenyl)-4,5-dihydroisoxazol-3-yl)benzoate (Compound 67)

Methyl 3-(chloro(hydroxyimino)methyl)benzoate (200 mg, 0.94 mmol) and 4-((3-chloro-4-vinylphenoxy)methyl)-5-cyclopropyl- 3-(2-(Trifluoromethoxy)phenyl)isoxazole (395 mg, 0.94 mmol) was added to triethylamine (5 mL) and was allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut elut

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=2.4 Hz, 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).

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 59)

The compound obtained in the first step (200 mg, 0.34 mmol) was dissolved in methanol (3 mL) and THF (6 mL), and aqueous sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography.

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 60)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (Compound 68)

Methyl 5-(chloro(hydroxyimino)methyl)-1-methyl-1H-pyrazole-3-carboxylate (200 mg, 0.81 mmol) and 4-((3-chloro-4-vinylphenoxy) Methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (301 mg, 0.69 mmol) was added to triethylamine (15 mL) and reacted at room temperature 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut elut

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 = 6.8 Hz, 6H), 1.18-1.08 (m, 5H).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Preparation of phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 60)

The compound obtained in the first step (300 mg, 0.47 mmol) was dissolved in methanol (4 mL) and THF (8 mL), and aqueous sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine.

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 = 6.8 Hz, 6H), 1.18-1.08 (m, 5H).

Example 21: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)) Preparation of Phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 61)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (Compound 69)

Methyl 5-(chloro(hydroxyimino)methyl)-1-methyl-1H-pyrazole-3-carboxylate (250 mg, 1.02 mmol) and 4-((3-chloro-4-vinylphenoxy) Methyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazole (400 mg, 0.95 mmol) was added to triethylamine (15 mL) and reacted at room temperature 12 hour. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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 = 6.8 Hz, 6H), 1.19-1.08 (m, 5H).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of Phenyl)-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 61)

The compound obtained in the first step (300 mg, 0.48 mmol) was dissolved in methanol (4mL) and THF (8 mL), and aqueous sodium hydroxide (32.0 mg, 0.80 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography.

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 = 6.8 Hz, 6H), 1.19-1.08 (m, 5H).

Example 22: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 62)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl 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 (230 mg, 0.94 mmol) and 4-((3-chloro-4-(propyl)- 1-Alken-2-yl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (407 mg, 0.94 mmol) was added to triethylamine (5 mL) And reacted at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

MS m/z (ESI): 643.1 [M+H] ⁺

¹ H-NMR (400 MHz, 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).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 62)

The compound obtained in the first step (50 mg, 0.08 mmol) was dissolved in methanol (1 mL) and THF (2 mL). Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine.

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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 16)

First step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl 5-methyl-4,5-dihydroisoxazol-3-yl)benzoate (Compound 43)

Methyl 3-(chloro(hydroxyimino)methyl)benzoate (200 mg, 0.94 mmol) and 4-((3-chloro-4-(prop-1-en-2-yl)phenoxy)methyl 5-(5,6-Dichlorophenyl)isoxazole (407 mg, 0.94 mmol) was added to triethylamine (5 mL) and allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 3-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 16)

The compound obtained in the first step (50 mg, 0.08 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (1 mL), and aqueous solution of sodium hydroxide (6.4 mg, 0.16 mmol) was added and allowed to react at room temperature for 2 hours. Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography chromatography chromatography

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: 4-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazole-3-yl)benzoic acid (Compound 63)

First step: 4-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl 5-methyl-4,5-dihydroisoxazol-3-yl)benzoate (Compound 71)

Methyl 4-(chloro(hydroxyimino)methyl)benzoate (200 mg, 0.94 mmol) and 4-((3-chloro-4-(prop-1-en-2-yl)phenoxy)methyl 5-(5,6-Dichlorophenyl)isoxazole (407 mg, 0.94 mmol) was added to triethylamine (5 mL) and allowed to react at room temperature for 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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).

