WO2018059314A1 - Azabicycle derivatives and preparation method and use thereof - Google Patents

Abstract

Provided are azabicycle derivatives and a preparation method and use thereof. In particular, provided are an FXR agonist compound and a stereomer, a tautomerid, a polymorphic substance, a solvate (such as a hydrate), a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide thereof and a chemically protected form and a prodrug thereof. Also provided are a method for preparing the compound, a pharmaceutical composition comprising the compound and a medicine box and the use thereof in treating FXR-mediated diseases or conditions.

Description

Azabicyclo derivative, preparation method and use thereof Technical field

The present invention generally relates to compounds for the treatment of diseases or conditions mediated by farnesoid X receptor (FXR), and more particularly to FXR agonist compounds, as well as stereoisomers, tautomers thereof, and more Forms, solvates (e.g., 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 technique

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; Calkin, AC; Tontonoz , P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol., 2012, 13, 213-224.). 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 benefits (Mudaliar, S.; Henry, RR; Sanyal, AJet al., Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2diabetes 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).

WO2016097933 discloses a method of treating an FXR agonist or a partial agonist of the formula (I) for the treatment of a condition mediated by FXR, which is incorporated herein by reference in its entirety:

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 the invention

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

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 ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E-OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-10 cycloalkyl-O-, -OC _1-6 alkyl-OR ₄ , -OC _3-10 heterocycloalkyl, -EC(O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ , -E-SO _x -R ₄ , -E-SO ₃ H, -E-SO ₂ -NR ₄ R ₅ , -E-SO ₂ -NR ₅ C(O)R ₄ , -E-NR ₄ -SO ₂ -R ₅ , -E-SO ₂ -C _3-10 a heterocycloalkyl group, and a 5-7 membered monocyclic nitrogen-containing heteroaryl group, wherein E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group, and wherein the alkyl group, cycloalkyl group, hetero The cycloalkyl and heteroaryl groups are unsubstituted or are independently selected from the group consisting of halogen, CN, C _1-3 alkyl, halo C _1-3 alkyl, OH, oxo, C(O)OH, SO _{3 1} , 2, 3 or 4 substituents of H, C _1-3 alkyl-O- and halo C _1-3 alkyl-O-;

R ₃ , R ₅ and R ₆ 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 _{4 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, C _{a 3-8} heterocycloalkyl group, a -C _1-6 alkyl-C _3-8 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 the group consisting of halogen, CN, OH, 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;

x 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, said aryl group Or a 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-, halo C _1-6 alkyl, halo C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN -C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkyl-S(O) _m -;

选自5至14元氮杂稠环系统，其任选地另外含有独立地选自N、O和S的1、2或3个杂原子，其中从N环原子伸出的“←”表示N原子直接与B键合，从A环系统延伸出的“→”表示A环与(CH₂)_p键合；并且

Selected from a 5 to 14 membered aza fused ring system, which optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein "←" extending from the N ring atom represents N The atom is directly bonded to B, and "→" extending from the A ring system means that the A ring is bonded to (CH ₂ ) _p ;

的N相连的B基团不与-(CH₂)_p-O-基团直接相邻；And ring

The N-linked B group is not directly adjacent to the -(CH ₂ ) _p -O- group;

被n个R₂基团取代，各R₂独立地选自氢、卤素、羟基、氧代、CN、C_1-6烷基、C_{1- 6}烷基-O-、卤代C_1-6烷基、羟基C_1-6烷基或C_3-6环烷基；ring

Substituted by n R ₂ groups, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, CN, C _1-6 alkyl, C _{1 6} alkyl-O-, halo C _1-6 An alkyl group, a hydroxy C _1-6 alkyl group or a C _3-6 cycloalkyl group;

m is 0, 1 or 2;

n is 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

D is:

Z is:

或Rd；

Or Rd;

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 and Rc are 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 and halogenated C _3-8 cycloalkyl;

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, optionally substituted by 1, 2 or 3 Re;

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;

W is selected from N, N-O and CRb, and Rb is as defined above.

In the present invention, the present invention relates to a FXR agonist compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), pharmaceutically acceptable salt, ester thereof , metabolites, 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 ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E-OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-10 cycloalkyl-O-, -OC _1-6 alkyl-OR ₄ , -OC _3-10 heterocycloalkyl, -EC(O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ , -E-SO _x -R ₄ , -E-SO ₃ H, -E-SO ₂ -NR ₄ R ₅ , -E-SO ₂ -NR ₅ C(O)R ₄ , -E-NR ₄ -SO ₂ -R ₅ , -E-SO ₂ -C _3-10 a heterocycloalkyl group, and a 5-7 membered monocyclic nitrogen-containing heteroaryl group, wherein E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group, and wherein the alkyl group, cycloalkyl group, hetero The cycloalkyl and heteroaryl groups are unsubstituted or are independently selected from the group consisting of halogen, CN, C _1-3 alkyl, halo C _1-3 alkyl, OH, oxo, C(O)OH, SO _{3 1} , 2, 3 or 4 substituents of H, C _1-3 alkyl-O- and halo C _1-3 alkyl-O-;

R ₃ , R ₅ and R ₆ 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 _{4 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, C _{a 3-8} heterocycloalkyl group, a -C _1-6 alkyl-C _3-8 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 the group consisting of halogen, CN, OH, 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;

x 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, said aryl group Or a 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-, halo C _1-6 alkyl, halo C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN -C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkyl-S(O) _m -;

选自5至14元氮杂稠环系统，其任选地另外含有独立地选自N、O和S的1、2或3个杂原子，其中从N环原子伸出的“←”表示N原子直接与B键合，从A环系统延伸出的“→”表示A环与(CH2)_p键合；并且

Selected from a 5 to 14 membered aza fused ring system, which optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein "←" extending from the N ring atom represents N The atom is directly bonded to B, and "→" extending from the A ring system means that the A ring is bonded to (CH2) _p ;

的N相连的B基团不与-(CH₂)_p-O-基团直接相邻；And ring

The N-linked B group is not directly adjacent to the -(CH ₂ ) _p -O- group;

被n个R₂基团取代，各R₂独立地选自氢、卤素、羟基、CN、C_1-6烷基、C_1-6烷基-O-、卤代C_1-6烷基、羟基C_1-6烷基或C_3-6环烷基；ring

Substituted by n R ₂ groups, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl, Hydroxy C _1-6 alkyl or C _3-6 cycloalkyl;

m is 0, 1 or 2;

n is 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

D is:

Z is:

或Rd；

Or Rd;

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 and Rc are 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 and halogenated C _3-8 cycloalkyl;

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, optionally substituted by 1, 2 or 3 Re;

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;

W is selected from N, N-O and CRb, and Rb is as defined above.

In a class of embodiments, the "5 to 14 membered aza fused ring system" refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, with the exception of a shared carbon atom. At least one (e.g., 1, 2 or 3) ring carbon atoms are replaced by nitrogen atoms. In another class of embodiments, the compound of formula (I) does not include: 2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl]methoxy}hexahydro-1H-isoindole-2(3H)-yl}benzo[d]thiazole-6-carboxylic acid; 2-{5-{[5-cyclopropyl-3-( 2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole-2(1H)-yl}benzo[d]thiazole-6-carboxylic acid ;2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole- 2(1H)-yl}benzo[d]oxazole-6-carboxylic acid.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I) 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 encompasses 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) or the pharmaceutical composition.

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

a) a first container comprising at least one compound of the formula (I) as the first therapeutic agent or the pharmaceutical composition as the 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 invention further encompasses the compounds of formula (I) or the pharmaceutical compositions for use in preventing or treating a disease or condition mediated by FXR.

The invention further encompasses the use of a compound of formula (I) or a 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 a process for the preparation of a compound of the formula (I).

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.

The present invention is described in detail with reference to the embodiments of the invention, but 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 within the scope of the invention. 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.

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 a class of embodiments, the alkyl group has from 1 to 8 carbon atoms (C _1-8 ), especially from 1 to 6 carbon atoms (C _1-6 ). In another class of 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 limited, the terms "carbocyclyl" and "carbocyclic" are used interchangeably herein to refer to 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. A carbocyclyl group can be saturated or partially unsaturated, but does not include a non-aromatic ring in which an aromatic ring is fused to an aromatic ring. 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 a class of embodiments, the 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 "fused ring system" as used herein, unless specifically defined, means a fused bicyclic or polycyclic form of a carbocyclic group having 5 to 14 ring carbon atoms (C _5-14 ), wherein two carbon rings are fused. Share two carbon atoms that are 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 "aza fused ring system" as used herein, refers to a fused ring system as described above, wherein in one type of embodiment, at least one (eg, 1, 2 or 3) ring carbons other than a shared carbon atom. The atom is replaced by a nitrogen atom; in another class of embodiments, at least one (eg, 1 or 2) of the shared carbon atoms is replaced by a nitrogen atom, and optionally, at least one other than the shared carbon atom (eg, 1 , 2 or 3) ring carbon atoms are replaced by nitrogen atoms. The aza-fused ring system may have from 5 to 14 ring members, especially from 5 to 10 ring members, for example 6, 7, 8, or 9 ring members. Examples of nitrogen heterofused ring systems include, but are not limited to, octahydrocyclopenta[c]pyrrole, octahydro-1H-indole, octahydro-1H-cyclopenta[c]pyridine, 3-aza [3.2.0] Heptane and octahydropyrrolo[1,2-a]pyrazine. The aza fused ring system optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S. The aza-heavy ring system can be attached to the remainder of the molecule via a heteroatom (e.g., N) or a carbon atom. The aza fused ring system can be optionally substituted with one or more (e.g., 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. 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 having, for example, 3 to 10 (suitably 3-8, more suitably 3-6) ring atoms, wherein At least one ring atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie having one or more double bonds in the ring and/or Or a triple bond) carbocyclic group. For example, a "3-10 membered heterocyclyl" is a ring carbon atom having 2-9 (eg, 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 heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( Dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl. 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, pyridyl, 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, thiazolopyridyl, isothiazolopyridyl, porphyrin , indolizinyl, pyridazinyl, isodecyl, pteridinyl, fluorenyl, furazyl, benzofurazinyl, quinoxalinyl, naphthyridyl or furopyridinyl. Preferably, the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, 1H-benzene And [d] imidazolyl, imidazo[1,2-a]pyridyl, thiazolo[4,5-b]pyridyl, isothiazolo[4,5-c]pyridinyl, quinolyl, 1H- Mercapto, 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, imidazo[1,2-b]pyridazinyl, Pyrazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl and [1,2,4]triazolo[1,5- a] Pyridyl. Heteroaryl can be optionally one One or more (eg, 1, 2, 3 or 4) substituents are substituted. The substituent may be bonded to the C ring atom of the heteroaryl group or, if applicable, to the N ring atom of the heteroaryl group.

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.

The term "substituted" means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the indicated group, provided that the specified atom is not exceeded in the current situation. The lower normal valence and the substitution form a substantially stable compound.

The term "optionally substituted" means that the group may be unsubstituted or may be substituted with a specified group or group of atoms. If a group is described as "optionally substituted with", the group may be substituted with (1) unsubstituted or (2) with a designated group.

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 described herein 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. When expressing 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 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.

The compounds of the invention may be prepared in racemic form, or a single enantiomer may be prepared by enantioselective synthesis or by resolution.

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, citrates, isonicotinic acid salts, salicylates, acid citrates, tartrates, oleates, citrates, pantoates, hydrogen tartrate, Ascorbate, gentisate, gluconate, glucuronate, saccharide). 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: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; S. V. Ley, Ed., Pergamon Press.

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. 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 whose position is isotopic. 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 ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E-OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-10 cycloalkyl-O-, -OC _1-6 alkyl-OR ₄ , -OC _3-10 heterocycloalkyl, -EC(O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ , -E-SO _x -R ₄ , -E-SO ₃ H, -E-SO ₂ -NR ₄ R ₅ , -E-SO ₂ -NR ₅ C(O)R ₄ , -E-NR ₄ -SO ₂ -R ₅ , -E-SO ₂ -C _3-10 a heterocycloalkyl group, and a 5-7 membered monocyclic nitrogen-containing heteroaryl group, wherein E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group, and wherein the alkyl group, cycloalkyl group, hetero The cycloalkyl and heteroaryl groups are unsubstituted or are independently selected from the group consisting of halogen, CN, C _1-3 alkyl, halo C _1-3 alkyl, OH, oxo, C(O)OH, SO _{3 1} , 2, 3 or 4 substituents of H, C _1-3 alkyl-O- and halo C _1-3 alkyl-O-;

R ₃ , R ₅ and R ₆ 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 _{4 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, C _{a 3-8} heterocycloalkyl group, a -C _1-6 alkyl-C _3-8 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 the group consisting of halogen, CN, OH, 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;

x 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, said aryl group Or a 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-, halo C _1-6 alkyl, halo C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN -C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkyl-S(O) _m -;

选自5至14元氮杂稠环系统，其任选地另外含有独立地选自N、O和S的1、2或3个杂原子，其中从N环原子伸出的“←”表示N原子直接与B键合，从A环系统延伸出的“→”表示A环与(CH₂)_p键合；并且

Selected from a 5 to 14 membered aza fused ring system, which optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein "←" extending from the N ring atom represents N The atom is directly bonded to B, and "→" extending from the A ring system means that the A ring is bonded to (CH ₂ ) _p ;

requirement is:

的N相连的B基团不与-(CH₂)_p-O-基团直接相邻；And ring

The N-linked B group is not directly adjacent to the -(CH ₂ ) _p -O- group;

被n个R₂基团取代，各R₂独立地选自氢、卤素、羟基、氧代、CN、C_1-6烷基、C_1-6烷基-O-、卤代C_1-6烷基、羟基C_1-6烷基或C_3-6环烷基；ring

Substituted by n R ₂ groups, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, CN, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 An alkyl group, a hydroxy C _1-6 alkyl group or a C _3-6 cycloalkyl group;

m is 0, 1 or 2;

n is 1, 2, 3 or 4;

p is 0, 1, 2 or 3;

D is:

Z is:

或Rd；

Or Rd;

Each Ra is independently selected from C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl; halo C _3-8 cycloalkyl and Halogenated C _1-6 alkyl-O-;

Rb and Rc are 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 and halogenated C _3-8 cycloalkyl;

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, optionally substituted by 1, 2 or 3 Re;

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;

W is selected from N, N-O and CRb, and Rb is as defined above.

In a class of embodiments, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl, hydroxy C _1-6 alkyl or C _3-6 cycloalkyl.

In a class of embodiments, the "5 to 14 membered aza fused ring system" refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, wherein in addition to the shared carbon atom At least one (e.g., 1, 2, or 3) ring carbon atoms other than the nitrogen atom are replaced by a nitrogen atom. In another class of embodiments, the "5 to 14 membered aza fused ring system" refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, wherein the shared carbon atom At least one (e.g., 1 or 2) is replaced by a nitrogen atom, and optionally, at least one (e.g., 1, 2, or 3) ring carbon atoms other than the common carbon atom are replaced by a nitrogen atom.

In another class of embodiments, the compound of formula (I) does not include: 2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl]methoxy}hexahydro-1H-isoindole-2(3H)-yl}benzo[d]thiazole-6-carboxylic acid; 2-{5-{[5-cyclopropyl-3-( 2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole-2(1H)-yl}benzo[d]thiazole-6-carboxylic acid ;2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole- 2(1H)-yl}benzo[d]oxazole-6-carboxylic acid.

选自5至10元饱和氮杂稠环系统，其通过环氮原子与B连接；任选地，所述5至10元饱和氮杂稠环系统还另外含有1个O原子或N原子。In one type of embodiment,

It is selected from a 5- to 10-membered saturated aza fused ring system which is bonded to B through a ring nitrogen atom; optionally, the 5 to 10 membered saturated aza fused ring system additionally contains 1 O atom or N atom.

选自：In another type of embodiment,

From:

还选自：In another type of embodiment,

Also selected from:

Where h is 0, 1, 2 or 3.

选自：In another type of embodiment,

From:

选自： Preferably

From:

In an embodiment of the compounds of the invention, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkane Base; and n is 1 or 2. In a class of embodiments, each R _{2 is} independently selected from the group consisting of hydrogen, F, Cl, hydroxy, oxo, C _1-3 alkyl, C _1-3 alkyl-O-, halo C _1-3 alkyl In particular, it is selected from the group consisting of hydrogen, hydroxyl and oxo. In another class of embodiments, p is 0, 1 or 2, in particular 0 or 1.

In an embodiment of the compound of the invention The parts together form a structure selected from the following:

部分一起形成选自以下的结构：Preferably,

The parts together form a structure selected from the following:

部分一起还可形成选自以下的结构：Preferably,

The parts together may also form a structure selected from the following:

部分选自以下的结构：Particularly preferably,

Part of the structure selected from the following:

In an embodiment of the compound of the present invention, R _{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, amino, C _1-4 alkyl, halo C _1-4 alkyl, hydroxy C _1-4 alkyl, C _{1- 4-} alkyl-O-, -C(O)NR ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E-OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-6 cycloalkyl-O-, -OC _1-4 alkyl-OR ₄ , C _3-6 heterocycloalkyl-O-, -EC (O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ , -E _{-SO x -R 4, -E-SO} 3 H, -E-SO 2 -NR 4 R 5, -E-SO 2 -NR 5 C (O) R 4, -E-NR 4 -SO 2 -R ₅ , -E-SO ₂ -C _3-6 heterocycloalkyl, and a 5 or 6 membered monocyclic nitrogen-containing heteroaryl group.

In a class of embodiments, R _{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, C _1-3 alkyl, halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _{1 -3} alkyl-O -, -C(O)NR ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -E-OR ₄ , -E-NR ₄ R ₅ , -OC _1-4 alkyl-OR ₄ , -EC(O)OR ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , pyrrolyl, pyrazolyl, triazole , tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and tri Azinyl.

Preferably, R _{1 is} selected from -C(O)NR ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -EC(O)OR ₄ and - EC(O)NR ₄ R ₅ .

In an embodiment of the compounds of the invention, E is a bond, a C _1-4 alkyl group or a C _3-5 cycloalkyl group. In a class of embodiments, E is a bond or an unsubstituted C _1-2 alkyl group, preferably a bond.

In an embodiment of the compounds of the invention, each R _{4 is} independently selected from hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, C _3-6 cycloalkyl, -C _1-4 alkyl -C _3-6 cycloalkyl, C _3-6 heterocycloalkyl (for example, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl or tetrahydrothiopyranyl), -C _1-3 alkyl-C _3-6 heterocycloalkyl, 5- or 6-membered heteroaryl and phenyl. In a class of embodiments of the invention, each R _{4 is} independently selected from the group consisting of hydrogen and C _1-3 alkyl.

In an embodiment of the compounds of the invention, R ₃ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, halo C _1-3 alkyl and cyclopropyl. In a class of embodiments, R ₃ , R ₅ and R ₆ are each independently hydrogen. In a class of embodiments of the invention, q is 1, 2 or 3, preferably 1.

更优选地，R₁选自C(O)OH、CH₂C(O)OH、C(O)NHCH₂C(O)OH和C(O)NH₂。Preferably, R _{1 is} selected from the group consisting of C(O)OH, CH ₂ C(O)OH, C(O)NHCH ₂ C(O)OH, C(O)NH ₂ , C(O)NHCH ₂ S(O) ₂ OH, C(O)NH(CH ₂ ) ₂ S(O) ₂ OH, C(O)NH(CH ₂ ) ₃ S(O) ₂ OH and

More preferably, R _{1 is} selected from the group consisting of C(O)OH, CH ₂ C(O)OH, C(O)NHCH ₂ C(O)OH, and C(O)NH ₂ .

In an embodiment of the compounds of the invention, B is selected from C _6-10 monocyclic or bicyclic aryl groups and 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Monocyclic or bicyclic heteroaryl.

In particular, the aryl or heteroaryl group is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, Triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, Quinolinyl, fluorenyl, pyrroloazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl , pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolyl, tetrahydroisoquinolinyl, benzimidazolyl, thiazolopyridyl, isothiazol Pyridyl, porphyrin, mesoindolyl, pyridazinyl, isodecyl, pteridinyl, fluorenyl, furazyl, benzofurazinyl, quinoxalinyl, naphthyridyl and furopyridine base,

More particularly, the aryl or heteroaryl is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d Isothiazolyl, 1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridyl, thiazolo[4,5-b]pyridyl, isothiazolo[4,5-c]pyridine , quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-carbazolyl, benzo[d] Azyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1, 2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl and [1,2,4] Triazolo[1,5-a]pyridinyl, and wherein the aryl or heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy , C _1-6 alkyl (eg C _1-3 alkyl), C _1-6 alkyl-O- (eg C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg halogen Generation C _1-3 alkyl), hydroxy C _1-6 alkyl group (e.g. hydroxy C _1-3 alkyl) and C _3-6 cycloalkyl (e.g. cyclopropyl), preferably halo, C _1-6 alkyl (E.g. C _1-3 alkyl), C _1-6 alkyl -O- (C _1-4 alkyl e.g. -O-), halo-C _1-6 alkyl group (e.g., halo C _1-3 alkyl And C _3-6 cycloalkyl (for example cyclopropyl). The substituent may be bonded to the C ring atom of the heteroaryl group or, if applicable, to the N ring atom of the heteroaryl group.