Second step: 4-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 5-methyl-4,5-dihydroisoxazol-3-yl)benzoic acid (Compound 63)

The compound obtained in the first step (50 mg, 0.08 mmol) was dissolved in methanol (1 mL) and THF (2 mL). Then, the organic solvent was removed, and the remaining aqueous phase was adjusted to pH with 2N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was concentrated and purified by ethylamine chromatography chromatography chromatography

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: 5-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 64)

First step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl-4,5-dihydroisoxazol-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (Compound 72)

Methyl 5-(chloro(hydroxyimino)methyl)-1-isopropyl-1H-pyrazole-3-carboxylate (0.7 g, 2.8 mmol) and 4-((3-chloro-4-vinyl) Phenoxy)methyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole (1.1 g, 2.8 mmol) was added to triethylamine (5 mL) and reacted at room temperature 12 hours. Then, water was added and extracted with ethyl acetate three times. The organic extracts were combined and washed with brine sat. The residue was purified to silicagel elut elut elut elut elut elut

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 = 6.8 Hz, 6H), 1.19-1.15 (m, 3H), 1.13-1.09 (m, 2H).

Second step: 5-(5-(2-chloro-4-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of-4,5-dihydroisoxazole-3-yl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Compound 64)

The compound obtained in the first step (0.3 g, 0.5 mmol) was dissolved in methanol (4 mL) and tetrahydrofuran (2 mL), and aqueous solution of sodium hydroxide (40 mg, 1 mmol) was added and reacted at room temperature. The organic phase was concentrated and purified by ethylamine chromatography.

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: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 2-oxopyrrolidin-1-yl)benzoic acid (Compound 18)

First step: 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzylidene) Preparation of diethyl diacid

2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde (200 mg, 0.47 mmol) was added to toluene ( In 10 mL), piperidine (81.6 mg, 0.96 mmol) and diethyl malonate (80 mg, 0.5 mmol) were added and heated at 110 ° C overnight. Then, the reaction mixture was poured into water, EtOAc (EtOAc m.

Second step: 2-(1-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of diethyl 2-nitroethyl)malonate

Nitromethane (54 mg, 0.89 mmol) was added to anhydrous tetrahydrofuran (5 mL), and sodium hydrogen hydride (36.8 mg, 0.92 mmol) was added under a nitrogen atmosphere and stirred at room temperature for 20 minutes, then the compound obtained in the first step was added ( A solution of 100 mg, 0.18 mmol) in tetrahydrofuran (3 mL) was reacted at room temperature for 2 hr. The reaction mixture was poured into aq.

The third step: 4-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2 -Preparation of oxopyrrolidine-3-carboxylic acid ethyl ester

The compound obtained in the second step (500 mg, 0.80 mmol) was added to a mixed solvent of glacial acetic acid (20 mL) and methanol (5 mL), and zinc powder (130 mg, 2.0 mmol) was added, and the mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated under reduced vacuo. EtOAc (EtOAc)EtOAc. Then, the reaction liquid was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried, evaporated, evaporated

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

The compound obtained in the third step (200 mg, 0.36 mmol) was added to a mixed solvent of tetrahydrofuran (20 mL) and methanol (10 mL). Then, the pH of the reaction mixture was adjusted to 2 with 2N hydrochloric acid, poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated

Step 5: 4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)pyrrolidine Preparation of 2-ketone

The compound obtained in the fourth step (160 mg, 0.31 mmol) was added to DMSO (20 mL) and reacted at 130 ° C for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated

Step 6: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl 2-oxopyrrolidin-1-yl)benzoate (Compound 45)

The compound obtained in the fifth step (120 mg, 0.25 mmol) was added to dioxane (20 mL), methyl 3-iodobenzoate (84 mg, 0.32 mmol), Xantphos (40 mg, 0.07 mmol), Pd ₂ (dba) ₃ (60 mg, 0.07 mmol) and sodium tert-butoxide (40 mg, 0.42 mmol) were replaced with nitrogen three times and then reacted in a microwave reactor at 90 ° C for 4 hours. The reaction mixture was concentrated and purified by preparative high-purpur chromatography to give the title compound (20 mg, 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).