In some embodiments, B is a 5 or 6 membered monocyclic heteroaryl or a 9 or 10 membered bicyclic heteroaryl,

Preferably, B is a group represented by one of the following structural formulae:

Wherein Y ¹ is CH or N; Y ² is CH or N; preferably, Y ¹ is CH and Y ² is CH; or Y ¹ is N and Y ² is CH; or Y ¹ is CH and Y ² is N;

or

Wherein Y ³ is CH or N; Y ⁴ is CH or N; Y ⁵ is S, O or NR ^f , and R ^f is H or C _1-6 alkyl; preferably, Y ³ is N; Y ⁴ is CH; Y ⁵ is S or O; or Y ³ is CH; Y ⁴ is N; Y ⁵ is NR ^f , R ^f is C _1-6 alkyl, preferably C _1-3 alkyl;

or

Wherein Y ⁶ is CH or N; Y ⁷ is S, O or NR ^g , and R ^g is H or C _1-6 alkyl, preferably H;

or

or

or

Wherein Y ⁸ is CH or N; Y ⁹ is CH or N; Y ¹⁰ is CH or N; Y ¹¹ is CH or N; preferably, Y ⁸ is CH or N, Y ⁹ is CH or N; Y ¹⁰ and Y ¹¹ either one is CH and the other is N;

or

Wherein Y ² and Y ¹³ are both CH; or, either Y ¹² and Y ¹³ are CH, the other is N; Y ¹⁴ is CH or N; Y ¹⁵ is CH or N; Y ¹⁶ is S , O or NR ^h , ^Rh is H or C _1-6 alkyl (eg C _1-3 alkyl);

Among them, in the formulas (a) to (g), "←" extending to the left indicates bonding with R ₁ , and "→" extending to the right indicates bonding with the A ring, and the R ₁ and A rings are respectively bonded. a C ring atom or an N ring atom which is available in B;

More preferably, B is pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, 1H-benzo[d]imidazolyl, Imidazo[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl, quinolinyl, 1H-indenyl, benzofuran , 1H-carbazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, 1H-pyrrolo[3,2-c]pyridyl, imidazo[1,2-b] Pyridazinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl or [1,2,4]triazolo[1,5-a]pyridinyl, pyrazolyl, Pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, quinolyl;

Even more preferably, B is pyridyl, thiazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 1H-carbazolyl, benzo[d]isothiazolyl, quinolyl;

Also, B is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl (eg, C _1-3 alkyl), C _{1- 6} alkyl-O- (eg C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg halogenated C _1-3 alkyl), hydroxy C _1-6 alkyl (eg hydroxyl C) _1-3 alkyl) and C _3-6 cycloalkyl (for example cyclopropyl), preferably halogen, C _1-6 alkyl (eg C _1-3 alkyl), C _1-6 alkyl-O- ( For example, C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg, halogenated C _1-3 alkyl), and C _3-6 cycloalkyl (eg, cyclopropyl), and the substitution The group may be attached to a C ring atom or, if applicable, to an N ring atom.

一起形成选自以下的结构：In a preferred embodiment,

Together form a structure selected from the following:

还可以一起形成选自以下的结构： In a preferred embodiment,

It is also possible to form a structure selected from the following:

In an embodiment of the compound of the invention, each Ra is independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkyl-O-, halo C _1-4 alkyl, Halogenated C _3-6 cycloalkyl and halo C _1-4 alkyl-O-. Preferably, each Ra is independently selected from C _1-4 alkyl, halo C _1-4 alkyl (eg, F or Cl substituted C _1-4 alkyl) and C _3-6 cycloalkyl, such as methyl. ,ethyl, n-propyl, isopropyl, fluoromethyl, chloromethyl, fluoroethyl, chloroethyl, 2-fluoro-propan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl.

并且Rb和Rc独立地选自氢、卤素、羟基、CN、C_1-3烷基、卤代C_1-3烷基、C_1-3烷基-O-、卤代C_1-3烷基-O-、C_3-6环烷基和卤代C_3-6环烷基。在一类实施方案中，Rb和Rc独立地选自氢、卤素、C_1-3烷基、卤代C_1-3烷基、C_1-3烷基-O-、卤代C_1-3烷基-O-，例如氢、F、Cl、Br、I、甲基、乙基、正丙基或异丙基、氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、氟乙基、氟丙基、氟甲氧基、二氟甲氧基、三氟甲氧基、环丙基或卤代环丙基。在另一类实施方案中，W是N；在又一类实施方案中，W是CRb，并且其中Rb如上文所定义，优选是氢。In an embodiment of the compounds of the invention, Z is

And Rb and Rc are 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 and halogenated C _3-6 cycloalkyl. In a class of embodiments, Rb and Rc are independently selected from the group consisting of hydrogen, halogen, _C1-3 alkyl, halo _C1-3 alkyl, _C1-3 alkyl-O-, halo _C1-3 Alkyl-O-, such as hydrogen, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, Chloromethyl, fluoroethyl, fluoropropyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl or halocyclopropyl. In another class of embodiments, W is N; in yet another class of embodiments, W is CRb, and wherein Rb is as defined above, preferably hydrogen.

In an embodiment of the compounds of the invention, Z is Rd. In a class of embodiments, Rd is selected from a _C3-6 cycloalkyl group or a _C5-11 saturated bridged ring system, a saturated fused ring system, or a saturated spiro ring system, optionally substituted with 1, 2, or 3 Re. In another class of 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 an embodiment, 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 another class of embodiments, Re is independently selected from the group consisting of hydrogen, _C1-3 alkyl, _C3-6 cycloalkyl (such as cyclopropyl), and phenyl.

Preferably, D is selected from:

Preferably, D is further selected from:

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.

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

Further preferably, the compound of the formula (I) of the invention is selected from the following compounds or any combination thereof:

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

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, especially for injections. 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 a class of 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, chemical protection thereof The form or prodrug, or the pharmaceutical composition of the invention.

In another class of embodiments, the invention relates to at least one compound of the formula (I), stereoisomers, tautomers, polymorphs, solvates thereof (eg, hydrates) of the invention, Pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, or pharmaceutical compositions of the invention are useful in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR the use of.

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 Hepatitis-related cholestasis and fibrosis 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 a foot Sufficient, and in other cases, larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first divided into several smaller doses for administration 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 another class of 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 one type of embodiment, the kit may also include a label or package insert on or associated with the container. The term "package insert" refers to instructions generally included in commercial packages of therapeutic products that include indications, usage, dosage, administration, contraindications, and/or warnings associated with the use of the therapeutic product. information. 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 another class of 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 pharmaceutical composition comprising the other therapeutic agent of the pharmaceutical composition. Thus, in one class of embodiments, the kit can include instructions for administering the first therapeutic agent or first pharmaceutical composition and the second therapeutic agent or second pharmaceutical composition, if present. For example, if the kit comprises a first composition comprising a compound of formula (I) and a second pharmaceutical composition comprising 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 another class of 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 invention is to provide a process for the preparation of a compound of the formula (I) according to the invention, which process comprises the steps of:

R₂、n、p和D如上文所定义；在一个优选的实施方案中，化合物IN-6中的R₁’由通式R”’-OC(O)-E-、R”’-OC(O)-(CHR₃)_qNR₆C(O)-或R”’-OS(O)₂(CHR₃)_qNR₆C(O)-表示，其中R”’选自C_1-6烷基(特别是C_1-4烷基)和苄基，其任选地被独立地选自卤素(例如F、Cl、Br或I)和硝基的一个或多个(例如1、2、3或4个)取代基取代，优选地选自甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基，更优选甲基；并且其中E、R₃、R₆、q、B、环

R₂、n、p和D如上文所定义。Wherein X is a halogen (e.g., F, Cl, Br, or I); PG is a protecting group, and in one embodiment, PG is R"-OC(O)-, wherein R" is selected from _C1-6 alkyl (particularly C _1-4 alkyl) and benzyl, which are optionally independently selected from one or more of halogen (eg F, Cl, Br or I) and nitro (eg 1, 2, 3 or 4) Substituent substitution, for example, the PG may be selected from the group consisting of trichloroethoxycarbonyl, dichloroethoxycarbonyl, monochloroethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl and 3,5-di Nitrobenzyloxycarbonyl, preferably Boc; Y is halogen (for example F, Cl, Br or I), sulfonyl (for example trifluoromethanesulfonyl or p-toluenesulfonyl), boronic acid group or boronic acid ester group R ₁ ' represents a group having a removable protecting group and which can provide R ₁ by removing the protecting group; and R ₁ , B, ring

R ₂ , n, p and D are as defined above; in a preferred embodiment, R ₁ ' in compound IN-6 is represented by the formula R"'-OC(O)-E-, R"'-OC (O)-(CHR ₃ ) _q NR ₆ C(O)- or R"'-OS(O) ₂ (CHR ₃ ) _q NR ₆ C(O)- represents wherein R"' is selected from C _1-6 An alkyl group (particularly a C _1-4 alkyl group) and a benzyl group, which are optionally independently selected from one or more of a halogen (eg, F, Cl, Br, or I) and a nitro group (eg, 1, 2, 3 or 4) substituent substitutions, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, more preferably methyl; and wherein E, R ₃ , R ₆ , q, B, ring

R ₂ , n, p and D are as defined above.

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

The reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of 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 in the presence of a suitable alkali metal alkoxide and a catalyst. The catalyst may be a catalyst system comprising a crown ether, which may be selected from the group consisting of sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and the crown ether is optional. From 15-crown-5 and 18-crown-6. Preferably, the alkali metal alkoxide and catalyst are a combination of sodium t-butoxide and/or potassium t-butoxide with 15-crown-5 and/or 18-crown-6, preferably sodium t-butoxide and 15 - Crown ether-5 combination or uncle A combination of potassium butoxide and 18-crown-6. The reaction is preferably carried out at a suitable temperature. The temperature is preferably room temperature (20-30 ° 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.

(2) removing the protecting group PG from the compound IN-3 to obtain the compound IN-4;

The reaction for removing the protective group PG 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. In embodiments wherein the protecting group PG is R"-OC(O)- (e.g., Boc) as defined above, the compound IN-3 is an ester, and the reaction is preferably carried out by acid hydrolysis of the ester in the presence of an acid. The acid may be a solution of a mineral acid in an organic solvent, such as a hydrogen chloride solution in dioxane; or a suitable organic acid such as a carboxylic acid or a halogenated acid including, but not limited to, formic acid, fluoroacetic acid , difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, and combinations thereof, preferably trifluoroacetic acid. The reaction is preferably carried out at a suitable temperature. The temperature is preferably room temperature (20-30 ° C). The reaction is preferably carried out for a suitable period of time, for example 1-3 h, for example 2 h.

(3) reacting compound IN-4 with compound IN-5 to give compound IN-6;

In one class of embodiments, compound IN-4 is subjected to a substitution reaction with compound IN-5 to give compound IN-6. The substitution reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, dimethyl sulfoxide, and any combination thereof, preferably dimethylformamide or dimethylacetamide. The substitution 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 substitution reaction is preferably carried out at a suitable temperature. The temperature may be, for example, 100 to 140 ° C, preferably 120 ° C or 130 ° C. The substitution reaction is preferably carried out for a suitable period of time, for example 2 to 24 hours, 2 to 18 hours or 2 to 12 hours, in particular 2 to 6 hours, for example 3, 4 or 5 hours.

In another class of embodiments, compound IN-4 is coupled with compound IN-5 to give compound IN-6. The coupling reaction is preferably carried out in the presence of a metal catalyst and a base. Preferably, the metal catalyst is a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium. The base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably cesium carbonate. Preferably, the coupling reaction is carried out in the presence of an organophosphorus compound derived from biphenyl selected from the group consisting of RuPhos, XPhos, SPhos and CPhos, preferably RuPhos. Preferably, the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of benzene, toluene and xylene, for example toluene. Preferably, the coupling reaction in a suitable protective atmosphere (e.g. N ₂ environment) under performed. Preferably, the coupling reaction is carried out at a suitable temperature, which may be, for example, 70-100 ° C, preferably 80 ° C. Preferably, the coupling reaction is carried out for a suitable period of time, for example 1-3 h, for example 2 h.

And (4) removing the protecting group from compound IN-6 to give a compound of formula (I);

The reaction for removing the protecting group 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 monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dichloromethane, and Any combination thereof is preferably tetrahydrofuran. In the formula R"'-OC(O)-E-, R"'-OC(O)-(CHR ₃ ) _q NR ₆ C(O)- or R"' where R ₁ 'is defined above In the embodiment represented by -OS(O) ₂ (CHR ₃ ) _q NR ₆ C(O)-, the compound IN-6 is an ester, and the reaction is preferably carried out by an alcoholysis reaction of the ester in the presence of an alcohol and a basic catalyst. The alcohol may be, for example, methanol or ethanol. The basic catalyst may be selected from the group consisting of alkali metal hydroxides, which may be selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide. The reaction is preferably carried out at a suitable temperature. The temperature may be, for example, from room temperature to 80 ° C, such as from 40 to 60 ° C. The reaction is preferably carried out for a suitable period of time, for example 2 to 5 h, for example 3 or 4 h.

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.

Intermediate compound

Certain intermediate compounds are novel and are claimed as aspects of the invention.

In a class of embodiments, the invention relates to the intermediate compound IN-6:

R₂、n、p和D如上文所定义。Wherein R ₁ ' represents a group having a removable protecting group and which can provide R ₁ by removing the protecting group; and R ₁ , B, ring

R ₂ , n, p and D are as defined above.

R₂、n、p和D如上文所定义。通过水解反应，使此类酯类化合物IN-6去除酯基保护基，从而得到作为酸的本发明的通式(I)的化合物。In a preferred embodiment, R ₁ 'represents R "' - OC (O) -E-, R"'- OC (O) - (CHR 3) q NR 6 C (O) - , or R "' - OS (O) ₂ (CHR ₃ ) _q NR ₆ C(O)-, wherein R"' is selected from C _1-6 alkyl (especially C _1-4 alkyl) and benzyl, optionally independently Substituted from one or more (eg 1, 2, 3 or 4) substituents selected from halogen (eg F, Cl, Br or I) and nitro, preferably selected from methyl, ethyl, propyl, iso a propyl group, a butyl group, an isobutyl group and a t-butyl group, more preferably a methyl group; and wherein E, R ₃ , R ₆ , q, B, ring

R _2, n, p and D are as defined above. The ester compound IN-6 is removed by a hydrolysis reaction to remove an ester group protecting group, thereby obtaining a compound of the formula (I) of the present invention as an acid.

Preferably, compound IN-6 is selected from the group consisting of:

Preferably, compound IN-6 is selected from the following compounds or any combination thereof:

detailed description

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.

Prepare a high performance liquid phase using Shimadzu preparative liquid chromatograph.

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

The reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound The polarity is adjusted differently or adjusted by adding triethylamine or the like.

Initiator+(400W,RT～300℃)微波反应器。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.

Example 1: 2-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 1)

First step: Preparation of (3aR, 5r, 6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-ol (0.5g, 3.05mmol) was dissolved in tetrahydrofuran (8mL) and water (4mL), then added Boc ₂ O (1.3 g, 6.1mmol) and _{Et 3 N (0.77g, 7.63mmol)} , stirred at room temperature for 2 hours. After concentrating the reaction mixture, the residue was purifiedjjjjjjjj

Second step: (3aR, 5r, 6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Preparation of dienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The compound obtained in the first step (68 mg, 2.57 mmol) was dissolved in dry THF (10 mL), then t-BuOK (0.58 g, 5.14 mmol), 18-crown-6 (1.36 g, 5.14 mmol) and 4- (Chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (771 mg, 2.57 mmol) was stirred at room temperature for 2 hr. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

The third step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole

The compound obtained in the second step (100 mg, 0.27 mmol) was evaporated. The mixture was concentrated to give the title compound.

The fourth step: 2-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The compound obtained in the third step (135 mg, 0.35 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (100 mg, 0.35 mmol) and DIPEA (0.45 g) , 3.5 mmol), stirred at 100 ° C - 110 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 602 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.14 (s, 1H), 7.77-7.74 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.22 (s, 2H) , 3.97-3.96 (m, 1H), 3.89 (s, 3H), 3.76-3.71 (m, 2H), 3.39-3.37 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H) , 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Step 5: 2-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The compound obtained in the fourth step (100 mg, 0.17 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (0.33 mg, 0.59 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 1 (70 mg, yield: 70.1%).

MS m/z (ESI): 588 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.14 (s, 1H), 7.77-7.74 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.22 (s, 2H) , 3.97-3.96 (m, 1H), 3.76-3.71 (m, 2H), 3.39-3.37 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H), 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Example 2: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 2)

First step: Preparation of (3aR, 5s, 6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

(3aR, 5s, 6aS)-octahydrocyclopenta[c]pyrrole-5-ol (0.5g, 3.05mmol) was dissolved in tetrahydrofuran (8mL) and water (4mL), then added Boc ₂ O (1.3g) 6.1 mmol) and Et ₃ N (0.77 g, 7.63 mmol) were stirred at room temperature for 2 h. After concentrating the reaction mixture, the residue was purifiedjjjjjjjj

Second step: (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Preparation of dienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The compound obtained in the first step (0.68 mg, 2.57 mmol) was dissolved in dry THF (10 mL), and then t-BuOK (0.58 g, 5.14 mmol), 18-crown-6 (1.36 g, 5.14 mmol) and 4 -(Chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (771 mg, 2.57 mmol) was stirred at room temperature for 2 hr. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Third step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole

The compound obtained in the second step (100 mg, 0.27 mmol) was evaporated. The mixture was concentrated to give the title compound.

The fourth step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The compound obtained in the third step (135 mg, 0.35 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (100 mg, 0.35 mmol) and DIPEA (0.45 g) , 3.5 mmol), stirred at 100 ° C - 120 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 602 [M+H] ⁺

Step 5: 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The compound obtained in the fourth step (100 mg, 0.17 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (0.33 mg, 0.59 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 2 (70 mg, yield: 70.1%).

MS m/z (ESI): 588 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.14 (s, 1H), 7.77-7.74 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.22 (s, 2H) , 3.97-3.96 (m, 1H), 3.76-3.71 (m, 2H), 3.39-3.37 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H), 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Example 3: 6-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic Acid (Compound 3)

First step: 6-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrogencyclopenta[c]pyrrole-2(1H)-yl)methyl Nicotinate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (79 mg, 0.2 mmol) was dissolved in DMA (4 mL), and ethyl 6-bromonicotinic acid (43 mg, 0.2 mmol) and DIPEA (258 mg, 2.0 mmol) were added at 120 ° C - 130 ° C Stir under 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 528 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d6} ) δ: 12.39 (s, 1H), 8.62 (s, 1H), 7.92-7.89 (m, 1H), 7.54-7.41 (m, 3H), 6.45-6.42 (m, 1H ), 4.17 (s, 2H), 3.90 (s, 3H), 3.88-3.58 (m, 3H), 3.23 - 3.21 (m, 2H), 2.63 (m, 2H), 2.25-1.98 (m, 3H), 1.25-1.22 (m, 2H), 1.08-1.03 (m, 4H).

Second step: 6-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of hydrogencyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid

The compound obtained in the first step (60 mg, 0.11 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (32 mg, 0.55 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 3 (28 mg, yield: 50%).

MS m/z (ESI): 514 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d6} ) δ: 12.39 (s, 1H), 8.62 (s, 1H), 7.92-7.89 (m, 1H), 7.54-7.41 (m, 3H), 6.45-6.42 (m, 1H ), 4.17 (s, 2H), 3.88-3.58 (m, 3H), 3.23 - 3.21 (m, 2H), 2.63 (m, 2H), 2.25-1.98 (m, 3H), 1.25-1.22 (m, 2H) ), 1.08-1.03 (m, 4H).