Step 7: 3-(4-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 2-oxopyrrolidin-1-yl)benzoic acid (Compound 18)

The compound obtained in the sixth step (20 mg, 0.03 mmol) was added to a mixed solvent of tetrahydrofuran (5 mL) and methanol (2 mL). Then, the pH of the reaction mixture was adjusted to 2 with 2N hydrochloric acid, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated

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: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of 2-oxooxazolidin-3-yl)benzoic acid (Compound 23)

First step: 4-((3-chloro-4-(oxiran-2-yl)phenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazole

Trimethyl sulfonium iodide (0.65 g, 3.2 mmol) was dissolved in DMSO (20 mL), sodium hydride (0.16 g, 4.0 mmol) was added, and then 2-chloro-4-((5-cyclopropyl-3) was added. -(2,6-Dichlorophenyl)isoxazol-4-yl)methoxy)benzaldehyde (1.2 g, 2.8 mmol) was reacted at room temperature for 2 hr. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with dichloromethane (30 mL × 3). The crude product was purified by silica gel column chromatography (jjjjjjjj

Step 2: 3-((2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)benzene) Preparation of methyl 2-hydroxyethyl)amino)benzoate

The compound obtained in the first step (1.21 g, 2.80 mmol) was added to methyl 3-aminobenzoate (0.44 g, 2.80 mmol) at room temperature, and lithium bromide (12 mg, 0.5 mmol) was added. Allow overnight until the starting material is completely reacted. The reaction mixture was poured with water (20 mL) The combined organic phases were washed with EtOAc EtOAc m.

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

The compound obtained in the second step (512 mg, 0.87 mmol) was added to dichloromethane (10 mL). After the addition was completed, the mixture was stirred at 0 ° C for 30 minutes, then added with phosgene (300 mg, 1.0 mmol) and reacted at 45 ° C for 2 hours, then diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with water, dried over anhydrous sodium sulfate The crude product was purified by silica gel chromatography chromatography eluting elut elut elut elut elut

MS m/z (ESI): 613.1 [M+H] ⁺ .

Step 4: 3-(5-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Synthesis of 2-oxooxazolidin-3-yl)benzoic acid (Compound 23)

The compound obtained in the third step (314 mg, 0.51 mmol) was added to methanol (10 mL), and water (2.0 mL) and lithium hydroxide (14 mg, 0.51 mmol). The mixture was reacted at room temperature overnight, then purified by preparative EtOAc (EtOAc)

MS m/z (ESI): 599.1 [M+H] ⁺

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

The compounds in Table 1 below were prepared in a similar manner to the methods of Examples 1-27 above:

Table 1.

Biological assay

Experimental Example 1. Bile acid receptor FXR coactivator binding assay

Test method

FXR activation assay of compounds using ^{Invitrogen · LanthaScreen TM TR-FRET Farnesoid} X Receptor Coactivator Assay kit.

The agonistic compound binds to the FXR receptor and recruits a coactivator short peptide to further bind to form a complex. According to this principle, an 铽-labeled antibody capable of recognizing the FXR receptor and a fluorescently labeled coactivator short peptide were designed, respectively. When the FXR receptor is activated and a fluorescent-labeled coactivator short peptide is recruited to form a complex, the added antibody binds to the FXR receptor, so that the fluorescent group labeled on the 铽-labeling group and the coactivator short peptide reaches the FRET production condition. Therefore, by stimulating the FXR receptor with different concentrations of compounds at room temperature, the signal size of FRET can be tested to reflect the agonistic effect of the compound on the FXR receptor. Group in a non-receptor protein is blank, calculated for the compound of FXR activation activity EC ₅₀ and maximal activation effect signal value Max (max values in the following formula):

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, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

In addition, with the chenodeoxycholic acid (ie CDCA) as a positive control, the relative activation effects of the compounds of the invention were calculated by the following formula:

Relative activation effect (%) = (Max / Max') × 100%

Wherein Max represents the maximum activation effect signal value of the compound of the present invention, and Max' represents the maximum activation effect signal value of CDCA, both of which are calculated by the formula shown above.