Example 4: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic Acid (Compound 5)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrogencyclopenta[c]pyrrole-2(1H)-yl)methyl Nicotinate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (79 mg, 0.2 mmol) was dissolved in DMA (4 mL), and ethyl 6-bromonicotinic acid (43 mg, 0.20 mmol) and DIPEA (258 mg, 2.0 mmol) were added at 120 ° C - 130 ° C Stir under 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 528 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 12.39 (s, 1H), 8.62 (s, 1H), 7.92-7.89 (m, 1H), 7.54-7.41 (m, 3H), 6.45-6.42 (m, 1H), 4.17 (s, 2H), 3.90 (s, 3H), 3.88-3.58 (m, 3H), 3.23 - 3.21 (m, 2H), 2.63 (m, 2H), 2.25-1.98 (m, 3H) , 1.25-1.22 (m, 2H), 1.08-1.03 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of hydrogencyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid

The compound obtained in the first step (50 mg, 0.09 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (18 mg, 0.45 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 5 (31 mg, yield: 66.7%).

MS m/z (ESI): 514 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 12.39 (s, 1H), 8.62 (s, 1H), 7.92-7.89 (m, 1H), 7.54-7.41 (m, 3H), 6.45-6.42 (m, 1H), 4.17 (s, 2H), 3.88-3.58 (m, 3H), 3.23 - 3.21 (m, 2H), 2.63 (m, 2H), 2.25-1.98 (m, 3H), 1.25-1.22 (m, 2H), 1.08-1.03 (m, 4H).

Example 5: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)thiazole-4-carboxylic acid (Compound 6)

First step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)thiazole-4-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (100 mg, 0.20 mmol) was dissolved in DMA (4 mL), EtOAc (EtOAc, EtOAc (EtOAc) Stir at 100 ° C - 110 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, EtOAc (EtOAc m.

MS m/z (ESI): 534 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 7.65-7.49 (m, 4H), 4.18 (s, 2H), 3.90 (s, 3H), 3.88 (m, 1H), 3.45-3.43 (m, 2H) , 3.11-3.08 (m, 2H), 2.61 (m, 2H), 2.32 - 2.31 (m, 1H), 1.68-1.67 (m, 2H), 1.50-1.46 (m, 2H), 1.14-1.07 (m, 4H).

Second step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)thiazole-4-carboxylic acid

The compound obtained in the first step (49 mg, 0.092 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (15.75 mg, 0.31 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 6 (20 mg, yield: 41.9%).

MS m/z (ESI): 520 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 7.65-7.49 (m, 4H), 4.18 (s, 2H), 3.88 (m, 1H), 3.45-3.43 (m, 2H), 3.11-3.08 (m, 2H), 2.61 (m, 2H), 2.32 - 2.31 (m, 1H), 1.68-1.67 (m, 2H), 1.50-1.46 (m, 2H), 1.14-1.07 (m, 4H).

Example 6: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]oxazole-6-carboxylic acid (Compound 7)

First step: Preparation of 2-mercaptobenzo[d]oxazole-6-carboxylic acid methyl ester

Methyl 4-amino-3-hydroxybenzoate (1.0 g, 5.98 mmol) was dissolved in tetrahydrofuran (50 mL). After the reaction mixture was diluted with dilute hydrochloric acid to dryness, EtOAc (EtOAc).

Step 2: Preparation of 2-chlorobenzo[d]oxazole-6-carboxylic acid methyl ester

The compound obtained in the first step (100 mg, 0.48 mmol) was dissolved in SOCI ₂ (0.49 mL, 6.77 mmol), and 1 D of DMF was added and stirred at 70 ° C for 10 min. Concentration gave the title compound (100 mg, yield: 100.0%).

The third step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]oxazole-6-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (80 mg, 0.20 mmol) was dissolved in DMA (4 mL), and the compound obtained in the second step (47.3 mg, 0.22 mmol) and DIPEA (263.2 mg, 2.04 mmol) at 120 ° C - 140 ° C Stir under 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 568 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.82-7.77 (m, 2H), 7.65-7.63 (m, 3H), 7.59-7.55 (m, 1H), 4.19 (s, 2H), 3.90 (m, 4H), 3.68-3.64 (m, 2H), 3.34-3.30 (m, 2H), 2.62-2.61 (m, 2H), 2.33-2.29 (m, 1H), 1.75-1.67 (m, 2H), 1.54- 1.48 (m, 2H), 1.16 - 1.07 (m, 4H).

The fourth step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]oxazole-6-carboxylic acid

The compound obtained in the third step (60 mg, 0.11 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (20.9mg, 0.37mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 7 (45 mg, yield: 74.0%).

MS m/z (ESI): 554 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.82-7.77 (m, 2H), 7.65-7.63 (m, 3H), 7.59-7.55 (m, 1H), 4.19 (s, 2H), 3.90 (m, 1H), 3.68-3.64 (m, 2H), 3.34-3.30 (m, 2H), 2.62-2.61 (m, 2H), 2.33-2.29 (m, 1H), 1.75-1.67 (m, 2H), 1.54- 1.48 (m, 2H), 1.16 - 1.07 (m, 4H).

Example 7: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (Compound 8)

First step: Preparation of methyl 2-amino-4-methoxybenzo[d]thiazole-6-carboxylate

Methyl 4-amino-3-methoxybenzoate (5.0 g, 0.028 mol) was dissolved in AcOH (50 mL), NaSCN (8.9 g, 0.11 mol) was added, then Br ₂ (1.6 mL, 0.031 mol) was added dropwise A solution of AcOH (5 mL) was stirred at room temperature overnight. The mixture was filtered, the filtrate was adjusted to pH = 8-9 with aqueous ammonia, filtered, and filtered to give the title compound (3 g, yield: 45.0%).

Second step: Preparation of methyl 2-bromo-4-methoxybenzo[d]thiazole-6-carboxylate

The compound CuBr ₂ (3.8 g, 0.017 mol) was dissolved in CH ₃ CN (40 mL), t-BuONO (2.9 mL, 0.025 mol) was added dropwise, then the compound obtained in the first step (2.5 g, 0.011 mol) was added at 30 Stir at ° C overnight. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

The third step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylate

The title compound was synthesized in this step. The compound obtained in the second step of this example (60.2 mg, 0.2 mmol) was used in place of 2-bromo-4-fluorobenzo[d]thiazole-6-. Methyl formate and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5) -yl)oxy)methyl)isoxazole trifluoroacetate (98.1 mg, 0.2 mmol) instead of 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((( 3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole trifluoroacetate gave the title compound (95mg, yield: 77.2 %).

MS m/z (ESI): 614 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.04 (s, 1H), 7.71-7.68 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.22 (s, 2H) , 3.97-3.96 (m, 4H), 3.89 (s, 3H), 3.76-3.71 (m, 2H), 3.39-3.37 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H) , 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

The fourth step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid

The synthesis of compound 8 was carried out in the same manner as in the fifth step of Example 1, and the compound obtained in the third step of this example (95 mg, 0.15 mmol) was used in place of the compound 2-((3aR,5r,6aS)-5-((5-ring) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluoro Benzo[d]thiazole-6-carboxylic acid methyl ester gave Compound 8 (65 mg, yield: 72.2%).

MS m/z (ESI): 600 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.04 (s, 1H), 7.71-7.68 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 1H), 4.22 (s, 2H) , 3.97-3.96 (m, 1H), 3.89 (s, 3H), 3.76-3.71 (m, 2H), 3.39-3.37 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H) , 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Example 8: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 9)

First step: Preparation of 2-trifluoromethylbenzaldehyde oxime

The 2-trifluoromethyl-benzaldehyde (2g, 0.012mol) was dissolved in ethanol (20mL) and water (7mL), was added NaOH (0.92g, 0.023mol) and _{NH 2 OH.HCl (1.2g, 0.017mol)} , Stir at room temperature overnight. The reaction mixture was concentrated and filtered, and then filtered, and the title compound was obtained from the title compound (2.2 g, yield: 100.0%).

Second step: Preparation of N-hydroxy-2-(trifluoromethyl)imine benzyl chloride

The compound obtained in the first step (0.79 g, 4.18 mmol) was dissolved in DMF (10 mL). Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Third step: preparation of methyl 5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazole-4-carboxylate

The second step The resulting compound (0.83g, 3.72m mol) was dissolved in Et ₃ N (5mL), was added 3-cyclopropyl-3-oxo-propionic acid methyl ester (0.57g, 5.54mmol), stirred at room temperature overnight. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Fourth step: Preparation of (5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methanol

The compound obtained in the third step (0.5 g, 1.61 mmol) was dissolved in dry THF (10 mL), and LiAlH ₄ (0.13 g, 3.22 mol) was added. Stir at 0 ° C until TLC showed the starting material was completely. The reaction was quenched by the addition of sodium sulfate EtOAc (EtOAc).

Step 5: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazole

The benzotriazole compound (0.25g, 2.07mmol) dissolved in dry DCM (10mL), was added dropwise at _{0 ℃ SOCl 2 (92.6mg, 2.07mmol} ). After stirring at room temperature for 30 min, the compound obtained in the fourth step (0.45 g, 1.59 m mol) was further added until TLC showed that the starting material was completely reacted. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Step 6: (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Preparation of dienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the title compound of this step was carried out in a similar manner to that of the second step of Example 1, using the compound obtained in the fifth step of this Example (0.22 g, 0.73 mmol) instead of 4-(chloromethyl)-5-cyclopropyl-3- (2,6-Dichlorophenyl)isoxazole gave the title compound (0.24 g, yield: 66.7%).

Step 7: 5-cyclopropyl-3-(2-trifluoromethylphenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole

The synthesis of the title compound of this step was carried out in the same manner as in the third step of Example 1, and the compound obtained in the sixth step of the present invention (0.24 g, 0.49 mmol) was used instead of the compound (3aR, 5r, 6aS)-5-((5-ring). Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester The title compound of this step. The obtained compound was used in the next reaction without purification.

Step 8: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The synthesis of the title compound of this step was carried out in the same manner as in the fourth step of Example 1, and the compound obtained in the seventh step of the present invention (191 mg, 0.49 mmol) was used in place of 5-cyclopropyl-3-(2,6-dichlorophenyl). - 4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (200mg, Rate: 68.0%).

MS m/z (ESI): 602 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.15 (s, 1H), 7.77-7.74 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 2H), 4.21 (s, 2H) , 3.98-3.96 (m, 1H), 3.90 (s, 3H), 3.76-3.70 (m, 2H), 3.39-3.36 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H) , 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Step 9: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The synthesis of compound 9 was carried out in the same manner as in the fifth step of Example 1, and the compound obtained in the eighth step of the present invention (200 mg, 0.33 mmol) was used instead of 2-((3aR,5r,6aS)-5-((5-cyclopropyl). 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzene And [d] thiazole-6-carboxylic acid methyl ester gave Compound 9 (150 mg, yield: 77.3%).

MS m / z (ESI): 588 [M + H] +

¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.15 (s, 1H), 7.77-7.74 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.34 (m, 2H), 4.21 (s, 2H) , 3.98-3.96 (m, 1H), 3.76-3.70 (m, 2H), 3.39-3.36 (m, 2H), 2.81 (m, 2H), 2.11-2.09 (m, 1H), 1.91-1.86 (m, 3H), 1.57-1.52 (m, 2H), 1.28-1.24 (m, 1H), 1.14-1.11 (m, 2H).

Example 9: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 10)

First step: Preparation of 2-difluoromethoxybenzaldehyde oxime

The title compound was synthesized in the same manner as in the first step of Example 8 and 2-bromomethoxybenzaldehyde (2 g, 0.012 mol) was used in place of 2-trifluoromethylbenzaldehyde to obtain the title compound (2.2). g, yield: 100.0%).

Second step: Preparation of 2-(difluoromethoxy)-N-hydroxyimine benzyl chloride

The title compound was synthesized in the same manner as in the second step of Example 8. The compound obtained in the first step of this Example (2.1 g, 0.011 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 2.2 g, yield: 90.5%).

The third step: preparation of methyl 5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazole-4-carboxylate

The synthesis of the title compound of this step was carried out in the same manner as in the third step of Example 8. The compound obtained in the second step of this Example (2.2 g, 9.95 mmol) was used in place of N-hydroxy-2-(trifluoromethyl)imide benzyl. Chlorine gave the title compound (2.0 g, yield: 65.1%).

The fourth step: preparation of (5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methanol

The synthesis of the title compound of this step was carried out in the same manner as in the fourth step of Example 8. The compound obtained in the third step of this Example (0.5 g, 1.62 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). Methyl isoxazole-4-carboxylate gave the title compound (0.4 g, yield: 87.9%).

Step 5: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazole

The synthesis of the title compound of this step was carried out in a similar manner to that in the fifth step of Example 8. The compound obtained in the fourth step of this Example (0.5 g, 1.78 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). The title compound (0.3 g, yield: 56.6%) was obtained from the title compound.

Step 6: (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy)hexahydrocyclohexane Preparation of pentadienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the title compound of this step was carried out in a similar manner to that in the sixth step of Example 8. The compound obtained in the fifth step of the present invention (0.15 g, 0.48 mmol) was used in place of 4-(chloromethyl)-5-cyclopropyl-3-. (2-Trifluoromethylphenyl)isoxazole gave the title compound (0.14 g, yield: 59.6%).

Step 7: 5-cyclopropyl-3-(2-difluoromethoxyphenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5) Preparation of -yl)oxy)methyl)isoxazole

The synthesis of the title compound of this step was carried out in a similar manner to that in the seventh step of Example 8. The compound obtained in the sixth step of the present invention (0.14 g, 0.29 mmol) was used instead of (3aR, 5s, 6aS)-5-((5-cyclopropyl) 3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester Step title compound. The obtained compound was used in the next reaction without purification.

Step 8: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy) Preparation of methyl hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The synthesis of the title compound of this step was carried out in a similar manner to that in the eighth step of Example 8. The compound obtained in the seventh step of this Example (113 mg, 0.29 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylphenyl). - 4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (150 mg, Rate: 86.7%).

MS m/z (ESI): 600 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.82 (s, 1H), 8.22 (s, 1H), 7.62-7.57 (m, 1H), 7.51-7.48 (m, 2H), 7.40-7.37 (m, 2H), 7.21 (t, J = 64.6, 1H), 4.25 (s, 2H), 3.97-3.96 (m, 1H), 3.90 (s, 3H), 3.69-3.64 (m, 2H), 3.39-3.37 ( m, 2H), 2.76-2.66 (m, 2H), 2.33 - 2.26 (m, 1H), 1.79-1.74 (m, 2H), 1.60-1.54 (m, 2H), 1.14-0.98 (m, 4H).

Step 9: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy) Preparation of Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The synthesis of compound 10 was carried out in the same manner as in the ninth step of Example 8. The compound obtained in the eighth step of the present invention (150 mg, 0.25 mmol) was used in place of the compound 2-((3aR,5s,6aS)-5-((5-ring) Propyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluoro Methyl benzo[d]thiazole-6-carboxylate gave Compound 10 (50 mg, yield: 34.2%).

MS m/z (ESI): 586 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.82 (s, 1H), 8.22 (s, 1H), 7.62-7.57 (m, 1H), 7.51-7.48 (m, 2H), 7.40-7.37 (m, 2H), 7.21 (t, J = 64.6, 1H), 4.25 (s, 2H), 3.97-3.96 (m, 1H), 3.69-3.64 (m, 2H), 3.39-3.37 (m, 2H), 2.76- 2.66 (m, 2H), 2.33 - 2.26 (m, 1H), 1.79-1.74 (m, 2H), 1.60-1.54 (m, 2H), 1.14 - 0.98 (m, 4H).

Example 10: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 11)

The first step: preparation of 2,6-difluorobenzaldehyde oxime

The title compound was synthesized in the same manner as in the first step of Example 8. Substituting 2,6-difluorobenzaldehyde (5 g, 0.035 mol) for 2-trifluoromethylbenzaldehyde gave the title compound (5.0 g). , yield: 90.9%).

The second step: preparation of 2,6-difluoro-N-hydroxyimine benzyl chloride

The title compound was synthesized in the same manner as in the second step of Example 8. The compound obtained in the first step of this Example (3.0 g, 0.019 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 3.2 g, yield: 88.9%).

The third step: preparation of methyl 5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole-4-carboxylate

The synthesis of the title compound of this step was carried out in a similar manner to the third step of Example 8. The compound obtained in the second step of this Example (3.2 g, 0.016 mol) was used in place of N-hydroxy-2-(trifluoromethyl)imide benzyl. Chlorine gave the title compound (3.5 g, yield: 78.5%).

Fourth step: Preparation of (5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methanol

The synthesis of the title compound of this step was carried out in the same manner as in the fourth step of Example 8. The compound obtained in the third step of this example (0.5 g, 1.79 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). Methyl isoxazole-4-carboxylate gave the title compound (0.4 g, yield: 89.1%).

Step 5: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole

The synthesis of the title compound of this step was carried out in the same manner as in the fifth step of Example 8. The compound obtained in the fourth step of the present invention (0.5 g, 1.99 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). The title compound (0.4 g, yield: 74.8%) was obtained from the title compound.

Step 6: (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Preparation of dienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the title compound of this step was carried out in a similar manner to that of the sixth step of Example 8. The compound obtained in the fifth step of the present invention (0.13 g, 0.48 mmol) was used in place of 4-(chloromethyl)-5-cyclopropyl-3-. (2-Trifluoromethylphenyl)isoxazole gave the title compound (0.11 g, yield: 50.0%).

Step 7: 5-cyclopropyl-3-(2,6-difluorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole

The synthesis of the title compound in this step was carried out in a similar manner to that in the seventh step of Example 8. The compound obtained in the sixth step of the present invention (0.11 g, 0.24 mmol) was used instead of (3aR, 5s, 6aS)-5-((5-cyclopropyl) 3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester Step title compound. The obtained compound was used in the next reaction without purification.

Step 8: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The synthesis of the title compound of this step was carried out in the same manner as in the eighth step of Example 8. The compound obtained in the seventh step of this Example (86.4 mg, 0.24 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). 4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (110 mg, Yield: 80.9%).

MS m/z (ESI): 570 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.20 (s, 1H), 7.68-7.56 (m, 2H), 7.32-7.28 (m, 2H), 4.25 (s, 2H), 3.93-3.92 (m, 4H), 3.68-3.63 (m, 2H), 3.31-3.27 (m, 2H), 2.68-2.67 (m, 2H), 2.33-2.29 (m, 1H), 1.74-1.69 (m, 2H), 1.58- 1.52 (m, 2H), 1.15 - 1.07 (m, 4H).

The ninth step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The synthesis of compound 11 was carried out in a similar manner to that in the ninth step of Example 8. The compound obtained in the eighth step of the present invention (110 mg, 0.19 mmol) was used in place of the compound 2-((3aR,5s,6aS)-5-((5-ring) Propyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluoro Benzo[d]thiazole-6-carboxylic acid methyl ester gave Compound 11 (50 mg, yield: 47.6%).

MS m/z (ESI): 556 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.20 (s, 1H), 7.68-7.56 (m, 2H), 7.32-7.28 (m, 2H), 4.25 (s, 2H), 3.93-3.92 (m, 1H), 3.68-3.63 (m, 2H), 3.31-3.27 (m, 2H), 2.68-2.67 (m, 2H), 2.33-2.29 (m, 1H), 1.74-1.69 (m, 2H), 1.58- 1.52 (m, 2H), 1.15 - 1.07 (m, 4H).

Example 11: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 12)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (79 mg, 0.20 mmol) was dissolved in DMA (4 mL), and ethyl 6-chloro-5-fluoronicotinate (38 mg, 0.20 mmol) and DIPEA (258 mg, 2.0 mmol). Stir at °C-120 ° C overnight. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 546 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.69 (s, 1H), 8.42-8.41 (m, 1H), 7.68-7.55 (m, 4H), 4.19 (s, 2H), 3.90-3.89 (m, 4H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53- 1.47 (m, 2H), 1.16.6.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

The compound obtained in the first step (57 mg, 0.1 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 12 (43 mg, yield: 80%).

MS m/z (ESI): 532 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.69 (s, 1H), 8.42-8.41 (m, 1H), 7.68-7.55 (m, 4H), 4.19 (s, 2H), 3.90-3.89 (m, 1H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53- 1.47 (m, 2H), 1.16.6.06 (m, 4H).

Example 12: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-6-methylpyrimidine-4-carboxylic acid (Compound 13)

First step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-6-methylpyrimidine-4-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (86 mg, 0.22 mmol) was dissolved in DMA (4 mL). Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (41 mg, 0.22 mmol) and DIPEA (284 mg, 2.2 mmol) ), stirring at 120 ° C - 130 ° C overnight. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 543 [M+H] ⁺

Second step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-6-methylpyrimidine-4-carboxylic acid

The compound obtained in the first step (81 mg, 0.15 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 13 (31 mg, yield: 40%).

MS m/z (ESI): 529 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 7.66-7.55 (m, 3H), 6.94 (s, 1H), 4.18 (s, 2H), 3.89-3.88 (m, 1H), 3.58-3.53 (m, 2H), 3.33-3.27 (m, 2H), 2.55-2.54 (m, 2H), 2.35-2.29 (m, 4H), 1.69-1.64 (m, 2H), 1.50-1.44 (m, 2H), 1.16- 1.06 (m, 4H).

Example 13: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-1-methyl-1H-indazole-3-carboxylic acid (Compound 14)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-1-methyl-1H-indazole-3-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (112 mg, 0.28 mmol), methyl 6-bromo-1-methyl-1H-carbazolecarboxylate (75 mg, 0.28 mmol), Pd ₂ (dba) ₃ (26 mg, 0.03 mmol) RuPhos (13 mg, 0.3 mmol) and Cs ₂ CO ₃ (274 mg, 0.84 mmol) were added to toluene and stirred at 80 ° C for 2 h under N ₂ . After cooling, the mixture was filtered, and the filtrate was evaporated. mjjjjjj

MS m/z (ESI): 581 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 7.80-7.78 (m, 1H), 7.65-7.55 (m, 3H), 6.79-6.77 (m, 1H), 6.54 (s, 1H), 4.21. 2H), 3.98 (s, 3H), 3.91 (m, 4H), 3.32 (m, 2H), 3.11-3.09 (m, 2H), 2.61 (m, 2H), 2.34-2.30 (m, 1H), 1.74 -1.72 (m, 2H), 1.51-1.47 (m, 2H), 1.15-1.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-1-methyl-1H-indazole-3-carboxylic acid

The compound obtained in the first step (100 mg, 0.17 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 14 (48 mg, yield: 47%).

MS m/z (ESI): 567 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 12.70 (s, 1H), 7.80-7.78 (m, 1H), 7.65-7.55 (m, 3H), 6.79-6.77 (m, 1H), 6.54 (s, 1H), 4.21 (s, 2H), 3.98 (s, 3H), 3.91 (m, 1H), 3.32 (m, 2H), 3.11-3.09 (m, 2H), 2.61 (m, 2H), 2.34-2.30 (m, 1H), 1.74-1.72 (m, 2H), 1.51-1.47 (m, 2H), 1.15-1.06 (m, 4H).

Example 14: 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-A) and 2-((3aR,5S,7aS)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-B)

First step: (3aS, 5R, 7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H -isoindole-2(3H)-tert-butyl formate (Compound 15-2A) and (3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of Isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-carboxylic acid tert-butyl ester (Compound 15-2B)

Compounds 15-1A and 15-1B (15-1A and 15-1B in any ratio, 100 mg, 0.41 mmol) were dissolved in dry THF (5 mL), then t-BuOK (92 mg, 0.82 mmol), 18-cr. Ether-6 (216 mg, 0.82 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (124 mg, 0.41 mmol). Stir at room temperature for 2 hours until TLC showed the starting material was completely. Water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (125 mg, yield: 61%).

Second step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aS,5R,7aR)-octahydro-1H-isoindole-5-yl)oxy) Methyl)isoxazole (Compound 15-3A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5S,7aS)-octahydro- Preparation of 1H-isoindole-5-yl)oxy)methyl)isoxazole (Compound 15-3B)

The product from the first step (125 mg, 0.25 mmol) was dissolved in DCM (4 mL). Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained product was used in the next reaction without purification.

The third step: 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (Compound 15-4A) and 2-((3aR,5S,7aS)-5 -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)- Preparation of methyl 4-fluorobenzo[d]thiazole-6-carboxylate (Compound 15-4B)

The product obtained in the second step (73 mg, 0.25 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (102 mg, 0.25 mmol) and DIPEA (323 mg) , 2.5 mmol). Stir at 100 ° C - 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (137 mg, yield: 88%).

MS m/z (ESI): 616 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.23 - 8.22 (m, 1H), 7.67 - 7.56 (m, 4H), 4.30 - 4.24 (m, 2H), 3.90 (s, 3H), 3.55 - 3.43 ( m, 5H), 2.36-2.31 (m, 1H), 2.23 (m, 2H), 1.58-1.48 (m, 4H), 1.23-1.08 (m, 6H).

The fourth step: 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-A) and 2-((3aR,5S,7aS)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-B)

The product from the third step (137 mg, 0.22 mmol) was dissolved in MeOH (5 mL) Stir at room temperature for 4 hours until TLC showed the starting material was completely. After cooling, water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford the desired product of the step (compound 15 as a mixture of compound 15-A and 15-B) , 65 mg, yield: 50%).

MS m/z (ESI): 602 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.90 (s, 1H), 8.23-8.22 (m, 1H), 7.67-7.56 (m, 4H), 4.30-4.24 (m, 2H), 3.55-3.43 ( m, 5H), 2.36-2.31 (m, 1H), 2.23 (m, 2H), 1.58-1.48 (m, 4H), 1.23-1.08 (m, 6H).

(化合物的测量浓度c＝8.2mg/mL，溶剂：DMF)；化合物15-t(2)：保留时间R_t＝12.503min，26mg，ee％＝98％，比旋光度

(化合物的测量浓度c＝9.0mg/mL，溶剂：DMF)。Compound 15 (65 mg) was separated by chiral chromatography (separation conditions: column: CHIRALPAK AD-H; mobile phase: n-hexane/isopropanol/glacial acetic acid: 65/35/0.1 (V/V/V) ; detection wavelength: 214 nm), two optical isomers - compound 15-t (1): retention time R _t = 9.261 min, 24 mg, ee% = 98%, specific optical rotation

(measured concentration of compound c=8.2 mg/mL, solvent: DMF); compound 15-t(2): retention time R _t = 12.503 min, 26 mg, ee% = 98%, specific optical rotation

(Measured concentration of compound c = 9.0 mg/mL, solvent: DMF).

Example 15: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]thiazole-6-carboxylic acid (Compound 28)

First step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]thiazole-6-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (100 mg, 0.25 mmol) was dissolved in DMA (4 mL), and 2-bromobenzothiazole-6-carboxylic acid methyl ester (73 mg, 0.25 mmol) and DIPEA (322 mg, 2.5 mmol) Stir at 100 ° C - 120 ° C overnight. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 584 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.42 (s, 1H), 7.98-7.55 (m, 5H), 4.19 (s, 2H), 3.90-3.89 (m, 4H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16- 1.06 (m, 4H).

Second step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]thiazole-6-carboxylic acid

The compound obtained in the first step (120 mg, 0.21 mmol) was dissolved in MeOH (4 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 28 (70 mg, yield: 59%).

MS m/z (ESI): 570 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.90 (s, 1H), 8.42 (s, 1H), 7.68-7.55 (m, 5H), 4.19 (s, 2H), 3.90-3.89 (m, 1H) , 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 ( m, 2H), 1.16-1.06 (m, 4H).

Example 16: 2-((3aR,5S,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxamido)acetic acid (Compound 29)

First step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxamido)acetate

2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Dienyl[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (70 mg, 0.12 mmol) was dissolved in DCM (4 mL). 014 mmol), EDCI (32.3 mg, 018 mmol), HOBT (24.3 mg, 0.18 mmol) and DIPEA (46.4 mg, 0.36 mmol). Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 659 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.17 (s, 1H), 7.82-7.50 (m, 2H), 7.46 (m ,, 2H), 6.90 (s, 1H), 4.80 (s, 2H), 4.36-4.20 (m, 1H), 4.11 (s, 2H), 3.93 (m, 2H), 3.73 (m, 2H), 3.63 (s, 3H), 2.73 (t, J = 20.2 Hz, 1H), 2.21. (m, 2H), 1.75 (m, 2H), 1.40-1.15 (m, 2H), 1.18-0.77 (m, 4H).

Second step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxamido)acetic acid

The compound obtained in the first step (50 mg, 0.076 mmol) was dissolved in MeOH (4 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 29 (30 mg, yield: 61%).

MS m/z (ESI): 645 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 12.87 (s, 1H), 8.17 (s, 1H), 7.82-7.50 (m, 2H), 7.46 (m ,, 2H), 6.90 (s, 1H), 4.80 (s, 2H), 4.36-4.20 (m, 1H), 4.11 (s, 2H), 3.93 (m, 2H), 3.73 (m, 2H), 2.73 (t, J = 20.2 Hz, 1H), 2.21. (m, 2H), 1.75 (m, 2H), 1.40-1.15 (m, 2H), 1.18-0.77 (m, 4H).

Example 17: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 33)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate

5-Cyclopropyl-3-(2,6-difluorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (84 mg, 0.22 mmol) was dissolved in DMA (4 mL), and ethyl 6-chloro-5-fluoronicotinate (41 mg, 0.22 mmol) and DIPEA (284 mg, 2.2 mmol) Stir at °C-120 ° C overnight. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 514 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.42-8.41 (m, 1H), 7.50-7.41 (m, 4H), 4.19 (s, 2H), 3.90-3.89 (m, 4H), 3.71-3.67 ( m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16-1.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

The compound obtained in the first step (40 mg, 0.078 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 33 (30 mg, yield: 77%).

MS m/z (ESI): 500 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.69 (s, 1H), 8.42-8.41 (m, 1H), 7.50-7.41 (m, 4H), 4.19 (s, 2H), 3.90-3.89 (m, 1H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53- 1.47 (m, 2H), 1.16.6.06 (m, 4H).

Example 18: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 34)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate

The synthesis of the title compound of this step was carried out by the procedure of the first step of Example 17, using 5-cyclopropyl-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Substituted 5-oxopropyl-3-(2,6-difluorophenyl) - 4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (100mg, Rate: 57%).

MS m/z (ESI): 546 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.41 (s, 1H), 7.91 (m, 1H), 7.67-7.50 (m, 4H), 4.19 (s, 2H), 3.90-3.89 (m, 4H) , 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 ( m, 2H), 1.16-1.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

Synthesis of Compound 34 Following the procedure of the second step of Example 17, using 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)) Isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate methyl ester (100 mg, 0.18 mmol) instead of 6-(( 3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c Pyrrole-2(1H)-yl)-5-fluoronicotinate methyl ester gave Compound 34 (57 mg, yield: 59%).

MS m/z (ESI): 532 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 12.70 (s, 1H), 8.41 (s, 1H), 7.91 (m, 1H), 7.67-7.50 (m, 4H), 4.19 (s, 2H), 3.90 -3.89 (m, 1H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16-1.06 (m, 4H).

Example 19: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic Acid (Compound 35)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrogencyclopenta[c]pyrrole-2(1H)-yl)methyl Nicotinate

The title compound was synthesized in the same manner as in the first step of the procedure. The title compound was obtained by substituting 6-chloro-nicotinic acid methyl ester (51 mg, 0.2 mmol) with methyl 6-chloro-5-fluoronicotinate. 80 mg, yield: 81%).

MS m/z (ESI): 496 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.42-8.41 (m, 1H), 7.50-7.41 (m, 4H), 7.20-7.15 (m, 1H), 4.19 (s, 2H), 3.90-3.89 ( m, 4H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16.6.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

Synthesis of Compound 35 Referring to the operation of the second step of Example 17, 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)) Zoxa-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate (60 mg, 0.1 mmol) in place of 6-((3aR,5s,6aS) 5-(-(5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2 (1H Methyl-5-fluoronicotinate gave compound 35 (48 mg, yield: 100%).

MS m/z (ESI): 482 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.69 (s, 1H), 8.42-8.41 (m, 1H), 7.50-7.41 (m, 4H), 7.20-7.15 (m, 1H), 4.19 (s, 2H), 3.90-3.89 (m, 1H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69- 1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16-1.06 (m, 4H).

Example 20: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid (compound 36)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate

In this step, the title compound was synthesized by the procedure of the first step of Example 18, using 6-chloro-nicotinic acid methyl ester (69 mg, 0.32 mmol) in place of methyl 6-chloro-5-fluoronicotinate to give the title compound (90 mg, Yield: 53%).

MS m/z (ESI): 528 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 8.41 (s, 1H), 7.91 (m, 1H), 7.67-7.50 (m, 5H), 4.19 (s, 2H), 3.90-3.89 (m, 4H) , 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 ( m, 2H), 1.16-1.06 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid

Synthesis of Compound 36 Referring to the procedure of the second step of Example 18, 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)) Isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate (90 mg, 0.17 mmol) instead of 6-((3aR,5s, 6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole Methyl-2(1H)-yl)-5-fluoronicotinate gave Compound 36 (30 mg, yield: 34%).

MS m/z (ESI): 514 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 12.70 (s, 1H), 8.41 (s, 1H), 7.91 (m, 1H), 7.67-7.50 (m, 5H), 4.19 (s, 2H), 3.90 -3.89 (m, 1H), 3.71-3.67 (m, 2H), 3.41-3.32 (m, 2H), 2.54-2.51 (m, 2H), 2.34-2.30 (m, 1H), 1.69-1.65 (m, 2H), 1.53-1.47 (m, 2H), 1.16-1.06 (m, 4H).

Example 21: 2-((3aR,5s,6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 37)

First step: (3aR, 5s, 6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl) Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

(3aR,5S,6aS)-5-(Hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (100 mg, 0.41 mmol) was dissolved in dry THF (5 mL) ), t-BuOK (66.9 g, 0.7 mmol), 18-crown-6 (89.9 mg, 0.34 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-) were added in that order. Dichlorophenyl)isoxazole (123 mg, 0.41 mmol) was stirred at room temperature for 2 hours. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Second step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of methoxy)methyl)isoxazole

The compound obtained in the first step (140 mg, 0.20 mmol) was evaporated. The mixture was concentrated to give the title compound.

The third step: 2-((3aR,5s,6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester

The compound obtained in the second step (111 mg, 0.28 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (80.9 mg, 0.28 mmol) and DIPEA (0.36) g, 2.8 mmol), stirred at 100 ° C - 120 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 616 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ: 8.22 (s, 1H), 7.79-7.22 (m, 4H), 4.24 (s, 2H), 3.90 (s, 3H), 3.71 (d, J = 7.4 Hz, 2H), 3.26 (d, J = 10.9 Hz, 2H), 3.16 (d, J = 6.4 Hz, 2H), 2.78 (s, 2H), 2.38 - 2.22 (m, 1H), 2.23 - 2.10 (m) , 1H), 1.63-1.29 (m, 4H), 1.25-1.00 (m, 4H).

Fourth step: 2-((3aR,5s,6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The compound obtained in the third step (160 mg, 0.26 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (50.96 mg, 0.91 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 37 (90 mg, yield: 57.7%).

MS m/z (ESI): 602 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ: 12.69 (s, 1H), 8.22 (s, 1H), 7.79-7.22 (m, 4H), 4.24 (s, 2H), 3.71 (d, J = 7.4 Hz, 2H), 3.26 (d, J = 10.9 Hz, 2H), 3.16 (d, J = 6.4 Hz, 2H), 2.78 (s, 2H), 2.38 - 2.22 (m, 1H), 2.23 - 2.10 (m) , 1H), 1.63-1.29 (m, 4H), 1.25-1.00 (m, 4H).

Example 22: 2-((1R,5S)-6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 38A) and 2-((1S,5R)-6-((5-cyclo) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 38B)

First step: (1R,5S)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo [3.2.0] tert-butyl heptane-3-carboxylate (compound 38-2A) and (1S,5R)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)) Preparation of tert-butyl ester of oxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptane-3-carboxylate (Compound 38-2B)

A mixture of the compound 38-1A and 38-1B (100 mg, 0.47 mmol) was dissolved in dry THF (5 mL), then t-BuOK (76.7 g, 0.8 mmol), and 18-crown ether-6 (103 mg, 0.39 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (141 mg, 0.47 mmol). Stir at room temperature for 2 hours until TLC showed the starting material was completely. Water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (110 mg, yield: 47.6%).

Second step: 4-(((1R,5S)-3-azabicyclo[3.2.0]heptan-6-yl)oxy)methyl)-5-cyclopropyl-3-(2, 6-Dichlorophenyl)isoxazole trifluoroacetate (compound 38-3A) and 4-((((1S,5R)-3-azabicyclo[3.2.0]heptan-6-yl)) Preparation of oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole trifluoroacetate (compound 38-3B)

The product obtained in the first step (110 mg, 0.20 mmol) was dissolved in DCM (4mL) Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained compound was used in the next reaction without purification.

The third step: 2-((1R,5S)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 38-4A) and 2-((1S,5R)-6-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)- Preparation of methyl 4-fluorobenzo[d]thiazole-6-carboxylate (Compound 38-4B)

The product obtained in the second step (86 mg, 0.22 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (66.6 mg, 0.22 mmol) and DIPEA ( 0.28 g, 2.2 mmol). Stir at 100 ° C - 120 ° C for 4 hours until TLC The starting material is completely reacted. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (90 mg, yield: 69.8%).

MS m/z (ESI): 588 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ: 8.21 (s, 1H), 7.75-7.39 (m, 4H), 4.14 (m, 2H), 3.97-3.70 (m, 5H), 3.19 (m, 2H ), 2.67 (s, 1H), 2.42-2.29 (m, 2H), 1.37 (d, J = 12.2 Hz, 1H), 1.23 (s, 2H), 1.11 (m, 4H).

Step 4: 2-((1R,5S)-6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 38A) and 2-((1S,5R)-6-((5-cyclo) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 38B)

The product obtained in the third step (90 mg, 0.15 mmol) was dissolved in THF (2mL) and MeOH (1mL), and KOH (29.5mg, 0.53mmol). Stir at 60 ° C for 4 hours until TLC showed the starting material was completely reacted. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried, and concentrated, and the residue was purified by silica gel chromatography to afford the desired product of compound (compound 38, compound 38A and 38B; Rate: 52.3%).

MS m/z (ESI): 574 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ: 12.34 (s, 1H), 8.21 (s, 1H), 7.75-7.39 (m, 4H), 4.14 (m, 2H), 3.97-3.70 (m, 2H ), 3.19 (m, 2H), 2.67 (s, 1H), 2.42-2.29 (m, 2H), 1.37 (d, J = 12.2 Hz, 1H), 1.23 (s, 2H), 1.11 (m, 4H) .

Example 23: 2-((3aS,4R,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39A) and 2-((3aR,4S,6aS)-4- ((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39B)

First step: (3aS, 4R, 6aR)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane Dienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 39-2A) and (3aR,4S,6aS)-4-((5-cyclopropyl-3-(2,6-di) Preparation of chlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 39-2B)

Compounds 39-1A and 39-1B (any ratio, 100 mg, 0.44 mmol) were dissolved in dry THF (5 mL), then t-BuOK (72 mg, 0.75 mmol), 18-crown-6 (96.5 mg, 0.37) Methyl) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (132 mg, 0.44 mmol). Stir at room temperature for 2 hours until TLC showed the starting material was completely. Water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to afford the desired product (200 mg, yield: 92.6%).

Second step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aS,4R,6aR)-octahydrocyclopentadiene[c]pyrrol-4-yl) Oxy)methyl)isoxazole trifluoroacetate (compound 39-3A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,4S) Of 6aS)-octahydrocyclopentadienyl[c]pyrrol-4-yl)oxy)methyl)isoxazole trifluoroacetate (Compound 39-3B)

The product obtained in the first step (200 mg, 0.42 mmol) was dissolved in DCM (4mL) Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained compound was used in the next reaction without purification.

The third step: 2-((3aS,4R,6aR)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (Compound 39-4A) and 2-((3aR,4S,6aS) -4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2 ( Preparation of 1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 39-4B)

The product obtained in the second step (159 mg, 0.41 mmol) was dissolved in DMA (4 mL), and ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (118 mg, 0.41 mmol) and DIPEA (0.53) g, 4.1 mmol). Stir at 100 ° C - 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (140 mg, yield: 56.9%).

MS m/z (ESI): 602 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.89 (s, 1H), 8.23 (s, 1H), 7.61 (m, 4H), 4.26-4.23 (m, 2H), 3.97 (s, 3H), 3.67 (d, J = 17.7 Hz, 3H), 3.20 (s, 2H), 2.70 (m, 1H), 2.41-2.26 (m, 2H), 2.08 (d, J = 4.5 Hz, 1H), 1.76 (s) , 2H), 1.54-1.30 (m, 2H), 1.29-1.01 (m, 4H).

The fourth step: 2-((3aS,4R,6aR)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39A) and 2-((3aR,4S,6aS)-4- ((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39B)

The product obtained in the third step (140 mg, 0.23 mmol) was dissolved in THF (2mL) and MeOH (1mL), and KOH (6.44mg, 0.12mmol). Stir at 60 ° C for 4 hours until TLC showed the starting material was completely reacted. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried, and concentrated, and the residue was purified by silica gel chromatography to afford the desired product of the product (compound 39, compound 39A and 39B; Rate: 68.9%).

MS m/z (ESI): 588 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.89 (s, 1H), 8.23 (s, 1H), 7.61 (m, 4H), 4.26-4.23 (m, 2H), 3.67 (d, J = 17.7 Hz, 3H), 3.20 (s, 2H), 2.70 (m, 1H), 2.41-2.26 (m, 2H), 2.08 (d, J = 4.5 Hz, 1H), 1.76 (s, 2H), 1.54-1.30 (m, 2H), 1.29-1.01 (m, 4H).