2. Test results

Table 2-1. EC ₅₀ of the compounds of the invention versus FXR

受试化合物Test compound	EC ₅₀(μM) EC ₅₀ (μM)
CDCACDCA	1.66±1.531.66±1.53
化合物1Compound 1	0.09±0.050.09±0.05
化合物2Compound 2	＜0.03<0.03
化合物3Compound 3	0.034±0.0020.034±0.002
化合物4Compound 4	0.48±0.040.48±0.04
化合物5Compound 5	0.26±0.040.26±0.04
化合物6Compound 6	0.45±0.160.45±0.16
化合物7Compound 7	0.51±0.080.51±0.08
化合物8Compound 8	0.062±0.0060.062±0.006
化合物9Compound 9	0.017±0.0020.017±0.002
化合物10Compound 10	0.060±0.0050.060±0.005
化合物16Compound 16	0.78±0.060.78±0.06
化合物18Compound 18	0.241±0.0250.241±0.025
化合物20Compound 20	0.010±0.0020.010±0.002
化合物21Compound 21	0.005±0.0010.005±0.001
化合物22Compound 22	0.128±0.0080.128±0.008
化合物23Compound 23	0.181±0.0260.181±0.026

化合物24Compound 24	0.194±0.0200.194±0.020
化合物25Compound 25	0.146±0.0260.146±0.026
化合物27Compound 27	0.023±0.0010.023±0.001
化合物57Compound 57	0.34±0.050.34±0.05
化合物58Compound 58	0.130±0.0110.130±0.011
化合物59Compound 59	0.273±0.0220.273±0.022
化合物60Compound 60	0.031±0.0020.031±0.002
化合物61Compound 61	0.038±0.0030.038±0.003
化合物62Compound 62	0.361±0.0750.361±0.075
化合物63Compound 63	0.425±0.0360.425±0.036

From Table 2-1, with respect to the positive control CDCA, compounds of the invention have a lower value of ₅₀ EC.

Table 2-2. Relative activation effects of the compounds of the invention on FXR

受试化合物Test compound	相对激活效应Relative activation effect
CDCACDCA	100％100%
化合物3Compound 3	139％139%
化合物4Compound 4	111％111%
化合物5Compound 5	160％160%
化合物7Compound 7	117％117%

As can be seen from Table 2-2, Compound 3, Compound 4, Compound 5 and Compound 7 of the present invention have a maximum activation effect which is significantly superior to CDCA. The remaining compounds of the invention also have a better maximum activation effect.

Experimental Example 2. Luciferase reporter gene assay

Test method

Human embryonic kidney cells HEK293 were cultured in DMEM medium containing 10% FBS. The plasmid was co-transfected to express high expression of FXR and human BSEP luciferase reporter gene. The transfected cells were digested, resuspended, counted, and then seeded in a multiwell plate. 10 μL of different concentrations of the test compound were added to the multiwell plate to a final concentration of 64 μM, 16 μM, 4 μM, 1 μM, 0.25 μM, 0.0625 μM, 0.0156 μM, 0.0039 μM, 0.000977 μM, 0 μM, and a final concentration of DMSO of 0.5%. After the cells were incubated with test compound for 18 h, added Brigh-Glo ^TM Reagent Detection by chemiluminescence detection multifunctional automatic microplate reader unit value (RLU), to blank wells (no compound) signal value is 100%, was calculated for each Percentage of relative signal (%) at compound concentration. Using four parameter fit model agonistic compound EC ₅₀ and maximal effect (percentage relative signal) with SigmaPlot 10 software.

2. Test results

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

table 3

受试化合物Test compound	最大激活效应Maximum activation effect
奥贝胆酸Obecholic acid	217％217%
化合物1Compound 1	313％313%
化合物2Compound 2	388％388%
化合物3Compound 3	420％420%
化合物4Compound 4	493％493%
化合物5Compound 5	445％445%

The results showed that the positive control with respect to the EC ₅₀ values of ADI acid 0.59 ± 0.20μM, compounds of the invention have a lower EC ₅₀ values, for example, compound 1 was 0.26 ± 0.04μM, Compound 3 was 0.08 ± 0.02μM. At the same time, the compounds of the invention show a better FXR maximal activation effect in in vitro cellular assays.