Example 24: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Hydrogen-1H-isoindole-2(3H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40A) and 2-((3aS,5R,7aR)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40B)

First step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl-1H-isoindole-2(3H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylate (Compound 40-2A) and 2-((3aS,5R,7aR) 5-(-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)octahydro-1H-isoindole-2(3H)-yl Preparation of methyl 4-methoxybenzo[d]thiazole-6-carboxylate (Compound 40-2B)

Compounds 40-1A and 40-1B (arbitrary ratio, 189 mg, 0.63 mmol) were dissolved in DMA (4 mL) and methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (309.9 mg, 0.63) Methyl) and DIPEA (812 mg, 6.3 mmol). Stir at 100 ° C - 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (300 mg, yield: 75.9%).

MS m/z (ESI): 628 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d, J = 1.3 Hz, 1H), 7.80-7.49 (m, 3H), 7.38 (s, 1H), 4.27 (d, J = 2.5 Hz, 2H), 3.89 (s, 3H), 3.43 (s, 4H), 2.33 (d, J = 5.0 Hz, 2H), 2.22 (s, 2H), 1.74-1.36 (m, 4H), 1.19-1.02 (m , 4H).

Second step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40A) and 2-((3aS,5R,7aR)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-2H-isoindole-2(3H)-yl)-4- Preparation of methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40B)

The product obtained in the first step (300 mg, 0.48 mmol) was dissolved in THF (2mL) and MeOH (1mL), and KOH (26.9mg, 1.68mmol). Stir at 60 ° C for 4 hours until TLC showed the starting material was completely reacted. After cooling, water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried, and concentrated, and the residue was purified by silica gel chromatography to afford the desired product of compound of compound (comp. 40, compound 40A and 40B; Rate: 51.0%).

MS m/z (ESI): 614 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.37 (s, 1H), 7.99 (d, J = 1.3Hz, 1H), 7.80-7.49 (m, 3H), 7.38 (s, 1H), 4.27 ( d, J = 2.5 Hz, 2H), 3.43 (s, 4H), 2.33 (d, J = 5.0 Hz, 2H), 2.22 (s, 2H), 1.74-1.36 (m, 4H), 1.19-1.02 (m , 4H).

Example 25: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)6 Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 41A) and 2-((3aS,5R,7aR)-5-((5) -cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 41B)

First step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 41-2A) and 2-((3aS,5R,7aR)-5 -((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)- Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 41-2B)

Compounds 41-1A and 41-1B (arbitrary ratio, 256 mg, 0.63 mmol) were dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (182 mg, 0.63 mmol) was added. ) and DIPEA (812 mg, 6.3 mmol). Stir at 100 ° C - 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by column chromatography to give the desired product (250 mg, yield: 68.1%).

MS m/z (ESI): 584 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.48 (s, 1H), 8.20 (s, 1H), 7.62 (m, 2H), 7.31 (t, J = 8.0Hz, 2H), 4.33 (s, 2H), 3.89 (s, 3H), 3.44 (m, 3H), 2.42-2.04 (m, 4H), 1.84-1.36 (m, 4H), 1.36-0.94 (m, 7H).

Second step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 41A) and 2-((3aS,5R,7aR)-5-((5) -cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 41B)

The compound obtained in the first step (250 mg, 0.43 mmol) was dissolved in THF (2mL) and MeOH (1mL), and KOH (83.9mg, 1.5mmol). Stir at 60 ° C for 4 hours until TLC showed the starting material was completely reacted. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried, and concentrated, and the residue was purified by silica gel chromatography to afford the desired product of compound (Comp. 41, Compounds 41A and 41B; Rate: 49.2%).

MS m/z (ESI): 570 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.48 (s, 1H), 8.20 (s, 1H), 7.62 (m, 2H), 7.31 (t, J = 8.0Hz, 2H), 4.33 (s, 2H), 3.44 (m, 3H), 2.42-2.04 (m, 4H), 1.84-1.36 (m, 4H), 1.36-0.94 (m, 7H).

Example 26: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid (compound 42A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-) 3-(2-(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid Preparation of Compound 42B)

First step: (3aR, 5S, 7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-carboxylic acid tert-butyl ester (compound 42-2A) and (3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-(difluoro)) Preparation of methoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-carboxylic acid tert-butyl ester (Compound 42-2B)

Compounds 42-1A and 42-1B (in any ratio, 200 mg, 0.829 mmol) were dissolved in dry tetrahydrofuran (5 mL), cooled to 0<0>C under N2 &_lt;0> 18-crown-6 (438 mg, 1.657 mmol) was stirred and added dropwise to 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl dissolved in dry tetrahydrofuran. Isooxazole (249 mg, 0.829 mmol) was stirred for 3 hours until TLC (PE: EA = 3:1) showed that the starting material was completely. Water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to give the desired product (400 mg, yield: 95.7%).

Second step: 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aR,5S,7aS)-octahydro-1H-isoindole-5-) Alkyloxy)methyl)isoxazole hydrochloride (compound 42-3A) and 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aS) Preparation of a mixture of 5R,7aR)-octahydro-1H-isoindol-5-yl)oxy)methyl)isoxazole hydrochloride (Compound 42-3B)

The product of the first step (400 mg, 0.793 mmol) was dissolved in EtOAc EtOAc (EtOAc (EtOAc) The target product of this step (300 mg, yield: 93.5%).

The third step: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinate (compound 42-4A) and 6-((3aS,5R,7aR)-5-((5- Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-5- Preparation of methyl fluoronicotinate (compound 42-4B)

The product of the second step (200 mg, 0.742 mmol), methyl 5-fluoro-6-chloronicotinate (125 mg, 0.661 mmol) and N,N-dimethylformamide (10 ml) were added to the reactor and stirred. Potassium carbonate (183 mg, 1.321 mmol) was stirred at 80 ° C for 4 hours. It was extracted with water and ethyl acetate and dried, and the residue was purified by silica gel chromatography (DCM: MeOH = 20:1) to give the desired product (300 mg, yield: 81.5%).

MS m/z (ESI): 558 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ8.42 (s, 1H), 7.71-7.56 (m, 2H), 7.56-7.48 (m, 1H), 7.38 (m, 2H), 4.33 (s, 2H ), 3.88 (s, 3H), 3.60 (s, 2H), 3.51-3.33 (m, 5H), 2.25 (m, 3H), 1.73-1.38 (m, 4H), 1.17-0.93 (m, 4H).

Fourth step: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid (compound 42A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-) 3-(2-(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid Preparation of Compound 42B)

The product of the third step (300 mg, 0.539 mmol) was dissolved in MeOH (5 mL). The mixture was stirred at 40 ° C overnight. The reaction was shown to be complete by LC-MS. Aqueous hydrochloric acid (2N) was added until the solution was acidified, and the mixture was concentrated directly. The desired product of this step was obtained by preparative HPLC (Compound 42 as a mixture of Compounds 42A and 42B; 29 mg, yield: 10.0%).

MS m/z (ESI): 544 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ12.41 (s, 1H), 8.42 (s, 1H), 7.71-7.56 (m, 2H), 7.56-7.48 (m, 1H), 7.38 (m, 2H ), 4.33 (s, 2H), 3.60 (s, 2H), 3.51-3.33 (m, 5H), 2.25 (m, 3H), 1.73-1.38 (m, 4H), 1.17-0.93 (m, 4H).

Example 27: 2-((7R,8aS)-7-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydro Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43A) and 2-((7S,8aR)-7-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydropyrrolo[1,2-a]pyrazine-2(1H) Of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43B)

First step: (7R, 8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (compounds 43-2A) and (7S,8aR)-7 -Hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (Compound 43-2B)

Compound 43-1A and Compound 43-1B (any ratio, 150 mg, 0.645 mmol) and Boc anhydride (282 mg, 1.292 mmol) were added to the reactor, dichloromethane (5 mL) was added, and four or five drops of triethylamine were added dropwise. The reaction was allowed to stand overnight until TLC showed the starting material was completely reacted. The reactant was directly concentrated to give the objective product of this step (130 mg, yield: 83.1%).

Second step: (7R,8aS)-7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydropyrrolo[1 , 2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (compound 43-3A) and (7S,8aR)-7-((5-cyclopropyl-3-(2,6-dichlorobenzene) Of oxazol-4-yl)methoxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylic acid tert-butyl ester (Compound 43-3B)

The product of the first step (130mg, 0.536mmol) was dissolved in dry tetrahydrofuran (20mL), under N ₂ protection cooled to about 0 ℃, potassium tert-butoxide (120mg, 1.073mmol) and 18-crown-6 (284 mg, 1.073 mmol). 4-Chloromethyl-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (174 mg, 0.536 mmol) dissolved in dry tetrahydrofuran was added dropwise with stirring, and stirred for 3 hours until TLC (PE: EA = 3:1) showed that the starting material was completely reacted. Water and ethyl acetate were added to the mixture, and the EA layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give the desired product (250 mg, yield: 91.7%).

Third step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(((7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-yl) )oxy)methyl)isoxazole hydrochloride (compound 43-4A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-(((7S,8aR)-eight) Preparation of Hydropyrrolo[1,2-a]pyrazin-7-yl)oxy)methyl)isoxazole Hydrochloride (Compound 43-4B)

The product of the second step (250 mg, 0.492 mmol) was dissolved in EtOAc EtOAc. The target product of this step (200 mg, yield: 99.5%).

Fourth step: 2-((7R,8aS)-7-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydro Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 43-5A) and 2-((7S,8aR) -7-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydropyrrolo[1,2-a]pyrazine- Preparation of 2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 43-5B)

The product of the third step (200 mg, 0.490 mmol), methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (119 mg, 0.408 mmol) and N,N-dimethylformamide (5 ml) It was added to the reactor, potassium carbonate (113 mg, 0.816 mmol) was added with stirring, and the reaction was stirred at 80 ° C for 6 hours. It was extracted with water and ethyl acetate, and dried, and the residue was purified by silica gel chromatography (DCM: MeOH = 20:1) to give the desired product (150 mg, yield: 59.6%).

MS m/z (ESI): 617 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ13.00 (s, 1H), 8.28 (s, 1H), 7.95-7.40 (m, 3H), 5.77 (s, 2H), 4.41-3.79 (m, 5H ), 3.89 (s, 3H), 3.34 (m, 3H), 3.00-2.98 (m, 1H), 2.34 (s, 1H), 2.31-1.32 (m, 4H), 1.26-0.95 (m, 4H).

Step 5: 2-((7R,8aS)-7-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydro Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43A) and 2-((7S,8aR)-7-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydropyrrolo[1,2-a]pyrazine-2(1H) Of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43B)

The product of the fourth step (150 mg, 0.243 mmol) was dissolved in methanol (5 mL). The mixture was stirred at 40 ° C overnight. The reaction was shown to be complete by LC-MS. Aqueous hydrochloric acid (2N) was added until the solution became acidic, and the mixture was concentrated directly. The desired product of this step was obtained by preparative HPLC (Compound 43 as a mixture of compound 43-A and 43-B; 59 mg, yield: 40.2% ).

MS m/z (ESI): 603 [M+H] ⁺

^{1 H NMR (400MHz, DMSO-} d 6) δ13.00 (s, 1H), 8.28 (s, 1H), 7.95-7.40 (m, 3H), 5.77 (s, 2H), 4.41-3.79 (m, 5H ), 3.34 (s, 3H), 3.00 (s, 1H), 2.34 (s, 1H), 2.31-1.32 (m, 4H), 1.26-0.95 (m, 4H).

Example 28: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 44)

First step: Preparation of 2-difluoromethylbenzaldehyde oxime

The 2-difluoromethyl-benzaldehyde (2g, 0.013mol) was dissolved in ethanol (30mL) and water (10mL), was added NaOH (0.92g, 0.026mol) and _{NH 2 OH.HCl (1.2g, 0.015mol)} , The mixture was heated to reflux and stirred overnight. The reaction mixture was concentrated and filtered, and then filtered, and the title compound was obtained from the title compound (2.2 g, yield: 100.0%).

The second step: preparation of 2-(difluoromethyl)-N-hydroxyimine benzyl chloride

The compound obtained in the first step (2 g, 11.7 mmol) was dissolved in DMF (20 mL). Water and ethyl acetate were added to the mixture, and the EA layer was evaporated.

Third step: preparation of methyl 5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazole-4-carboxylate

The compound obtained in the second step (2 g, 9.75 mmol) was dissolved in Et ₃ N (20 mL). Methyl 3-cyclopropyl-3-oxopropanoate (1.53 g, 10.73 mmol). . Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Fourth step: Preparation of (5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methanol

The compound obtained in the third step (1 g, 3.4 mmol) was dissolved in dry THF (20mL), and LiAlH ₄ (0.26 g, 6.8 mol) was added. The mixture was stirred at 0 ° C until TLC showed the starting material was completely. To the mixture was added sodium sulfate decahydrate to terminate the reaction, which was filtered, dried, and evaporated.

Step 5: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazole

The benzotriazole (0.75g, 6.56mmol) was dissolved in dry DCM (20mL), was added dropwise SOCl ₂ (0.78g, 6.56mmol) at 0 ℃. After stirring at room temperature for 30 min, the compound obtained in the fourth step (0.9 g, 3.28 m mol) was added until TLC showed that the starting material was completely reacted. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.

Step 6: (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro Preparation of cyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the title compound of this step was carried out in the same manner as in the second step of Example 1, and the compound obtained in the fifth step of the present invention (0.5 g, 1.76 mmol) was used in place of 4-(chloromethyl)-5-cyclopropyl-3-. (2,6-Dichlorophenyl)isoxazole gave the title compound (0.55 g, yield: 65%).

Step 7: 5-cyclopropyl-3-(2-(difluoromethyl)phenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole- Preparation of 5-yl)oxy)methyl)isoxazole trifluoroacetate

The synthesis of the title compound of this step was carried out in the same manner as in the third step of Example 1. The compound obtained in the sixth step of the present invention (0.55 g, 1.15 mmol) was used in place of the compound (3aR, 5r, 6aS)-5-((5-ring). Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester The title compound was obtained in this step, and the obtained compound was used for the next reaction without purification.

Step 8: 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate

The synthesis of the title compound of this step was carried out in the same manner as in the fourth step of Example 1, and the compound obtained in the seventh step of the present invention (0.55 g, 1.15 mmol) was used in place of 5-cyclopropyl-3-(2,6-dichlorobenzene). 4-(((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (350mg, Yield: 52.0%).

MS m/z (ESI): 584 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.23 (d, J = 1.4Hz, 1H), 7.85-7.79 (m, 1H), 7.71 (m, 2H), 7.64-7.57 (m, 2H), 7.05-6.77 (t, J=56 Hz, 1H), 4.21 (s, 2H), 4.01 (s, 1H), 3.90 (s, 3H), 3.77-3.65 (m, 2H), 3.59 (m, 2H), 2.79 (s) , 2H), 2.38-2.28 (m, 1H), 1.89-1.58 (m, 5H), 1.30-1.05 (m, 3H).

Step 9: 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

Synthesis of Compound 44 The compound obtained in the eighth step of this Example (350 mg, 0.59 mmol) was used instead of compound 2-((3aR,5r,6aS)-5-((5-ring). Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluoro Benzo[d]thiazole-6-carboxylic acid methyl ester gave Compound 44 (220 mg, yield: 64.7%).

MS m/z (ESI): 570 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.9.0 (br, 1H), 8.23 (d, J = 1.4Hz, 1H), 7.85-7.79 (m, 1H), 7.71 (m, 2H), 7.64-7.57 (m , 2H), 7.05-6.77 (t, J = 56 Hz, 1H), 4.21 (s, 2H), 4.01 (s, 1H), 3.77-3.65 (m, 2H), 3.59 (m, 2H), 2.79 (s) , 2H), 2.38-2.28 (m, 1H), 1.89-1.58 (m, 5H), 1.30-1.05 (m, 3H).

Example 29: 7-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (Compound 46)

First step: 7-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Ethyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)imidazo[1,2-a]pyridine-3-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (500 mg, 1.86 mmol) was dissolved in toluene (10 mL), and ethyl 7-bromo-imidazo[1,2-a]pyridine-3-carboxylate (900 mg, 2.23 mmol) and RuPhos were added. (120 mg, 0.25 mmol), Cs ₂ CO ₃ (1.5 g, 4.60 mmol), Pd ₂ (dba) ₃ (150 mg, 0.26 mmol), and stirred at 90 ° C for 8 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 581 [M+H] ⁺

^{1 HNMR (400MHz, DMSO) δ} : 12.45 (s, 1H), 8.17-8.23 (m, 1H), 7.66-7.69 (m, 3H), 6.77 (s, 1H), 5.55-5.59 (m, 1H), 4.30 (m, 2H), 4.20 (s, 2H), 3.92 (s, 1H), 3.61-3.66 (m, 2H), 3.08-3.34 (m, 2H), 2.66 (s, 2H), 2.47 (s, 3H), 2.30-2.34 (m, 1H), 1.68-1.72 (m, 2H), 1.51-1.55 (m, 2H), 1.09-1.29 (m, 7H).

Second step: 7-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

The compound obtained in the first step (8 mg, 0.014 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (0.33 mg, 0.59 mmol) was added and stirred at 60 ° C for 2 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 46 (5 mg, yield: 64.1%).

MS m/z (ESI): 567 [M+H] ⁺

^{1 HNMR (400MHz, DMSO) δ} : 12.45 (s, 1H), 8.17-8.23 (m, 1H), 7.66-7.69 (m, 3H), 6.77 (s, 1H), 5.55-5.59 (m, 1H), 4.20 (s, 2H), 3.92 (s, 1H), 3.61-3.66 (m, 2H), 3.08-3.34 (m, 2H), 2.66 (s, 2H), 2.47 (s, 3H), 2.30-2.34 ( m, 1H), 1.68-1.72 (m, 2H), 1.51-1.55 (m, 2H), 1.09-1.23 (m, 4H).

Example 30: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methylbenzo[d]thiazole-6-carboxylic acid (Compound 47)

First step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methylbenzo[d]thiazole-6-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (135 mg, 0.35 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-methylbenzo[d]thiazole-6-carboxylic acid methyl ester (100 mg, 0.35 mmol) and DIPEA (0.45 g, 3.5 mmol), stirred at 100 ° C - 110 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 598 [M+H] ⁺

^{1 HNMR (400MHz, DMSO) δ} : 12.45 (s, 1H), 8.17 (s, 1H), 7.66-7.69 (m, 2H), 7.64 (s, 1H), 7.55-7.59 (m, 1H), 4.20 ( s, 2H), 3.92 (s, 1H), 3.89 (s, 3H), 3.61-3.66 (m, 2H), 3.08-3.34 (m, 2H), 2.66 (s, 2H), 2.47 (s, 3H) , 2.30-2.34 (m, 1H), 1.68-1.72 (m, 2H), 1.51-1.55 (m, 2H), 1.09-1.23 (m, 4H).

Second step: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methylbenzo[d]thiazole-6-carboxylic acid

The compound obtained in the first step (100 mg, 0.17 mmol) was dissolved in THF (2mL) and MeOH (1mL), KOH (0.33 mg, 0.59 mmol) was added and stirred at 60 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 47 (70 mg, yield: 70.1%).

MS m/z (ESI): 584 [M+H] ⁺

^{1 HNMR (400MHz, DMSO) δ} : 12.45 (s, 1H), 8.17 (s, 1H), 7.66-7.69 (m, 2H), 7.64 (s, 1H), 7.55-7.59 (m, 1H), 4.20 ( s, 2H), 3.92 (s, 1H), 3.61-3.66 (m, 2H), 3.08-3.34 (m, 2H), 2.66 (s, 2H), 2.47 (s, 3H), 2.30-2.34 (m, 1H), 1.68-1.72 (m, 2H), 1.51-1.55 (m, 2H), 1.09-1.23 (m, 4H).

Example 31: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48B)

First step: (3aR, 5S, 7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro -1H-isoindole-2(3H)-tert-butyl formate (Compound 48-2A) and (3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-(difluoromethoxy) Preparation of tert-butyl ester of phenyl)isoxazole-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-carboxylate (Compound 48-2B)

Compounds 48-1A and 48-1B (in any ratio, 300 mg, 1.24 mmol) were dissolved in dry THF (15 mL), then t-BuOK (278 mg, 2.48 mmol), 18-crown-6 (655 mg, 2.48 mmol) And 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole (372 mg, 1.24 mmol). Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was combined with water and ethyl acetate. EtOAc (EtOAc m.

Second step: 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aR,5S,7aS)-octahydro-1H-isoindole-5-) Ethyl)oxy)methyl)isoxazole trifluoroacetate (compound 48-3A) and 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((( Preparation of (3aS,5R,7aR)-octahydro-1H-isoindol-5-yl)oxy)methyl)isoxazole trifluoroacetate (Compound 48-3B)

The product of the first step (492 mg, 0.98 mmol) was dissolved in EtOAc (EtOAc) Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the objective product of this step, and the obtained product was used for the next reaction without purification.

The third step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (compound 48-4A) and 2-((3aS,5R,7aR) -5-((5-Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2 ( Preparation of 3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 48-4B)

The product of the second step (100 mg, 0.25 mmol) was dissolved in MeOH (5 mL), and ethyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (73 mg, 0.25 mmol) and DIPEA (323 mg, 2.5 mmol). Stir at 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, the mixture was combined with water and ethyl acetate. EtOAc (EtOAc m.

MS m/z (ESI): 614 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.16 (S, 1H), 7.63-7.52 (m, 3H), 7.42-7.06 (m, 3H), 4.36 - 4.29 (m, 2H), 3.89 (s, 3H), 3.46 (m, 5H), 2.36-2.26 (m, 3H), 1.63-1.47 (m, 4H), 1.23-1.06 (m, 6H).

The fourth step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48B)

The product from the third step (64 mg, 0.1 mmol) was dissolved in MeOH (5 mL). Stir at room temperature for 4 hours. After cooling, the mixture was combined with water and ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj : 30%).

MS m/z (ESI): 600 [M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.16 (S, 1H), 7.63-7.52 (m, 3H), 7.42-7.06 (m, 3H), 4.36-4.29 (m, 2H), 3.46 (m, 5H), 2.36-2.26 (m, 3H), 1.63-1.47 (m, 4H), 1.23-1.06 (m, 6H).

(c＝3.2336mg/mL，溶剂：MeOH；化合物48-t(2)：保留时间R_t＝9.885min，6mg，ee％＝95％，比旋光度

(c＝3.9628mg/mL，溶剂：MeOH)。Compound 48 (16 mg) was separated by chiral chromatography (separation conditions: column: CHIRALPAK AD-H; mobile phase: n-hexane/ethanol/glacial acetic acid: 70/30/0.1 (V/V/V); Wavelength: 254 nm), two optical isomers were obtained - compound 48-t (1): retention time R _t = 8.197 min, 7 mg, ee% = 98%, specific optical rotation

(c=3.2336 mg/mL, solvent: MeOH; compound 48-t(2): retention time R _t =9.885 min, 6 mg, ee%=95%, specific optical rotation

(c = 3.9628 mg/mL, solvent: MeOH).

Example 32: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]isothiazole-3-carboxylic acid (Compound 16)

First step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]isothiazole-3-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (98 mg, 0.25 mmol), methyl 6-bromobenzo[d]isothiazole-3-carboxylate (68 mg, 0.25 mmol), Pd ₂ (dba) ₃ (26 mg, 0.03 mmol) RuPhos (13 mg, 0.3 mmol) and Cs ₂ CO ₃ (245 mg, 0.75 mmol) were added to toluene, and stirred at 80 ° C for 2 h under N ₂ atmosphere. After the mixture was cooled, the mixture was filtered and evaporated.

MS m/z (ESI): 584 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.35 (d, J = 9.0Hz, 1H), 7.59 (m, 3H), 7.13 (s, 1H), 6.92 (d, J = 8.7Hz, 1H), 4.19 ( s, 2H), 3.91 (s, 1H), 3.82 (s, 3H), 3.39 (m, 2H), 3.11 (m, 2H), 2.63 (s, 2H), 2.32 (m, 1H), 1.71 (s) , 2H), 1.58-1.41 (m, 2H), 1.08 (m, 4H).

Second step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]isothiazole-3-carboxylic acid

The compound obtained in the first step (103 mg, 0.18 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 16 (56 mg, yield: 55.6%).

MS m/z (ESI): 570 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.35 (d, J = 9.0Hz, 1H), 7.59 (m, 3H), 7.13 (s, 1H), 6.92 (d, J = 8.7Hz, 1H), 4.19 ( s, 2H), 3.91 (s, 1H), 3.39 (m, 2H), 3.11 (m, 2H), 2.63 (s, 2H), 2.32 (m, 1H), 1.71 (s, 2H), 1.58-1.41 (m, 2H), 1.08 (m, 4H).

Example 33: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)pyridinecarboxylic Acid (Compound 18)

First step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)pyridinecarboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (68 mg, 0.17 mmol), methyl 6-bromomethyl 6-bromopyridinecarboxylate (37 mg, 0.17 mmol), Pd ₂ (dba) ₃ (16 mg, 0.02 mmol), RuPhos (8 mg) 0.2 mmol), Cs ₂ CO ₃ (167 mg, 0.51 mmol) was added to toluene, and stirred at 80 ° C for 2 h under N ₂ atmosphere. After the mixture was cooled, the mixture was filtered and evaporated.

MS m/z (ESI): 528 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 7.78-7.50 (m, 6H), 4.20 (s, 2H), 3.92 (m, 1H), 3.86 (s, 3H), 3.65 (m, 2H), 3.29 (m, 2H), 2.64 (m, 2H), 2.32 (m, 1H), 1.79-1.40 (m, 4H), 1.22-0.93 (m, 4H).

Second step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)pyridinecarboxylic acid

The compound obtained in the first step (60 mg, 0.11 mmol) was dissolved in MeOH (5 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 18 (28 mg, yield: 47.9%).

MS m/z (ESI): 514 [M+H] ⁺

^{1 HNMR (400MHz, DMSO-d} 6) δ: 7.78-7.50 (m, 6H), 4.20 (s, 2H), 3.92 (m, 1H), 3.65 (m, 2H), 3.29 (m, 2H), 2.64 (m, 2H), 2.32 (m, 1H), 1.79-1.40 (m, 4H), 1.22-0.93 (m, 4H).

Example 34: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)quinoline-6-carboxylic acid (Compound 22)

First step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)quinoline-6-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (1.6 g, 6.09 mmol) was dissolved in DMA (4 mL), and 2-bromoquinoline-6-carboxylic acid methyl ester (1.6 g, 7.31 mmol) and DIPEA (7.9 g, 60.9 mmol) Stir at 120 ° C - 130 ° C for 2 h. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 578 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 8.8, 2.0 Hz, 1H), 7.73-7.40 (m, 4H), 6.91 (d, J = 9.1 Hz, 1H), 4.20 (s, 2H), 3.92 (m, 1H), 3.85 (s, 3H), 3.65 (m) , 2H), 3.29 (m, 2H), 2.64 (m, 2H), 2.32 (m, 1H), 1.79-1.40 (m, 4H), 1.22-0.93 (m, 4H).

Second step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)quinoline-6-carboxylic acid

The compound obtained in the first step (2.1 g, 3.63 mmol) was dissolved in MeOH (20 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 22 (1.3 g, yield: 65.2%).

MS m/z (ESI): 564 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 8.8, 2.0 Hz, 1H), 7.73-7.40 (m, 4H), 6.91 (d, J = 9.1 Hz, 1H), 4.20 (s, 2H), 3.92 (m, 1H), 3.65 (m, 2H), 3.29 (m) , 2H), 2.64 (m, 2H), 2.32 (m, 1H), 1.79-1.40 (m, 4H), 1.22-0.93 (m, 4H).

Example 35: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 23)

First step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (180 mg, 0.44 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (128 mg, 0.44 mmol) and DIPEA ( 568 mg, 4.4 mmol), stirred at 120 ° C - 130 ° C for 2 h. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.

MS m/z (ESI): 618 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.93 (s, 1H), 8.23 (d, J = 1.3Hz, 1H), 7.85-7.23 (m, 5H), 4.25 (s, 2H), 3.97 (s, 1H ), 3.89 (s, 3H), 3.81-3.54 (m, 2H), 3.31 (m, 2H), 2.74 (s, 2H), 2.31 (m, 1H), 1.90 - 1.45 (m, 4H), 1.20- 0.90 (m, 4H).

Second step: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The compound obtained in the first step (140 mg, 0.23 mmol) was dissolved in MeOH (7 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 23 (82 mg, yield: 60.9%).

MS m/z (ESI): 604 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.93 (s, 1H), 8.23 (d, J = 1.3Hz, 1H), 7.85-7.23 (m, 5H), 4.25 (s, 2H), 3.97 (s, 1H ), 3.81-3.54 (m, 2H), 3.31 (m, 2H), 2.74 (s, 2H), 2.31 (m, 1H), 1.90-1.45 (m, 4H), 1.20-0.90 (m, 4H).

Example 36: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 27)

First step: Preparation of 3,5-dichloroisonicotinaldoxime

The title compound was synthesized in the same manner as in the first step of Example 8. Substituting 3,5-dichloroisonicotin (5 g, 0.028 mol) for 2-trifluoromethylbenzaldehyde gave the title compound (4.3). g, yield: 80.3%).

The second step: preparation of 3,5-dichloro-N-hydroxyisonicotinyl chloride

The title compound was synthesized in the same manner as in the second step of Example 8. The compound obtained in the first step of this Example (2.0 g, 0.010 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 1.2 g, yield: 50.3%).

The third step: preparation of methyl 5-cyclopropyl-3-(2,4-dichloropyridin-3-yl)isoxazole-4-carboxylate

The synthesis of the title compound of this step was carried out in a similar manner to the third step of Example 8. The compound obtained in the second step of this example (1.1 g, 0.005 mol) was used in place of N-hydroxy-2-(trifluoromethyl)imide benzyl. Chlorine gave the title compound (0.95 g, yield: 60%).

Step 4: Preparation of (5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methanol

The synthesis of the title compound of this step was carried out in a similar manner to that in the fourth step of Example 8. The compound obtained in the third step of this Example (0.95 g, 3.03 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylbenzene). Methyl isoxazole-4-carboxylate gave the title compound (335 mg, yield: 38.9%).

Step 5: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole

The synthesis of the title compound of this step was carried out in a similar manner to that in the fifth step of Example 8. The compound obtained in the fourth step of this Example (172 mg, 0.6 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylphenyl). Isooxazol-4-yl)methanol gave the title compound (133 g, yield: 73.3%).

Step 6: (3aR, 5S, 6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the title compound of this step was carried out in a similar manner to that in the sixth step of the procedure of Example 8. The compound obtained in the fifth step of the present invention (133 mg, 0.44 mmol) was used in place of 4-(chloromethyl)-5-cyclopropyl-3-( 2-Trifluoromethylphenyl)isoxazole gave the title compound (114 mg, yield: 52.3%).

Step 7: 5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)-4-((((3aR,5S,6aS)-octahydrocyclopenta[c]pyrrole) Preparation of 5-(5-yl)oxy)methyl)isoxazole

The synthesis of the title compound of this step was carried out in a similar manner to that of the seventh step of Example 8 and substituting the compound obtained in the sixth step of the present invention (114 mg, 0.23 mmol) (3aR, 5s, 6aS)-5-((5-cyclopropyl) 3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, obtained this step Title compound. The obtained compound was used in the next reaction without purification.

Step 8: 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester

The synthesis of the title compound of this step was carried out in a similar manner to that in the eighth step of Example 8. The compound obtained in the seventh step of this Example (91 mg, 0.23 mmol) was used in place of 5-cyclopropyl-3-(2-trifluoromethylphenyl). - 4-(((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (108mg, Rate: 73.9%).

MS m/z (ESI): 603 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.89 (s, 1H), 8.86 (s, 2H), 8.23 (d, J = 1.3Hz, 1H), 7.59 (m, 1H), 4.26 (s, 2H), 3.92 (s, 1H), 3.85 (s, 3H), 3.72-3.54 (m, 2H), 3.28 (s, 2H), 2.65 (s, 2H), 2.34 (m, 1H), 1.76-1.40 (m, 4H), 1.31 - 0.93 (m, 4H).

Step 9: 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid

The synthesis of compound 27 was carried out in a similar manner to that in the ninth step of Example 8. The compound obtained in the eighth step of the present invention (108 mg, 0.17 mmol) was used in place of the compound 2-((3aR,5s,6aS)-5-((5- Cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4- Methyl fluorobenzo[d]thiazole-6-carboxylate gave Compound 27 (48 mg, yield: 47.1%).

MS m/z (ESI): 556 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ12.89 (s, 1H), 8.86 (s, 2H), 8.23 (d, J = 1.3Hz, 1H), 7.59 (m, 1H), 4.26 (s, 2H), 3.92(s,1H), 3.72-3.54(m,2H), 3.28(s,2H), 2.65(s,2H), 2.34(m,1H),1.76-1.40(m,4H),1.31-0.93( m, 4H).

Example 37: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 49)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate

The synthesis of the title compound of this step was carried out in a similar manner to that in the first step of Example 11, using the compound 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aR, 5s) ,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole (115 mg, 0.30 mmol) in place of the compound 5-cyclopropyl-3-(2,6- Dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole gives the title compound of this step (85 mg, yield: 53.3%).

MS m/z (ESI): 544 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.74 - 6.94 (m, 6H), 4.24 (s, 2H), 3.93 (s, 1H), 3.83 (s, 3H), 3.74 - 3.60 (m, 2H), 3.39 (d, J = 11.4 Hz, 2H), 2.59 (s, 2H), 2.35-2.19 (m, 1H), 1.74 (m, 2H), 1.58-1.43 (m, 2H), 1.20-0.94 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

The synthesis of compound 49 was carried out in a similar manner to that in the second step of Example 11 and the compound obtained in the first step of this example (85 mg, 0.16 mmol) was used instead of 6-((3aR,5s,6aS)-5-((5-cyclopropyl) 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluorosmoke Methyl ester gave Compound 49 (33 mg, yield: 37.5%).

MS m/z (ESI): 530 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.41 (s, 1H), 7.74-6.94 (m, 6H), 4.24 (s, 2H), 3.93 (s, 1H), 3.74-3.60 (m, 2H), 3.39 (d, J = 11.4 Hz, 2H), 2.59 (s, 2H), 2.35-2.19 (m, 1H), 1.74 (m, 2H), 1.58-1.43 (m, 2H), 1.20-0.94 (m, 4H) ).

Example 38: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 50)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinate

The synthesis of the title compound of this step was carried out in a similar manner to that in the first step of Example 11 using the compound 5-cyclopropyl-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole- 5-yl)oxy)methyl)-3-(2-(trifluoromethoxy)phenyl)isoxazole (94 mg, 0.23 mmol) in place of 5-cyclopropyl-3-(2,6-di Chlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)methyl)isoxazole, the title compound 58 mg, yield: 43.5%).

MS m/z (ESI): 562 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 8.41 (t, J = 1.7 Hz, 1H), 7.73-7.45 (m, 5H), 4.24 (s, 2H), 3.95 (s, 1H), 3.85 (s, 3H) ), 3.68 (m, 2H), 3.41 (m, 2H), 2.61 (s, 2H), 2.31 (m, 1H), 1.83-1.66 (m, 2H), 1.59-1.46 (m, 2H), 1.20- 0.95 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid

The synthesis of compound 50 was carried out in a similar manner to that in the second step of Example 11. The compound obtained in the first step of this example (58 mg, 0.10 mmol) was used instead of 6-((3aR,5s,6aS)-5-((5-cyclopropyl) 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluorosmoke Methyl ester gave compound 50 (48 mg, yield: 88%).

MS m/z (ESI): 548 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.41 (t, J = 1.7Hz, 1H), 7.73-7.45 (m, 5H), 4.24 (s, 2H), 3.95 (s, 1H), 3.68 (m, 2H ), 3.41 (m, 2H), 2.61 (s, 2H), 2.31 (m, 1H), 1.83-1.66 (m, 2H), 1.59-1.46 (m, 2H), 1.20-0.95 (m, 4H).

Example 39: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid (Compound 51)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate

The synthesis of the title compound of this step was carried out in a similar manner to the first step of Example 2, using 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aR, 5s, 6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole (105 mg, 0.26 mmol) instead of 5-cyclopropyl-3-(2,6-dichloro Phenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole gives the title compound (44mg) , yield: 30.8%).

MS m/z (ESI): 526 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.41 (s, 1H), 8.07-6.38 (m, 7H), 4.24 (s, 2H), 3.93 (s, 1H), 3.86 (s, 3H), 3.74-3.60 (m, 2H), 3.39 (d, J = 11.4 Hz, 2H), 2.59 (s, 2H), 2.35-2.19 (m, 1H), 1.74 (m, 2H), 1.58-1.43 (m, 2H), 1.20-0.94 (m, 4H).

Second step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid

Synthesis of Compound 51 The compound obtained in the first step of this Example (56 mg, 0.11 mmol) was used in place of the compound 6-((3aR,5s,6aS)-5-((5-ring). Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate Compound 51 (11 mg, yield: 15.4%) was obtained.

MS m/z (ESI): 512 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.41 (s, 1H), 8.07-6.38 (m, 7H), 4.24 (s, 2H), 3.93 (s, 1H), 3.74-3.60 (m, 2H), 3.39 (d, J = 11.4 Hz, 2H), 2.59 (s, 2H), 2.35-2.19 (m, 1H), 1.74 (m, 2H), 1.58-1.43 (m, 2H), 1.20-0.94 (m, 4H) ).

Example 40: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid (compound 52)

First step: 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate

The title compound was synthesized in the same manner as in the first step of Example 2, using 5-cyclopropyl-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5). -yl)oxy)methyl)-3-(2-(trifluoromethoxy)phenyl)isoxazole (74 mg, 0.18 mmol) in place of 5-cyclopropyl-3-(2,6-dichloro Phenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (27mg , yield: 27.8%).

MS m/z (ESI): 544 [M+H] ⁺

^{1 H NMR (400MHz, CDCl3)} δ8.86 (s, 1H), 8.07 (d, J = 8.8Hz, 1H), 7.61-7.33 (m, 4H), 6.38 (d, J = 9.0Hz, 1H), 4.28 (s, 2H), 4.08-3.91 (m, 1H), 3.86 (s, 3H), 3.72 (s, 2H), 3.35 (d, J = 9.6 Hz, 2H), 2.81 (s, 2H), 2.11 (m, 1H), 1.92 (m, 2H), 1.65-1.53 (m, 2H), 1.26-1.01 (m, 4H).

Second step: 6-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid

The synthesis of compound 52 was carried out in a similar manner to the second step of Example 2, using the compound obtained in the first step of this example (27 mg, 0.05 mmol) instead of 6-((3aR,5s,6aS)-5-((5-cyclopropyl) Methyl 3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)methyl nicotinate, Compound 52 (7 mg, yield: 20%) was obtained.

MS m/z (ESI): 530 [M+H] ⁺

^{1 H NMR (400MHz, CDCl3)} δ8.86 (s, 1H), 8.07 (d, J = 8.8Hz, 1H), 7.61-7.33 (m, 4H), 6.38 (d, J = 9.0Hz, 1H), 4.28 (s, 2H), 4.08-3.91 (m, 1H), 3.72 (s, 2H), 3.35 (d, J = 9.6 Hz, 2H), 2.81 (s, 2H), 2.11 (m, 1H), 1.92 (m, 2H), 1.65-1.53 (m, 2H), 1.26-1.01 (m, 4H).

Example 41: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53B)

First step: (3aR, 5S, 7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro -1H-isoindole-2(3H)-tert-butyl formate (compound 53-2A) and (3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy) Of phenyl)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-carboxylic acid tert-butyl ester (Compound 53-2B)

The synthesis of the target product of this step was carried out in a similar manner to the first step of Example 31, using the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl) Oxazole (74 mg, 0.18 mmol) was substituted for the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole to obtain the target product of this step ( 118 mg, yield: 56.1%).

Second step: 5-cyclopropyl-4-((((3aR,5S,7aS)-octahydro-1H-isoindol-5-yl)oxy)methyl)-3-(2-(three) Fluoromethoxy)phenyl)isoxazole trifluoroacetate (compound 53-3A) and 5-cyclopropyl-4-((((3aS,5R,7aR)-octahydro-1H-isoindole) Preparation of 5-(5-yl)oxy)methyl)-3-(2-(trifluoromethoxy)phenyl)isoxazole trifluoroacetate (Compound 53-3B)

The synthesis of the target product of this step was carried out in a similar manner to the second step of Example 31, and the product of the first step of Example 31 (118 mg, 0.18 mmol) was used in place of the product of the first step of Example 31 to obtain the target product of this step. The obtained product was used in the next reaction without purification.

The third step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (compound 53-4A) and 2-((3aS,5R,7aR) -5-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2 ( Preparation of 3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 53-4B)

The synthesis of the target product of this step was carried out in the same manner as in the third step of Example 31, and the product of the second step of Example 31 was replaced with the product of the second step of the present example (97 mg, 0.23 mmol) to obtain the target product of this step ( 125 mg, yield: 87%).