Experimental Example 3 Biochemical hERG experiment

experiment method

This experiment evaluated the potential of compound-induced cardiac QT prolongation using a biochemical hERG assay kit based on fluorescence polarization (Invitrogen). The test compound was added to a microplate containing hERG cell membrane, and a high hERG affinity tracer was added. After incubating the microplate at 25 ° C for 2 hours, the fluorescence polarization value was detected using a BMG PHAREStar multi-plate reader. The change, the percentage inhibition rate (%) of the compound to hERG at different concentrations was calculated, and the range of the half maximum inhibitory concentration (IC ₅₀ ) of the compound was judged.

The results show that Compound 2 on the hERG IC ₅₀ values greater than 30μM. Remaining compounds of the present invention on hERG IC ₅₀ of greater than 30μM, show that they have better security. Tests have shown that the compounds of the invention have no significant hERG toxicity.

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

Claims

a compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite, N-oxide, and Chemical protection forms and prodrugs:

among them

R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, 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 , -ER 5 , -E-OR 5 , -E-CN, -E-NR 5 R 6 , C 3-10 cycloalkyl-O-, -OC 1-6 alkyl-OR 5 , 3 to 10 membered heterocycloalkyl-O-, -EC(O)OR 5 , -EC(O R 5 , -EC(O)NR 5 R 6 , -EC(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 a 10-membered heterocycloalkyl group, and a 5, 6 or 7 membered monocyclic nitrogen-containing heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group and heteroaryl group are unsubstituted or independently selected from Halogen, CN, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy, oxo, C(O)OH, SO 3 H, C 1-3 alkyl-O- and halogenated C 1- Substituting 1, 2, 3 or 4 substituents of 3 alkyl-O-; preferably, R 1 is selected from: -EC(O)OR 5 and -EC(O)NR 5 R 6 ; more preferably, R 1 is -EC(O)OR 5 ;

E is a bond, a C 1-6 alkyl group or a C 3-8 cycloalkyl group, preferably a bond;

R 4 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl; preferably, R 4 , R 6 and R 7 Each is independently selected from the group consisting of hydrogen, C 1-3 alkyl, halo C 1-3 alkyl, and cyclopropyl; more preferably, R 4 , R 6 and R 7 are each independently hydrogen;

Each R 5 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, 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; preferably, each R 5 is independently selected from hydrogen and C 1 a -6 alkyl group; wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are unsubstituted or selected from halogen, CN, hydroxyl, oxo, C(O)OH, C 1-3 alkyl, halogenated C 1-3 alkyl, SO 3 H, C 1-3 alkyl-O-, halogenated C 1-3 alkyl-O- and -SO 2 -C 1-3 alkane Substituting 1, 2, 3 or 4 substituents of the radical;

p is 0, 1 or 2;

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

B is selected from a C 6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S; preferably, B a C 6-10 monocyclic or bicyclic aryl group and a 5 or 6 membered monocyclic heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; in particular, said The aryl group is selected from the group consisting of phenyl; the heteroaryl group is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazole a group, a tetrazolyl group, an isoxazolyl group, an isothiazolyl group, an imidazolyl group, a triazinyl group, an oxadiazolyl group, a thiadiazolyl group, and a furazyl group, and more particularly, the heteroaryl group is selected from pyridyl groups and Pyrazolyl; wherein the 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 alkane , C 1-6 alkyl-O-, C 1-6 alkyl-OC 1-6 alkyl-O-, halogenated C 1-6 alkyl, halogenated C 1-6 alkyl-O-, Hydroxy C 1-6 alkyl, CN-C 1-6 alkyl, C 3-6 cycloalkyl, and 3 to 6 members comprising 1, 2 or 3 heteroatoms independently selected from N, O and S Heterocycloalkyl and C 1-6 alkyl-S(O) p -, preferably C 1-6 alkyl, halo C 1-6 alkyl, and 1, 2 independently selected from N, O and S Or a 3 to 6 membered heterocycloalkyl group of 3 heteroatoms (e.g., oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, aziridine, azetidinyl, and pyrrolidine) a group, particularly an oxiranyl group, an oxetanyl group, a tetrahydrofuranyl group and a tetrahydropyranyl group, preferably an oxetanyl group;

Is a 5 to 14 membered monocyclic or bicyclic heteroaryl group or a saturated or partially unsaturated 3 to 10 membered heterocyclic group optionally substituted by oxo; preferably,
Is a 5 or 6 membered heteroaryl or a saturated or partially unsaturated 4, 5 or 6 membered heterocyclyl optionally substituted by oxo; wherein said heteroaryl or heterocyclyl comprises independently selected from N, 1, 2 or 3 heteroatoms of O and S;
Linking to a B group through a C ring atom or in the presence of an N ring atom through the N ring atom;

X is selected from N and CRc';

Each R 2 is independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O- a halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl; preferably, each R 2 is independently selected from hydrogen and C 1-6 alkyl;

Each R 3 is independently selected from the group consisting of hydrogen, halogen, CN, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O- a halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl group and a halogenated C 3-8 cycloalkyl group; preferably, each R 3 is independently selected from the group consisting of hydrogen, halogen and halogen C 1- 6 alkyl;

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

D is:

Preferably:

Z is:

Or Rd;

W is selected from N, N-O and CRc', preferably CRc';

Each Ra is independently selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkyl-O- group, a halogenated C 1-6 alkyl group, a halogenated C 3-8 cycloalkyl group, and Halogen C 1-6 alkyl-O-; preferably, each Ra is independently selected from C 3-6 cycloalkyl; more preferably, each Ra is independently cyclopropyl;

Rb, Rc and Rc' are each independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1- 6 alkyl-O-, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 3-8 cycloalkyl-O- and halogenated C 3-8 cycloalkyl-O-; preferred ground, Rb and Rc are each independently selected from hydrogen, halo, halo-C 1-6 alkyl and halogenated C 1-6 alkyl -O-, Rc 'is hydrogen;

Rd is selected from a C 3-10 cycloalkyl or C 5-14 bridged ring system, a fused ring system or a spiro ring system; preferably, Rd is selected from a C 3-6 cycloalkyl or C 5-11 saturated bridged ring system, a saturated fused ring system or a saturated spiro ring system, such as bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[2.5]octyl, bicyclo[4.1.0]heptyl, a cyclopropyl, cyclohexyl and cyclopentyl group; wherein the 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 the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl-O a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, and a C 6-10 monocyclic or bicyclic aryl group; preferably, each Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1 -3 alkyl, halo C 1-3 alkyl, C 1-3 alkyl-O-, halo C 1-3 alkyl-O-, C 3-6 cycloalkyl, halogenated C 3-6 a cycloalkyl group and a phenyl group;

requirement is:

(1) and ring
Connected B groups do not
The groups are directly adjacent;

(2) When the ring
for
When R 2 is not a hydroxyl group;

(3) When X is N, the ring
Not
and

(4) When X is CRc', the ring
Not
A compound according to claim 1, wherein R 1 is -EC(O)OR 5 , E is a bond, and R 5 is selected from the group consisting of hydrogen and C 1-6 alkyl (preferably C 1-4 alkyl).
A compound according to claim 1 or 2, wherein R 1 is selected from the group consisting of 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 .
The compound according to any one of claims 1 to 3, wherein X is N, a ring
Is a 5 to 14 membered monocyclic or bicyclic heteroaryl or a saturated or partially unsaturated 3 to 10 membered heterocyclic group optionally substituted by oxo, preferably a 5 or 6 membered heteroaryl or optionally oxygenated Substituted substituted saturated or partially unsaturated 4, 5 or 6 membered heterocyclic group wherein said heteroaryl or heterocyclic group comprises 1, 2 or 3 heteroatoms independently selected from N, O and S;

X is CRc'(Rc' is preferably H), ring
Yes:

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

An unsubstituted saturated 4-membered heterocyclic group, wherein the heterocyclic group contains 1, 2 or 3 hetero atoms independently selected from O and S;

It may be attached to the B group through the C ring atom or in the presence of an N ring atom through the N ring atom.
A compound according to any one of claims 1 to 4, wherein
From:

More preferably,
From:

Wherein from the ring
C or N ring atom extended
Representing that the C or N atom is directly bonded to the B group from the ring
Outstretched
Ring
versus
Group bonding.
A compound according to any one of claims 1 to 5, wherein
Yes
And R 2 is hydrogen.
The compound of any one of claims 1 to 5, wherein X is N, and
Yes
A compound according to any one of claims 1 to 5, wherein

Is unsubstituted
and

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

More preferably, B is selected from the group consisting of: an unsubstituted phenyl group; an unsubstituted pyridyl group;

Pyrazolyl substituted with 1, 2 or 3 methyl, ethyl, propyl or isopropyl groups, for example
A compound according to any one of claims 1 to 6, wherein Rc' is hydrogen.
The compound according to any one of claims 1-9, wherein the halogen is selected from the group consisting of F, Cl, Br and I, preferably F or Cl.
A compound according to claim 1, wherein the compound is a compound of the formula (Ia), (Ib), (Ic) or (Id):

Wherein R 1 , B, R 2 , n, X, R 3 , m and D are as defined in claim 1.
The compound of any one of claims 1-5 or 9-11, wherein the compound is selected from the group consisting of:
A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 12, a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable Salts, esters, metabolites, chemically protected forms or prodrugs thereof, and one or more pharmaceutically acceptable carriers.
The pharmaceutical composition according to claim 13, which is in a form selected from the group consisting of a tablet, a capsule, a troche, a hard candy, a powder, a spray, a cream, an ointment, a suppository, a gel, a paste, and a wash. Agents, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.
A kit, which includes:

a) a first container comprising, as a first therapeutic agent, at least one compound according to any one of claims 1 to 12, stereoisomers, tautomers, polymorphs, solvates thereof (such as water) a compound, a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or prodrug thereof, or a pharmaceutical composition according to claim 13 or 14 as a first pharmaceutical composition;

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

c) Optional package inserts.
A compound according to any one of claims 1 to 12, a stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite, N- Use of an oxide, a chemically protected form or prodrug thereof, or a pharmaceutical composition according to claim 12 or 14 for the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by a farnesoid X receptor.
a method of preparing a compound of the following formula (Ia), (Ib), (Ic) or (Id),

Wherein R 1 , B, R 2 , n, X, R 3 , m and D are as defined in claim 1;

(i) A method of preparing the formula (Ia) includes:

Wherein X' is a leaving group (for example, Cl, Br, I, OMs or OTs); R 1 ' represents a group having a removable protecting group and which can provide R 1 by removing the protecting group;

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

(2) The compound IN-3 is subjected to a Wittig reaction to obtain a 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 compound IN-4 in a ring-closing reaction to obtain compound IN-8;

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

(ii) A method of preparing the general formula (Ib) includes:

Wherein X' and R 1 ' are as defined in the above method (i); PG is a suitable hydroxy protecting group;

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

(2) Deprotecting the compound IN-11 to give the compound IN-12;

(3) reacting compound IN-12 with compound IN-2 to give compound IN-13;

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

(iii) A method of preparing the formula (Ic) includes:

Wherein X' and R 1 ' are as defined in method (i) above;

(1) subjecting compound IN-14 to a hydrazino reaction to obtain compound IN-15;

(2) acylation of compound IN-15 with compound IN-16 to give compound IN-17;

(3) The compound IN-17 is subjected to a ring-closing reaction to obtain a compound IN-18;

(4) reacting compound IN-18 with compound IN-2 to give compound IN-19;

(5) reacting compound IN-19 to give the compound of the formula (Ic);

(iv) A method of preparing the formula (Id) includes:

Wherein R 1 'and X' are as defined in method (i) above and PG is as defined in method (ii) above;

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

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

(3) The compound IN-21 is reacted to obtain the compound of the formula (Id).