MS m/z (ESI): 632 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.20 (d, J = 1.1Hz, 1H), 7.79-7.49 (m, 5H), 4.40-4.20 (m, 2H), 3.86 (s, 3H), 3.49 (m , 5H), 2.32 (m, 3H), 1.54 (m, 4H), 1.32-1.00 (m, 6H).

Fourth step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53B)

The synthesis of the target product of this step was carried out in the same manner as in the fourth step of Example 31, and the product of the third step of Example 31 was replaced by the product of the third step of the present example (125 mg, 0.20 mmol) to obtain the target product of this step ( Compound 53, which is a mixture of Compounds 53A and 53B; 100 mg, yield: 80%).

MS m/z (ESI): 618 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.20 (d, J = 1.1Hz, 1H), 7.79-7.49 (m, 5H), 4.40-4.20 (m, 2H), 3.49 (m, 5H), 2.32 (m , 3H), 1.54 (m, 4H), 1.32-1.00 (m, 6H).

Example 42: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl-1H-isoindolin-2(3H)-yl)nicotinic acid (54A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-) Preparation of (difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)nicotinic acid (54B)

First step: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl)hexahydro-1H-isoindole-2(3H)-yl)methyl nicotinate (compound 54-2A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-) 3-(2-(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)methyl nicotinate (54- Preparation of 2B)

Compounds 54-1A and 54-1B (105 mg, 0.26 mmol) were dissolved in DMA (5 mL). <EMI ID=9.1>> Stir at 120 ° C for 4 hours until TLC showed the starting material was completely. After cooling, the mixture was combined with water and ethyl acetate. EtOAc (EtOAc m.

MS m/z (ESI): 540 [M+H] ⁺

^{1 H NMR (400MHz, CDCl3)} δ8.86 (d, J = 2.0Hz, 1H), 8.02 (m, 1H), 7.59-7.39 (m, 2H), 7.37-7.28 (m, 2H), 6.44 (m , 2H), 4.37 (m, 2H), 3.83 (s, 3H), 3.48 (m, 4H), 2.52-1.98 (m, 4H), 1.64 (m, 4H), 1.46-1.02 (m, 6H).

Second step: 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl-1H-isoindolin-2(3H)-yl)nicotinic acid (compound 54A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2) -(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)nicotinic acid (Compound 54B)

The product from the first step (44 mg, 0.08 mmol) was dissolved in MeOH (5 mL) Stir at room temperature for 4 hours until TLC showed the starting material was completely. After cooling, the mixture was combined with water and ethyl acetate. EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated. : 25%).

MS m/z (ESI): 526 [M+H] ⁺

^{1 H NMR (400MHz, CDCl3)} δ8.86 (d, J = 2.0Hz, 1H), 8.02 (m, 1H), 7.59-7.39 (m, 2H), 7.37-7.28 (m, 2H), 6.44 (m , 2H), 4.37 (m, 2H), 3.48 (m, 4H), 2.52-1.98 (m, 4H), 1.64 (m, 4H), 1.46-1.02 (m, 6H).

Example 43: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-1-methyl-1H-indole-3-carboxylic acid (Compound 55)

First step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-1-methyl-1H-indole-3-carboxylate

5-Cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy) Methyl)isoxazole (690 mg, 1.78 mmol), methyl 6-bromo-1-methyl-1H-indole-3-carboxylate (472 mg, 1.76 mmol), Pd ₂ (dba) ₃ (165 mg, 0.18 mmol), RuPhos (84 mg, 0.18 mmol), Cs ₂ CO ₃ (1.7 g, 5.28 mmol) were added to toluene and stirred at 80 ° C for 5 h under N ₂ atmosphere. After cooling, the mixture was filtered, and the filtrate was concentrated.

MS m/z (ESI): 580 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ11.71 (s, 1H), 7.87-7.35 (m, 5H), 6.65 (m, 1H), 6.55 (d, J = 1.6Hz, 1H), 4.21 (s, 2H ), 3.98-3.81 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.24 - 2.96 (m, 4H), 2.58 (s, 2H), 2.39-2.19 (m, 1H), 1.84-1.60 (m, 2H), 1.48 (m, 2H), 1.19-1.00 (m, 4H).

Second step: 6-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-1-methyl-1H-indole-3-carboxylic acid

The compound obtained in the first step (1 g, 1.72 mmol) was dissolved in MeOH (15 mL). After cooling, water and ethyl acetate were added to the mixture, the EA layer was washed with water, dried and concentrated, and the residue was purified by silica gel chromatography to afford compound 55 (90 mg, yield: 9%).

MS m/z (ESI): 566 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ11.71 (s, 1H), 7.87-7.35 (m, 5H), 6.65 (m, 1H), 6.55 (d, J = 1.6Hz, 1H), 4.21 (s, 2H ), 3.98-3.81 (m, 1H), 3.73 (s, 3H), 3.24 - 2.96 (m, 4H), 2.58 (s, 2H), 2.39-2.19 (m, 1H), 1.84-1.60 (m, 2H) ), 1.48 (m, 2H), 1.19-1.00 (m, 4H).

Example 44: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (56A) and 2-((3aS,5R,7aR)-5-(( 5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4 -Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (56B)

First step: (3aR, 5S, 7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro -1H-isoindole-2(3H)-tert-butyl formate (compound 56-2A) and (3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-(trifluoro)) Preparation of a mixture of phenyl)isoxazole-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-carboxylic acid tert-butyl ester (Compound 56-2B)

The synthesis of the target product of this step was carried out in the same manner as in the first step of Example 31, using the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl). The azole (320 mg, 1.1 mmol) was substituted for the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole to give the desired product (322 mg). , yield: 58.2%).

Second step: 5-cyclopropyl-4-((((3aR,5S,7aS)-octahydro-1H-isoindol-5-yl)oxy)methyl)-3-(2-(three) Fluoromethyl)phenyl)isoxazole trifluoroacetate (compound 56-3A) and 5-cyclopropyl-4-((((3aS,5R,7aR)-octahydro-1H-isoindole- Preparation of 5-yl)oxy)methyl)-3-(2-(trifluoromethyl)phenyl)isoxazole trifluoroacetate (Compound 56-3B)

The synthesis of the target product of this step was carried out in a similar manner to the second step of Example 31, and the product of the first step of Example 31 (322 mg, 0.64 mmol) was used in place of the product of the first step of Example 31 to give the title compound of this step. The obtained product was used in the next reaction without purification.

Third step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 56-4A) and 2-((3aR,5R,7aR) -5-((5-cyclopropyl-3-(2-)trifluoro Methyl)phenyl)isoxazole-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester Preparation of (Compound 56-4B)

The synthesis of the target product of this step was carried out in the same manner as in the third step of Example 31, and the product of the second step of Example 31 was replaced by the product of the second step of the present example (160 mg, 0.39 mmol) to obtain the target product of this step ( 190 mg, yield: 79.5%).

MS m/z (ESI): 616 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.22 (s, 1H), 7.97-7.50 (m, 5H), 4.33-4.15 (m, 2H), 3.85 (s, 3H), 3.48 (s, 2H), 3.43 (s, 2H), 2.40-2.08 (m, 3H), 1.69-1.39 (m, 4H), 1.30-1.04 (m, 7H).

Fourth step: 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 56A) and 2-((3aS,5R,7aR)-5-( (5-Cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)- Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 56B)

The synthesis of the target product of this step was carried out in the same manner as in the fourth step of Example 31, and the product of the third step of the present example (190 mg, 0.31 mmol) was used instead of the product of the third step of Example 31 to obtain the target product of this step ( Compound 56, which is a mixture of Compounds 56A and 56B; 150 mg, yield: 80%).

MS m/z (ESI): 602 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ8.22 (s, 1H), 7.97-7.50 (m, 5H), 4.33-4.15 (m, 2H), 3.48 (s, 2H), 3.43 (s, 2H), 2.40 -2.08 (m, 3H), 1.69-1.39 (m, 4H), 1.30-1.04 (m, 7H).

Example 45: 2-((3aR,4r,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) A Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57A) and 2-((3aS,4s,6aS) 4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole- Preparation of 2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57B)

First step: (3aR, 4r, 6aR)-4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl) Hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 57-2A) and (3aS,4s,6aS)-4-(((5-cyclopropyl-3-() Preparation of 2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester

The synthesis of the target product of this step was carried out in a similar manner to the second step of Example 2, replacing the compound (3aR, 5S, 6aS)-5-hydroxyhexahydrogen with 57-1A and 57-1B (arbitrary ratio, 200 mg, 0.83 mmol). Cyclopentadienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester gave the objective product of this step (234mg, yield: 55.4%).

Second step: 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,4r,6aR)-octahydrocyclopenta[c]pyrrole-4- Methoxy)methyl)isoxazole trifluoroacetate (compound 57-3A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aS) ,4s,6aS)-Preparation of a mixture of octahydrocyclopenta[c]pyrrol-4-yl)methoxy)methyl)isoxazole trifluoroacetate (57-3B)

The title compound of this step was synthesized in a similar manner to the third step of Example 2, and the product of the first step of this example (234 mg, 0.46 mmol) was used in place of the compound (3aR, 5S, 6aS)-5-((5-ring) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester The target product of this step. The obtained product was used in the next reaction without purification.

The third step: 2-((3aR, 4r, 6aR)-4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 57-4A) and 2-((3aS) ,4s,6aS)-4-(((5-cyclopropyl-3-) (2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo Preparation of [d]methyl thiazole-6-carboxylate (Compound 57-4B)

The synthesis of the target product of this step was carried out in the same manner as in the fourth step of Example 2, and the product of the second step of this example (188 mg, 0.46 mmol) was used in place of the compound 5-cyclopropyl-3-(2,6-dichloro). Phenyl)-4-((((3aR,5S,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)oxy)methyl)isoxazole, which gives the target product of this step ( 200 mg, yield: 67.4%).

MS m/z (ESI): 616 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 8.20 (d, J = 1.2 Hz, 1H), 7.72-7.37 (m, 4H), 4.28 (s, 2H), 3.86 (s, 3H), 3.74 - 3.60 (m) , 1H), 3.61-3.47 (m, 1H), 3.28-3.16 (m, 4H), 2.80-2.68 (m, 1H), 2.39-2.21 (m, 2H), 1.92-1.65 (m, 3H), 1.41 -1.01 (m, 6H).

Step 4: 2-((3aR,4r,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) A Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57-A) and 2-((3aS,4s, 6aS)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c] Preparation of pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57-B)

The synthesis of the target product of this step was carried out in the same manner as in the fifth step of Example 2, and the product of the third step of this example (200 mg, 0.31 mmol) was used instead of the compound 2-((3aR,5S,6aS)-5-(( 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)- 4-Fluorobenzo[d]thiazole-6-carboxylic acid methyl ester gave the title compound (Compound 57, which is a mixture of Compounds 57A and 57B; 68 mg, yield: 35.5%).

MS m/z (ESI): 602 [M+H] ⁺

¹ H NMR (400 MHz, DMSO) δ 8.20 (d, J = 1.2 Hz, 1H), 7.72-7.37 (m, 4H), 4.28 (s, 2H), 3.74 - 3.60 (m, 1H), 3.61-3.47 (m, 1H), 3.28-3.16 (m, 4H), 2.80-2.68 (m, 1H), 2.39-2.21 (m, 2H), 1.92-1.65 (m, 3H), 1.41-1.01 (m, 6H) .

Example 46: 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl-)-4-fluorobenzo[d]oxazole-6-carboxylic acid (Compound 32)

First step: Preparation of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene

5-Bromo-1,3-difluoro-2-nitrobenzene (500 mg, 2.1 mmol) was dissolved in MeOH (10 mL). The solution was diluted with EtOAc (EtOAc)EtOAc.

The second step: preparation of 4-bromo-2-fluoro-6-methoxyaniline

The compound obtained in the first step (1 g, 4 mmol) was dissolved in MeOH (40 mL), and Raney-Ni was added, and hydrazine hydrate (1 g, 20 mmol) was slowly added dropwise and stirred at room temperature for 2 hours. The reaction mixture was filtered over EtOAc EtOAcjjjjjjjj

The third step: preparation of 2-amino-5-bromo-3-fluorophenol

The second step The resulting compound (932mg, 4.2mmol) was dissolved in DCM (30 mL) was added dropwise under ice-cooling BBr ₃ (2.1g, 8.4mmol), IH stirred at room temperature, the reaction was poured into water and extracted with DCM The organic phase was evaporated to dryness crystals

The fourth step: preparation of 6-bromo-4-fluorobenzo[d]oxazole-2-thiol

The compound obtained in the third step (500 mg, 2.4 mmol) was dissolved in THF. The reaction mixture was extracted with EtOAc EtOAcjjjjjjjj

Step 5: Preparation of 6-bromo-2-chloro-4-fluorobenzo[d]oxazole

The fourth step the obtained compound was dissolved in SOCl ₂ (5mL), was added 3 drops of DMF, was heated at reflux for 20min, the reaction solution was evaporated to dryness, the residue was purified by preparative silica gel plate to afford the title compound (359mg, 75.8%).

Step 6: 6-Bromo-2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)) Preparation of oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole

The compound obtained in the fifth step (359 mg, 1.44 mmol), 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5S,6aS)-octahydrocyclopentane) Iso[c]pyrrole-5-yl)oxy)methyl)isoxazole (566 mg, 1.44 mmol) and DIEA (1.9 g, 14.4 mmol) were dissolved in EtOAc (10 mL). The reaction mixture was poured into EtOAc EtOAc m.

Step 7: 2-((3aR,5S,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole-6-carbonitrile

The compound obtained in the sixth step (814 mg, 1.34 mmol), ZnCN ₂ (235 mg, 2.01 mmol), Pd ₂ (dba) ₃ (123 mg, 0.13 mmol), XantPhos (78 mg, 0.13 mmol) was added to DMF (15 mL) Stir at 110 ° C for 4 h under N ₂ environment. After the mixture was cooled, EtOAc mjjjjjjjj

Step 8: 2-((3aR,5S,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole-6-carboxylic acid

The compound obtained in the seventh step (513 mg, 0.93 mmol) was dissolved in EtOH (8 mL), 40% aqueous EtOAc (3 mL). The organic phase was purified by silica gel chromatography eluting

MS m/z (ESI): 572 [M+H] ⁺

^{1 H NMR (400MHz, DMSO)} δ13.05 (s, 1H), 7.64 (m, 5H), 4.20 (s, 2H), 3.91 (s, 1H), 3.70 (s, 2H), 3.35 (s, 4H ), 2.64 (s, 2H), 2.34 (s, 1H), 1.62 (m, 4H), 1.12 (m, 4H).

The compounds in Table 1 below were prepared in a similar manner to the methods of Examples 1-46 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.

After the receptor was incubated with different concentrations of the compound at room temperature, the fluorescently labeled coactivator short peptide and the europium-labeled antibody were added, and the FRET signal was detected after the reaction at room temperature. Group in a non-receptor protein is blank, calculated for the compound of FXR activation activity EC ₅₀ and maximal activation Effect 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 potency of the compounds of the invention was calculated by the following formula:

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

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

2. Test results

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

Compound number EC ₅₀ (μM) Chenodeoxycholic acid (CDCA) 5.77 Compound 1 0.20 Compound 2 0.0024 Compound 3 1.50 Compound 5 0.04 Compound 6 0.08 Compound 7 0.04 Compound 8 0.001 Compound 9 0.06 Compound 10 0.026 Compound 11 0.024 Compound 12 0.02 Compound 14 0.22 Compound 15 0.003 Compound 16 0.012 Compound 22 0.007 Compound 23 0.013 Compound 27 0.03 Compound 28 0.011 Compound 36 0.507 Compound 40 0.008 Compound 48 0.136 Compound 48-t(2) 0.068 Compound 49 0.353 Compound 50 0.171 Compound 52 0.136 Compound 53 0.073

Data in Table 2 show, with respect to the EC chenodeoxycholic acid (CDCA) value of 5.77μM _50, compounds of the invention have a lower EC ₅₀ 3 (1.50 m), the present invention other compounds having even lower the EC ₅₀ (0.001μM ~ 0.62μM), show that the compounds of the invention have better activity against activation of FXR.

Table 3. Relative activation potency of compounds of the invention on FXR

Compound number Relative activation effectiveness CDCA 100% Compound 2 112% Compound 3 104% Compound 5 148% Compound 7 133% Compound 8 138% Compound 9 157% Compound 10 302% Compound 11 188% Compound 12 152% Compound 14 164% Compound 15 171% Compound 16 125% Compound 22 121% Compound 23 245% Compound 27 159% Compound 28 150% Compound 36 175% Compound 40 141% Compound 48 138% Compound 48-t(2) 149% Compound 49 210% Compound 50 232% Compound 52 148% Compound 53 152%

The data in Table 3 shows that the relative activation potency values of the compounds of the invention are both greater than the relative activation potency of chenodeoxycholic acid (CDCA), indicating that the compounds of the invention have a better maximal activation effect on FXR.

Integrated Table 2 and EC ₅₀ values and relative potency activation data in Table 3 show that the compounds of the present invention have a good effect on FXR. In particular, Compound 2, Compound 5, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 14, Compound 15, Compound 23, Compound 27, Compound 28, Compound 40 and Compound 53 showed strong The activation of FXR.

Other compounds of the invention also have similar EC ₅₀ values and relative potency values of activation, have similar activating activity and activation of the FXR.

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 give final concentrations of 64 μM, 16 μM, 4 μM, 1 μM, 0.25 μM, 0.0625 μM, 0.0156 μM, 0.0039 μM, 0.000975 μM, 0.000244 μM, 0 μM, and the final concentration of DMSO was 0.5%. After the cells were incubated with test compound for 18 h, added Brigh-Glo ^TM Reagent detected, multifunction automatic microplate reader to detect the relative chemiluminescence value units (RLU), EC fit compound _50, Emax with GraphPad Prism 5 software.

2. Test results

The results of the measurements are shown in Table 4 below.

Table 4

Compound number EC ₅₀ (μM) Emax Compound 2 0.07 320% Compound 7 0.39 470% Compound 8 0.0088 408% Compound 9 0.48 653% Compound 12 0.54 500% Compound 15-t(1) 0.07 423% Compound 15-t(2) 0.09 410% Compound 16 0.12 399% Compound 22 0.05 533% Compound 23 0.05 557% Compound 27 0.46 571% Compound 28 0.12 473% Compound 40 0.01 256% Compound 48 1.15 364% Compound 48-t(2) 0.21 531% Compound 53 0.2 327%

The data in Table 4 shows the compound compound 2, compound 7, compound 8, compound 9, compound 12, compound 15-t(1), compound 15-t(2), compound 16, compound 22, compound 23, Compound 27, Compound 28, Compound 40, Compound 48, Compound 48-t(2), Compound 53 have an EC ₅₀ value between 0.008 μM and 1.15 μM and an Emax value greater than 250% in an in vitro cell assay, indicating the above-described invention. The compounds have good FXR activating activity in in vitro cellular assays.

Other compounds of the invention also have similar values and the EC ₅₀ EC _max values, FXR activators have similar activity in vitro cell assay.

Experimental Example 3. Hypolipidemic test in hyperlipidemic mice

Test method

Male C57BL/6 mice were fed a high-fat diet (feed formula: base diet + 10% sucrose + 10% lard + 5% cholesterol) for 1 month, and were randomly grouped according to animal body weight. The treatment group was intragastrically administered with 10 mg/kg of the compound of the present invention, administered once a day for 14 days, and continued to be fed with a high-fat diet while administering. The control group was given the same volume of physiological saline.

After the last administration, the animals were fasted overnight, blood was collected from the blood collection tube, and the hearts were centrifuged at 4000 rpm for 10 minutes at 4 °C. After centrifugation, serum was separated and serum total cholesterol (TC) was measured by a Beckman biochemical analyzer. The rate of TC reduction in the treatment group relative to the control group was calculated.

The TC reduction rate of the administration group was 100%* (control group TC-treatment group TC)/control group TC.

2. Test results

The results of the measurements are shown in Table 5 below.

Table 5. Effect of the compound of the present invention on serum TC in hyperlipidemic mice

Compound number Dosage Mode of administration and frequency TC reduction rate Compound 2 10mg/kg Po, qd*14 0.27% Compound 15 10mg/kg Po, qd*14 0.20% Compound 23 10mg/kg Po, qd*14 0.29% Compound 48 10mg/kg Po, qd*14 0.36% Compound 48-t(2) 10mg/kg Po, qd*14 0.60%

The data in Table 5 shows that oral administration of 10 mg/kg of the compound of the present invention, Compound 2, Compound 23, Compound 48, Compound 48-t(2), for 14 consecutive days, can significantly reduce total cholesterol in hyperlipidemic mice. Level, the degree of reduction is between 20% and 60%. It is shown that the compounds of the present invention have good pharmacological effects in in vivo tests.

Experimental Example 4. Rat pharmacokinetics (PK) study

The compounds of the present invention and the positive compounds were administered to male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics. The doses of IV and PO were 1 mg/kg and 2 mg/kg, respectively, and the vehicle system was 5% DMSO: 5% Solutol: 90% normal saline. After IV and PO administration, blood was collected at different time points, and the blood was anticoagulated with sodium heparin. After centrifugation, plasma samples were obtained and stored at -80 °C. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.

The pharmacokinetic parameters were calculated using WinNonlin 6.3 software using a non-compartmental model. The results are shown in Tables 6-1 and 6-2.

Table 6-1. Pharmacokinetic parameters of IV-administered compounds in rats

The data in Table 6-1 shows that the AUC _{last of the} compound of the present invention and the compound 15 administered by IV at a dose of 1 mg/kg in the body were 552 h*ng/ml and 435 h*ng/ml, respectively, corresponding C _Max was 1297 ng/ml and 1111 ng/ml, respectively, indicating that Compound 10 and Compound 15 of the present invention have excellent drug exposure in rats by IV administration.

Table 6-2. Pharmacokinetic parameters of compounds administered by PO in rats

The data in Table 6-2 shows that the AUC _last of the present compounds 10 and 15 administered by PO at a dose of 2 mg/kg in rats were 309 h*ng/ml and 209 h*ng/ml, respectively, and their bioavailability. The degrees were 28% and 24%, respectively, indicating that the compound 10 and the compound 15 of the present invention have excellent drug exposure and bioavailability in rats by PO administration.

In summary Table 6-1 and Table 6-2, Compound 10 and Compound 15 of the present invention have sufficiently excellent plasma drug exposure and oral bioavailability in rats by IV and PO administration.

Other compounds of the invention also have similar results with similar pharmacokinetic properties in rats.

The compounds of the present invention show good effects in drug safety when applied to drugs for FXR-mediated diseases, and exhibit good drug activity in animal or in vitro pharmacodynamics or pharmacokinetics. Metabolic advantages in the body.

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 (30)

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 ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E-OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-10 cycloalkyl-O-, -OC _1-6 alkyl-OR ₄ , -OC _3-10 heterocycloalkyl, -EC(O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ , -E-SO _x -R ₄ , -E-SO ₃ H, -E-SO ₂ -NR ₄ R ₅ , -E-SO ₂ -NR ₅ C(O)R ₄ , -E-NR ₄ -SO ₂ -R ₅ , -E-SO ₂ -C _3-10 a heterocycloalkyl group, and a 5-7 membered monocyclic nitrogen-containing heteroaryl group, wherein E is a bond, a C _1-6 alkyl group or a C _3-8 cycloalkyl group, and wherein the alkyl group, cycloalkyl group, hetero The cycloalkyl and heteroaryl groups are unsubstituted or are independently selected from the group consisting of halogen, CN, C _1-3 alkyl, halo C _1-3 alkyl, OH, oxo, C(O)OH, SO _{3 1} , 2, 3 or 4 substituents of H, C _1-3 alkyl-O- and halo C _1-3 alkyl-O-; R ₃ , R ₅ and R ₆ 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 _{4 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, C _{a 3-8} heterocycloalkyl group, a -C _1-6 alkyl-C _3-8 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 the group consisting of halogen, CN, OH, 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; x 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, said aryl group Or a 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-, halo C _1-6 alkyl, halo C _1-6 alkyl-O-, hydroxy C _1-6 alkyl, CN -C _1-6 alkyl, C _3-6 cycloalkyl and C _1-6 alkyl-S(O) _m -;

Described from a 5 to 14 membered aza fused ring system, optionally additionally containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein from the N ring atom

Indicates that the N atom is directly bonded to B and extends from the A ring system.

Representing the A ring and (CH ₂ ) _p bonding; And ring

The N-linked B group is not directly adjacent to the -(CH ₂ ) _p -O- group; ring

Substituted by n R ₂ groups, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, CN, C _1-6 alkyl, C _{1 6} alkyl-O-, halo C _1-6 An alkyl group, a hydroxy C _1-6 alkyl group or a C _3-6 cycloalkyl group; m is 0, 1 or 2; n is 1, 2, 3 or 4; p is 0, 1, 2 or 3; D is:

Z is:

Or Rd; 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 and Rc are 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 and halogenated C _3-8 cycloalkyl; 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, optionally substituted by 1, 2 or 3 Re; 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; W is selected from N, N-O and CRb, and Rb is as defined above; Wherein the compound of the formula (I) does not include: 2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexa Hydrogen-1H-isoindole-2(3H)-yl}benzo[d]thiazole-6-carboxylic acid; 2-{5-{[5-cyclopropyl-3-(2,6-dichlorophenyl) Isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole-2(1H)-yl}benzo[d]thiazole-6-carboxylic acid; 2-{5-{[ 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}hexahydrocyclopenta[c]pyrrole-2(1H)-yl}benzene And [d] oxazole-6-formic acid. A compound according to claim 1, wherein each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl, hydroxy C _1-6 alkyl or C _3-6 cycloalkyl; Preferably, the 5 to 14 membered aza fused ring system is a 5 to 14 membered fused bicyclic carbocyclic group sharing two mutually bonded carbon atoms, wherein at least one other than the shared carbon atom (for example 1, 2 or 3) The ring carbon atom is replaced by a nitrogen atom. The compound of claim 1 or 2, wherein

From:

Preferably,

From:

Where h is 0, 1, 2 or 3; More preferably,

From:

Particularly preferably,

From:

The compound according to any one of claims 1 to 3, wherein each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, C _1-6 alkyl, C _1-6 alkyl-O-, halogen C _{1 -6} alkyl; in particular, each R _{2 is} independently selected from the group consisting of hydrogen, F, Cl, hydroxy, oxo, C _1-3 alkyl, C _1-3 alkyl-O- and halo C _1-3 alkane a group, preferably selected from the group consisting of hydrogen, hydroxy and oxo; More preferably, each R _{2 is} independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkyl-O-, halo C _1-6 alkyl; more preferably, each R ₂ Independently selected from the group consisting of hydrogen, F, Cl, hydroxy, C _1-3 alkyl, C _1-3 alkyl-O-, and halogenated C _1-3 alkyl, more preferably selected from hydrogen and hydroxy; n is 1 or 2. A compound according to any one of claims 1 to 4, wherein p is 0, 1 or 2; in particular, p is 0 or 1. A compound according to any one of claims 1 to 5, wherein

The parts together form a structure selected from the following:

Preferably,

The parts together form a structure selected from the following:

More preferably,

The parts together form a structure selected from the following:

Particularly preferably,

The parts together form a structure selected from the following:

A compound according to any one of claims 1 to 6, wherein R _{1 is} selected from the group consisting of hydrogen, halogen, hydroxy, amino, C _1-4 alkyl, halo C _1-4 alkyl, hydroxy C _1-4 alkyl, C _1-4 alkyl-O-, -C(O)NR ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -ER ₄ , -E -OR ₄ , -E-CN, -E-NR ₄ R ₅ , C _3-6 cycloalkyl-O-, -OC _1-4 alkyl-OR ₄ , -OC _3-6 heterocycloalkyl, - EC(O)OR ₄ , -EC(O)R ₄ , -EC(O)NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , -E-NR ₄ C(O)R ₄ ,- E-SO _x -R ₄ , -E-SO ₃ H, -E-SO ₂ -NR ₄ R ₅ , -E-SO ₂ -NR ₅ C(O)R ₄ , -E-NR ₄ -SO ₂ - R ₅ , -E-SO ₂ -C _3-6 heterocycloalkyl, and 5 or 6 membered monocyclic nitrogen-containing heteroaryl; in particular, R _{1 is} selected from the group consisting of: hydrogen, halogen, hydroxy, C _1-3 alkane , halo C _1-3 alkyl, hydroxy C _1-3 alkyl, C _1-3 alkyl-O-, -C(O)NR ₆ (CHR ₃ ) _q CO ₂ R ₄ , -C(O )NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -E-OR ₄ , -E-NR ₄ R ₅ , -OC _1-4 alkyl-OR ₄ , -EC(O)OR ₄ , -EC(O )NR ₄ R ₅ , -EC(O)NR ₄ SO ₂ R ₄ , pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, Isothiazolyl, thiadipine , Imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl; more in particular, R _{1 is} selected _{from: -C (O) NR 6 (} CHR 3) q CO 2 R 4, - C(O)NR ₆ (CHR ₃ ) _q SO ₃ R ₅ , -EC(O)OR ₄ and -EC(O)NR ₄ R ₅ . The compound according to any one of claims 1 to 7, wherein E is a bond, a C _1-4 alkyl group or a C _3-5 cycloalkyl group; in particular, E is a bond or an unsubstituted C _1-2 alkyl group, preferably For the key. The compound according to any one of claims 1-8, wherein each R _{4 is} independently selected from the group consisting of hydrogen, C _1-4 alkyl, halo C _1-4 alkyl, C _{3 6} cycloalkyl, -C _{1- 4-} alkyl-C _3-6 cycloalkyl, C _3-6 heterocycloalkyl, -C _1-3 alkyl-C _3-6 heterocycloalkyl, 5 or 6-membered heteroaryl and phenyl; Each R _{4 is} independently selected from the group consisting of hydrogen and C _1-3 alkyl. The compound according to any one of claims 1-9, wherein R ₃ , R ₅ and R ₆ are each independently selected from the group consisting of hydrogen, C _1-3 alkyl, halo C _1-3 alkyl and cyclopropyl; R ₃ , R ₅ and R ₆ are each independently hydrogen. A compound according to any one of claims 1 to 10, wherein q is 1, 2 or 3; in particular, q is 1. A compound according to any one of claims 1-11, wherein R _{1 is} selected from the group consisting of C(O)OH, CH ₂ C(O)OH, C(O)NHCH ₂ C(O)OH, C(O)NH ₂ , C(O)NHCH ₂ S(O) ₂ OH, C(O)NH(CH ₂ ) ₂ S(O) ₂ OH, C(O)NH(CH ₂ ) ₃ S(O) ₂ OH and

Preferably, R _{1 is} selected from the group consisting of C(O)OH, CH ₂ C(O)OH, C(O)NHCH ₂ C(O)OH, and C(O)NH ₂ . A compound according to any one of claims 1 to 12, wherein B is selected from C _6-10 monocyclic or bicyclic aryl groups and 5 comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S To a 10-membered monocyclic or bicyclic heteroaryl group, in particular, the aryl or heteroaryl group is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl , furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, Benzoisothiazolyl, imidazopyridyl, quinolyl, fluorenyl, pyrrolopyridazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazole , quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolyl, tetrahydroisoquinolinyl, benzo Imidazolyl, thiazolopyridinyl, isothiazolopyridyl, porphyrin, mesoindolyl, pyridazinyl, isodecyl, pteridinyl, fluorenyl, furazyl, benzofurazinyl, quin Porphyrin group, Pyridyl and furopyridinyl, more particularly, said aryl or heteroaryl is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzo[d Thiazolyl, benzo[d]isothiazolyl, 1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridyl, thiazolo[4,5-b]pyridyl, isothiazole [4,5-c]pyridyl, quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-carbazole Benzo, benzo[d]oxazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a] Pyrimidinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, 1H-[1,2,3]triazolo[4,5-b]pyridyl And [1,2,4]triazolo[1,5-a]pyridinyl; preferably, the aryl or heteroaryl is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl , thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, Thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazolium Pyridyl, quinolyl, fluorenyl, pyrrolopyridazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrole Pyridyl, pyrazolopyrimidinyl, imidazopyridazinyl, pyrazolopyridyl, triazolopyridyl, isoquinolyl, tetrahydroisoquinolinyl, benzimidazolyl, porphyrinyl, middle Aziridine, pyridazinyl, isodecyl, pteridinyl, fluorenyl, furazyl, benzofurazinyl, quinoxalinyl, naphthyridinyl and furopyridinyl, more preferably, said The aryl or heteroaryl group is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, imidazole And [1,2-a]pyridyl, quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-indole Azyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a Pyrimidinyl, imidazo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, 1H-[1,2,3]triazolo[4,5-b]pyridine Base; and Wherein the aryl or heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl (eg C _1-3 alkane) , C _1-6 alkyl-O- (eg C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg halogenated C _1-3 alkyl), hydroxy C _1-6 An alkyl group (e.g., a hydroxy C _1-3 alkyl group) and a C _3-6 cycloalkyl group (e.g., a cyclopropyl group), preferably a halogen, a C _1-6 alkyl group (e.g., a C _1-3 alkyl group), C _1-6 Alkyl-O- (eg, C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg, halo C _1-3 alkyl), and C _3-6 cycloalkyl (eg, cyclopropyl) Preferred; halogen, hydroxy, C _1-6 alkyl (eg C _1-3 alkyl), C _1-6 alkyl-O- (eg C _1-4 alkyl-O-), halogen C _{1- a 6} alkyl group (e.g., a halogenated C _1-3 alkyl group), a hydroxy C _1-6 alkyl group (e.g., a hydroxy C _1-3 alkyl group), and a C _3-6 cycloalkyl group (e.g., a cyclopropyl group), preferably a halogen, C _1-6 alkyl (eg C _1-3 alkyl), C _1-6 alkyl-O- (eg C _1-4 alkyl-O-) and halogenated C _1-6 alkyl (eg halogenated C _1-3 alkyl). A compound according to any one of claims 1 to 12, wherein B is a 5 or 6 membered monocyclic heteroaryl group or a 9 or 10 membered bicyclic heteroaryl group, Preferably, B is a group represented by one of the following structural formulae:

Wherein Y ¹ is CH or N; Y ² is CH or N; Preferably, Y ¹ is CH and Y ² is CH; or Y ¹ is N and Y ² is CH; or Y ¹ is CH and Y ² is N; or

Wherein Y ³ is CH or N; Y ⁴ is CH or N; Y ⁵ is S, O or NR ^f , and R ^f is H or C _1-6 alkyl; Preferably, Y ³ is N; Y ⁴ is CH; Y ⁵ is S or O; or Y ³ is CH; Y ⁴ is N; Y ⁵ is NR ^f , and R ^f is C _1-6 alkyl, preferably C _{1 -3} alkyl; or

Wherein Y ⁶ is CH or N; Y ⁷ is S, O or NR ^g , and R ^g is H or C _1-6 alkyl, preferably H; or

or

or

Wherein Y ⁸ is CH or N; Y ⁹ is CH or N; Y ¹⁰ is CH or N; Y ¹¹ is CH or N; preferably, Y ⁸ is CH or N, Y ⁹ is CH or N; Y ¹⁰ and Y ¹¹ either one is CH and the other is N; or

Wherein Y ² and Y ¹³ are both CH; or, either Y ¹² and Y ¹³ are CH, the other is N; Y ¹⁴ is CH or N; Y ¹⁵ is CH or N; Y ¹⁶ is S , O or NR ^h , ^Rh is H or C _1-6 alkyl (eg C _1-3 alkyl); Wherein, in the formulas (a)-(g), extending to the left

Indicates bonding to R ₁ and extending to the right

Representing bonding to the A ring, respectively, the R ₁ and A rings are bonded to the C ring atom or N ring atom available in B; More preferably, B is pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, 1H-benzo[d]imidazolyl, Imidazo[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl, quinolinyl, 1H-indenyl, benzofuran , 1H-carbazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, 1H-pyrrolo[3,2-c]pyridyl, imidazo[1,2-b] Pyridazinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl or [1,2,4]triazolo[1,5-a]pyridinyl, pyrazolyl, Pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-a]pyridinyl, quinolyl; Even more preferably, B is pyridyl, thiazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 1H-carbazolyl, benzo[d]isothiazolyl, quinolyl; Also, B is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, C _1-6 alkyl (eg, C _1-3 alkyl), C _{1- 6} alkyl-O- (eg C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg halogenated C _1-3 alkyl), hydroxy C _1-6 alkyl (eg hydroxyl C) _1-3 alkyl) and C _3-6 cycloalkyl (e.g., cyclopropyl), preferably halogen, C _1-6 alkyl (e.g., C _1-3 alkyl), C _1-6 alkyl-O- ( For example, C _1-4 alkyl-O-), halogenated C _1-6 alkyl (eg, halogenated C _1-3 alkyl), and C _3-6 cycloalkyl (eg, cyclopropyl), and the substitution The group may be attached to a C ring atom or, if applicable, to an N ring atom. A compound according to any one of claims 1 to 14, wherein

Together form a structure selected from the following:

Preferably,

Together form a structure selected from the following:

The compound according to any one of claims 1 to 15, wherein each Ra is independently selected from C _1-4 alkyl, C _3-6 cycloalkyl, C _1-4 alkyl-O-, halogenated C _1-4 An alkyl group, a halogenated C _3-6 cycloalkyl group and a halogenated C _1-4 alkyl-O- group; preferably, each Ra is independently selected from a C _1-4 alkyl group, a halogenated C _1-4 alkyl group ( For example, F or Cl substituted C _1-4 alkyl) and C _3-6 cycloalkyl. A compound according to any one of claims 1 to 16, wherein Z is

and Rb and Rc are 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 and halo C _3-6 cycloalkyl; in particular, Rb and Rc are independently selected from hydrogen, halogen, C _1-3 alkyl, halo C _1-3 alkyl C _1-3 alkyl-O-, halo C _1-3 alkyl-O-, cyclopropyl and halocyclopropyl. The compound of any one of claims 1-17, wherein W is N. A compound according to any one of claims 1 to 17, wherein W is CRb, and wherein Rb is as defined in claim 17; preferably Rb is hydrogen. A compound according to any one of claims 1 to 16, wherein Z is Rd. The compound of claim 20, wherein 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 by 1, 2 or 3 Re; In particular, Rd is selected from bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[2.5]octyl, bicyclic optionally substituted by 1, 2 or 3 Re [4.1.0] Heptyl, cyclopropyl, cyclohexyl and cyclopentyl. A compound according to any one of claims 1 to 21, wherein 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 a halogenated C _1-3 alkyl-O-, C _3-6 cycloalkyl group, a halogenated C _3-6 cycloalkyl group, and a phenyl group; in particular, Re is independently selected from hydrogen, C _1-3 alkane a C _3-6 cycloalkyl group such as a cyclopropyl group and a phenyl group. A compound according to any one of claims 1 to 22, wherein D is selected from the group consisting of

Preferably, D is selected from:

The compound according to any one of claims 1 to 23, wherein the halogen is selected from the group consisting of F, Cl, Br and I, preferably F or Cl. The compound of claim 1 wherein said compound is selected from the group consisting of:

Preferably selected from the following compounds or any combination thereof:

A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 25, 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. 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 25, a stereoisomer, a tautomer, a polymorph thereof, a solvate (such as water) a pharmaceutical composition, a pharmaceutically acceptable salt, an ester, a metabolite, a chemically protected form or prodrug thereof, or a pharmaceutical composition according to claim 26 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 25, 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 26 for the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by a farnesoid X-like receptor; in particular The disease or condition includes: 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 Hepatitis-related cholestasis and fibrosis effects; liver failure or hepatic ischemia after partial hepatectomy; chemotherapy-related steatohepatitis (CASH); acute liver failure; and/or 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 profibrotic 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); and/or 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. A method of preparing a compound of any of claims 1-25, the method comprising:

Wherein X is a halogen (for example, F, Cl, Br or I); PG is a protecting group; Y is a halogen (for example, F, Cl, Br or I), a sulfonyl group (for example, trifluoromethanesulfonyl or p-methylbenzenesulfonate) An acyl group, a boronic acid group or a boronic acid ester group; R ₁ ' represents a group having a removable protecting group and which can provide R ₁ by removing the protecting group; and R ₁ , B, ring

R ₂ , n, p and D are as defined in any one of claims 1 to 24; (1) reacting compound IN-1 with compound IN-2 to give compound IN-3; (2) removing the protecting group PG from the compound IN-3 to obtain the compound IN-4; (3) reacting compound IN-4 with compound IN-5 to give compound IN-6; (4) The compound IN-6 is removed from the protecting group to give a compound of the formula (I). Compound of the formula IN-6:

among them R ₁ ' represents R"'-OC(O)-E-, R"'-OC(O)-(CHR ₃ ) _q NR ₆ C(O)- or R"'-OS(O) ₂ (CHR _{3 q} NR ₆ C(O)-, Wherein R"' is selected from _C1-6 alkyl (especially _C1-4 alkyl) and benzyl, which are optionally independently selected from halo (eg, F, Cl, Br or I) and nitro Substituted by one or more (eg 1, 2, 3 or 4) substituents, preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, more preferably A Base; and Wherein E, R ₃ , R ₆ , q, B, ring

R ₂ , n, p and D are as defined in any one of claims 1 to 24; Preferably, the compound is selected from the group consisting of

Preferably selected from the following compounds or any combination thereof: