CN106995416A

CN106995416A - FXR activators and its preparation method and application

Info

Publication number: CN106995416A
Application number: CN201610575260.0A
Authority: CN
Inventors: 何剑林; 包如迪; 李元念
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansen Biological Medicine Technology Co Ltd
Priority date: 2016-01-26
Filing date: 2016-07-21
Publication date: 2017-08-01
Also published as: CN109071470A; TW201726634A; CN109071470B

Abstract

The present invention discloses FXR activators and its preparation method and application, and in particular to compound, its stereoisomer or its pharmaceutically-acceptable salts with formula (I) structure.The series compound can be used for the disease for treating FXR mediations, including angiocardiopathy, atherosclerosis, artery sclerosis, hypercholesterolemia, high fat of blood chronic liver disease, chronic liver disease, gastrointestinal disease, nephrosis, angiocardiopathy, metabolic disease, cancer (such as colorectal cancer) or neural sign disease as apoplexy, with extensive medical application, it is expected to develop into FXR adjusting control agents of new generation.

Description

FXR activators and its preparation method and application

Technical field

The invention belongs to pharmaceutical synthesis field, and in particular to a kind of 3- (2,6- dichlorophenyl) with FXR agonist activities Isothiazole/different Evil azoles series compounds and its preparation method and application.

Background technology

Method Buddhist nun's ester derivant X acceptors (FXR) belong to a member of hormone nuclear receptor superfamily, and it is mainly in liver, small intestine, kidney The expression of dirty and adrenal gland, the less expression in adipose tissue and heart.It is its part to be initially considered that farnesol, and is thus gained the name. When FXR parts and FXR carboxyl terminals ligand binding domain (LBD) directly in conjunction with after, nuclear receptor space conformation change and with regarding Yellow aldehyde derivatives acceptor (RXR) forms heterodimer, is finally combined to adjust with the specific FXRDNA response elements of target gene The transcription of target gene, participates in the regulation and control of glucose-lipid metabolism, is important energy regulator.Primary bile acid chenodesoxycholic acid is FXR Maximally effective part, secondary bile acid lithocholic acid and deoxycholic acid can also activate FXR.There is synthesis FXR parts (such as 6- at present ECDCA, GW4064 etc.), itself and FXR adhesions several times stronger than native ligand.FXR major target gene includes Bile salt export pump (BSEP), cholic acid associated proteins (IBABP) and small heterodimer companion acceptor (SHP) etc., FXR by with these gene promoters FXR response elements (FXRE) on son combine to regulate and control the expression of these genes.But such as cholesterol 7α-hdroxylase (CYP7 α 1) No typical case's FXR association reaction sequences in promoter sequence etc. main FXR controlling genes, FXR is then indirectly by induction and turned Inhibiting factor SHP expression is recorded, then SHP and the promoter liver receptor homolog things (LRH-1) of CYP7 α 1 formation inhibition compound, from And block CYP7 α 1 and other LRH-1 target genes to transcribe.Due to important function of the FXR in bile acid and cholesterol metabolic, this Itself and liver related disease relation will be made of increasing concern.It is comprehensive that the searching new activators of FXR include cholestasis into treatment The study hotspot of the liver diseases such as disease is closed, 6- acetylene chenodesoxycholic acid (shellfish cholic acid difficult to understand) is used as treatment PBC (PBC) III clinical trial phases have been completed, will have been listed earliest in 2015, and the compound is in non-alcoholic fatty liver Also gratifying therapeutic effect is shown in scorching patient.FXR activators both can be by stimulating Bile salt export pump (BSEP) to increase Plus bile acid dependence courage stream and MRP2 can also be stimulated to increase non-bile acid dependence courage stream to mitigate cholestasis.FXR has Hope that turning into screening treatment includes the new medicine of other metabolic diseases such as cholestatic disease and nonalcoholic fatty liver disease Target spot.Moreover, current research it has been shown that FXR activators may in following disease have treatment and researching value, Including atherosclerosis, cholestatic disease, liver fibrosis, hepatic sclerosis caused by bile acid is disorderly, cancer etc. (are shown in Table 1)。

Table 1.FXR activators can be to treating helpful disease

The content of the invention

Inventor has found that a class has the compound of formula (I) structure in research process.Such compound has to FXR activity There is significantly agonism, can be used to treat the disease that FXR is mediated, including angiocardiopathy, Atherosclerosis for treating Change, artery sclerosis, hypercholesterolemia, high fat of blood chronic liver disease, chronic liver disease, gastrointestinal disease, nephrosis, angiocardiopathy, Metabolic disease, cancer (such as colorectal cancer) or neural sign disease as apoplexy, with extensive medical application, are expected to develop into FXR adjusting control agents of new generation.

One aspect of the present invention provides a kind of compound, its stereoisomer or its pharmacy having such as following formula (I) structure Upper acceptable salt：

Wherein,

X is selected from S or O；

Y is selected from CR₆Or N；

Z is selected from CR₆, N or NO；

Ar is selected from C_5-10Aryl or 5-10 unit's heteroaryls, are optionally further selected from halogen, cyano group, nitre by one or more Base, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryl oxygen Base, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O) R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced,

Optionally further it is selected from halogen, cyano group, nitro, azido, C by one or more again_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles base sulphur Base, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 member heteroaryls Base sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8- NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

R is selected from C_3-8Cycloalkyl or 3-8 circle heterocycles bases, optionally further by it is one or more selected from halogen, cyano group, nitro, Azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 members Heterocyclic radical epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5- 10 unit's heteroaryl epoxides, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O) R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Take Replaced for base；

R₁、R₂、R₃、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8 Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Virtue Base, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,- C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C (O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈,

Optionally further it is selected from halogen, cyano group, nitro, azido, C by one or more_1-8Alkyl, C_2-8Alkenyl, C_2-8 Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls Sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8- NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

R₇Selected from hydrogen, deuterium, C_1-8Alkyl, C_2-8Alkenyl, C_3-8Cycloalkyl, halogen substitution C_1-8Alkyl, phenyl, to methylbenzene Base, amino, list C_1-8Alkyl amino, two C_1-8Alkyl amino or C_1-8Alkyl amido；

R₈Selected from hydrogen, deuterium, C_1-8Alkyl, C_3-8Cycloalkyl, halogen substitution C_1-8Alkyl or hydroxyl substitution C_1-8Alkyl；

R₉Selected from hydrogen, deuterium, C_1-8Alkyl, C_1-8Alkoxy, C_3-8Cycloalkyl, C_3-8Cycloalkyloxy, halogen substitution C_1-8Alkyl, halogen Replace C_1-8Alkoxy, hydroxyl substitution C_1-8Alkyl or hydroxyl substitution C_1-8Alkoxy；

R₁₀、R₁₁It is independently selected from hydrogen, deuterium, hydroxyl, amino, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Ring Alkyl, 3-8 circle heterocycles base, C_5-10Aryl, 5-10 unit's heteroaryls or C_1-8Alkanoyl,

Optionally further it is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, acetylamino, azido, sulphur by one or more Acyl group, mesyl, C_1-8Alkyl, trifluoromethyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, C_1-8 Alkoxy, C_1-8Alkoxy carbonyl group, C_1-8Alkyl-carbonyl, C_1-8Alkyl carbonyl epoxide, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles base sulphur Base, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 member heteroaryls Base sulfenyl, amino, list C_1-8Alkyl amino or two C_1-8The substituent of alkyl amino is replaced；

M is 0,1 or 2；

R is 0,1 or 2.

It is used as further preferred scheme, formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, Y Selected from CR₆；

Ar is selected from C_6-10Aryl or 6-10 unit's heteroaryls, optionally further by it is one or more selected from halogen, cyano group, Nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles base oxygen Base, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 member heteroaryls Base epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O- C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent taken Generation,

R is selected from C_3-6Cycloalkyl or 3-6 circle heterocycles bases, optionally further by it is one or more selected from halogen, cyano group, nitro, Azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 members Heterocyclic radical epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5- 10 unit's heteroaryl epoxides, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O) R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Take Replaced for base；

R₁、R₂、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, cyano group, nitro, azido, C_1-8Alkyl, halogen substitution C_1-8Alkyl, halogen substitution C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, halogen substitution C_3-8Cycloalkyl, 3-8 members are miscellaneous Ring group, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 members Heteroaryl, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、- C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C (O)OR₈；

M is 0.

Ar is selected from following structure：

Optionally further it is selected from halogen, C by one or more_5-10Aryl, 5-10 unit's heteroaryls ,-C_0-8-O-R₈、-C_0-4-S (O)_rR₇、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉Or-C_0-4-C(O)NR₁₀R₁₁Substituent replaced, then Optionally further it is selected from halogen, C by one or more_5-10Aryl, 5-10 unit's heteroaryls ,-C_0-4-S(O)_rR₇、-C_0-4-C(O) OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉Or-C_0-4-C(O)NR₁₀R₁₁Substituent replaced；

R is selected from following structure：

Optionally further it is selected from halogen, sulfydryl ,-C by one or more_0-4-O-R₈Or-C_0-4-NR₁₀R₁₁Substituent taken Generation；

R₁、R₂、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halogen substitution C_1-4Alkyl, halogen substitution C_1-8 Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl group, C_3-6Cycloalkyl, halogen substitution C_3-6Cycloalkyl, 3-6 circle heterocycles base, 3-6 circle heterocycles bases Epoxide, 3-6 circle heterocycles bases sulfenyl ,-C_0-4-S(O)_rR₇、-C_0-4-O-R₈、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C (O)R₉、-C_0-4-NR₁₀R₁₁、-C_0-4-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈；

M is 0.

As further preferred scheme, formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, Selected from formula (II) compound：

Wherein, Ar is selected from following structure：

Optionally further it is selected from fluorine, chlorine, carboxyl, sulfonyl, mesyl, isopropylsulfonyl, methoxy by one or more Carbonyl, carbethoxyl group, butyloxycarbonyl, acetyl group or the substituent selected from following structure are replaced；

R is selected from following structure：

Optionally further taken by one or more substituents selected from hydroxyl, sulfydryl, methoxyl group, ethyoxyl or amino Generation；

R₁Selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, pi-allyl, acetenyl, cyclopropyl, methoxyl group, second Epoxide, isopropoxy or amino；

R₂Selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, sulfydryl, methyl, ethyl, isopropyl, trifluoromethyl, pi-allyl, acetenyl, Cyclopropyl, cyclobutyl, methoxyl group, ethyoxyl, isopropoxy or amino.

R₄、R₅Be independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxyl group or Ethyoxyl.

As optimal case, formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, selected from as follows Compound：

As further preferred scheme, formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, Selected from formula (III) compound：

Wherein,

Ar is selected from following structure：

Optionally further it is selected from halogen, phenyl ,-C by one or more_0-8-O-R₈、-C_0-4-S(O)_rR₇、-C_0-4-C(O) OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉、-C_0-4-C(O)NR₁₀R₁₁Or the substituent selected from following structure is replaced；

R is selected from following structure：

R₄、R₅It is independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halogen substitution C_1-4Alkyl, halogen substitution C_1-8Alkoxy, C_2-4Alkenyl, C_2-4Alkynyl group, C_3-6Cycloalkyl, halogen substitution C_3-6Cycloalkyl, 3-6 circle heterocycles base, 3-6 circle heterocycles bases epoxide, 3-6 Circle heterocycles base sulfenyl ,-C_0-4-S(O)_rR₇、-C_0-4-O-R₈、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉、- C_0-4-NR₁₀R₁₁、-C_0-4-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈。

As scheme still more preferably, formula (I) compound, its stereoisomer or its can pharmaceutically connect By salt, selected from formula (III a), (III b), (III c) or (III d) compound：

Wherein, Ar is selected from following structure：

Optionally further by it is one or more selected from fluorine, it is chlorine, methoxyl group, ethyoxyl, carboxyl, sulfonyl, mesyl, different Third sulfonyl, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group or the substituent selected from following structure are replaced；

R₄、R₅It is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, difluoro Methoxyl group, cyclopropyl, methoxy or ethoxy.

Optimal case, formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, selected from as follows the most Compound：

Another aspect of the present invention provide pharmaceutical composition, it include treatment effective dose foregoing formula (I) compound, its Stereoisomer or its pharmaceutically-acceptable salts and pharmaceutically useful carrier.

Another aspect of the present invention provides foregoing formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, or Foregoing pharmaceutical composition is preparing the application in being used to preventing or treating the disease of FXR mediations or the medicine of situation；The FXR It is chronic that the disease or situation of mediation preferably are selected from angiocardiopathy, atherosclerosis, artery sclerosis, hypercholesterolemia, high fat of blood Hepatitis disease, chronic liver disease, gastrointestinal disease, nephrosis, angiocardiopathy, metabolic disease, cancer (such as colorectal cancer) or nerve Sign such as apoplexy.

As further preferred scheme, the chronic liver disease is selected from hepatitis B, primary hardening (PBC), the dirty property vitiligoidea of brain Disease (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasia, intrahepatic cholestasis of pregnancy, parenteral suction Receive associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral liver Inflammation, AML, NASH disease (NAFLD), nonalcoholic fatty liver disease (NASH), liver transfer operation correlation are moved Graft versus host disease, live donor liver transfer operation regeneration, congenital hepatic fibrosis, choledocholithiasis, granular hepatopathy, the inner or outer evil of liver Property tumour, Sjogren syndromes, sarcoidosis, Wilson's diseases, Gaucher's diseases, hemochromatosis or the primary antibody membrane proteolytic enzymes of α 1 Deficiency disease；The gastrointestinal disease preferably is selected from IBD (IBD) (including Crohn's diseases and routed characteristic of disease enteritis), intestines easily swash Syndrome (IBS), bacterial overgrowth, nutrient absorption are bad, reflection postcolon is scorching or microscopic colitis；The nephrosis is preferred From diabetic nephropathy, Focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulus inflammation, chronic transplant Glomerulopathy, arteriosclerotic kidney or polycystic kidney disease；The angiocardiopathy preferably is selected from arteriosclerosis, artery sclerosis, blood Fat obstacle, hypercholesterolemia or hypertriglyceridemia；The metabolic disease preferably is selected from insulin resistance, type i diabetes, II Patients with type Ⅰ DM or obesity.

Another aspect of the present invention provides a kind of disease or the method for situation prevented or treat FXR mediations, including applies Foregoing formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts of therapeutically effective amount, or foregoing drug regimen Thing.

Embodiment

Describe in detail：Unless stated to the contrary, it is following that there is following contain with term in the specification and in the claims Justice.

“C_1-8Alkyl ", which refers to, includes the straight chained alkyl and containg branched alkyl radical of 1 to 8 carbon atom, and alkyl refers to the aliphatic hydrocarbon of saturation Group, C_0-8Refer to not carbon atoms or C_1-8Alkyl, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, The tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrates Base, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl Amyl group, 4- methyl amyls, 2,3- dimethylbutyls, n-heptyl, 2- methylhexyls, 3- methylhexyls, 4- methylhexyls, 5- methyl Hexyl, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups, 2- ethyl pentyl groups, 3- ethyl pentyl groups, n-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethyl oneself Base, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethylhexyls, 3- ethylhexyls, 4- ethylhexyls, 2- methyl -2- second Base amyl group, 2- methyl -3- ethyl pentyl groups or its various branched chain isomer etc..

Alkyl can be substituted or unsubstituted, and when substituted, substituent can be in any workable tie point It is upper substituted, preferably one or more following groups, independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8 Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Virtue Base, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,- C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C (O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, " C_3-8Cycloalkyl " refer to including 3 to The cycloalkyl of 8 carbon atoms, " 5-10 members cycloalkyl ", which refers to, includes the cycloalkyl of 5 to 10 carbon atoms, for example：

The non-limiting example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, ring Hexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..

Polycyclic naphthene base includes the cycloalkyl of loop coil, condensed ring and bridged ring." spiro cycloalkyl group " refer to it is monocyclic between share a carbon The polycyclic moiety of atom (title spiro-atom), these can contain one or more double bonds, but neither one ring has total conjugated Pi-electron system.Spiro cycloalkyl group is divided into by single spiro cycloalkyl group, double spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring Base or many spiro cycloalkyl groups, the non-limiting example of spiro cycloalkyl group are included：

" cycloalkyl " refers to the full carbon of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system Polycyclic moiety, wherein one or more rings can contain one or more double bonds, but neither one ring has the π electricity of total conjugated Subsystem.Bicyclic, three rings, Fourth Ring or polycyclic fused ring alkyl can be divided into according to the number of composition ring, cycloalkyl it is unrestricted Property embodiment is included：

" bridge ring alkyl " refers to the full carbon polycyclic moiety that any two ring shares two carbon atoms being not directly connected, and these can With containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Can be with according to the number of composition ring It is divided into bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting example of bridge ring alkyl is included：

The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure Ring together is cycloalkyl, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..

Cycloalkyl can be it is optionally substituted or unsubstituted, when substituted, substituent be preferably it is one or more with Lower group, independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Aryl sulphur Base, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8- C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈

" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, wherein one or more annular atoms Selected from nitrogen, oxygen or S (O)_rThe hetero atom of (wherein r is integer 0,1,2), but do not include-O-O- ,-O-S- or-S-S- ring portion Point, remaining annular atom is carbon." 5-10 circle heterocycles base " refers to the ring group for including 5 to 10 annular atoms, and " 3-8 circle heterocycles base ", which refers to, to be included The ring group of 3 to 8 annular atoms.

The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine Base, homopiperazine base etc..

Multiring heterocyclic includes the heterocyclic radical of loop coil, condensed ring and bridged ring." spiro heterocyclic radical " refer to it is monocyclic between share an original The polycyclic heterocyclic group of sub (title spiro-atom), wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_r(wherein r be integer 0, 1st, hetero atom 2), remaining annular atom is carbon.These can contain one or more double bonds, but neither one ring is with completely common The pi-electron system of yoke.Spiro cycloalkyl group is divided into by single spiro heterocyclic radical, double spiroheterocyclics according to the number of shared spiro-atom between ring and ring Base or many spiro heterocyclic radicals.The non-limiting example of spiro cycloalkyl group is included：

Each ring that " condensed hetero ring base " refers in system shares the polycyclic miscellaneous of a pair of the atoms adjoined with other rings in system Cyclic group, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated System, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)_rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom For carbon.Bicyclic, three rings, Fourth Ring or polycyclic fused heterocycloalkyl can be divided into according to the number of composition ring, condensed hetero ring base it is unrestricted Property embodiment is included：

" bridge heterocyclic radical " refers to any two ring and shares two polycyclic heterocyclic groups of atom being not directly connected, and these can be with Containing one or more double bonds, but neither one ring has the pi-electron system of total conjugated, the choosing of wherein one or more annular atoms From nitrogen, oxygen or S (O)_rThe hetero atom of (wherein r is integer 0,1,2), remaining annular atom is carbon.Can be with according to the number of composition ring It is divided into bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting example of bridge ring alkyl is included：

The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure The ring risen is heterocyclic radical, and non-limiting example is included：

Heterocyclic radical can be it is optionally substituted or unsubstituted, when substituted, substituent be preferably it is one or more with Lower group, independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Aryl sulphur Base, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8- C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

" aryl " refers to that full carbon is monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, with conjugation Polycyclic (i.e. its ring for carrying phase adjacency pair carbon atom) group, " C of pi-electron system_5-10Aryl " refers to the full carbon containing 5-10 carbon Aryl, " 5-10 members aryl " refers to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthyl.The aryl rings can condense in On heteroaryl, heterocyclic radical or cycloalkyl ring, wherein being aryl rings, non-limiting example with the ring that precursor structure links together Comprising：

Aryl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, Independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 members are miscellaneous Ring group, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 members Heteroaryl, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、- C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C (O)OR₈Substituent replaced；

" heteroaryl " refers to comprising 1 to 4 heteroatomic heteroaromatic system, and the hetero atom includes nitrogen, oxygen and S (O)_r(its Middle r is integer 0,1, hetero atom 2), and 5-7 unit's heteroaryls refer to the heteroaromatic system containing 5-7 annular atom, 5-10 unit's heteroaryls Refer to the heteroaromatic system containing 5-10 annular atom, for example furyl, thienyl, pyridine radicals, pyrrole radicals, N- alkyl pyrrole radicals, Pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocyclic radical or cycloalkyl ring, The ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example is included：

Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent be preferably it is one or more with Lower group, independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Aryl sulphur Base, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8- C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

" alkenyl " refers to the alkyl as defined above being made up of at least two carbon atoms and at least one carbon-to-carbon double bond, C_2-8 Alkenyl refers to the straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- Cyclobutenyl etc..

Alkenyl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, Independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 members are miscellaneous Ring group, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 members Heteroaryl, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、- C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C (O)OR₈Substituent replaced；

" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are constituted, C_2-8Chain Alkynyl refers to the straight chain containing 2-8 carbon or containing branch alkynyl.Such as acetenyl, 1- propinyls, 2-propynyl, 1-, 2- or 3- fourths Alkynyl etc..

Alkynyl can be substituted or unsubstituted, and when substituted, substituent is preferably one or more following groups, Independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 members are miscellaneous Ring group, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 members Heteroaryl, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、- C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C (O)OR₈Substituent replaced；

" alkoxy " refers to-O- (alkyl), and wherein alkyl is as defined above.C_1-8Alkoxy refers to the alkyl containing 1-8 carbon Epoxide, non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy etc..

Alkoxy can be it is optionally substituted or unsubstituted, when substituted, substituent, it is preferably one or more with Lower group, independently selected from halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O) NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

" halogen " refers to fluorine, chlorine, bromine or iodine.

" PE " refers to petroleum ether.

" THF " refers to tetrahydrofuran.

" EA " refers to ethyl acetate.

" BINAP " refers to (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalenes.

" CDI " refers to N, N- carbonyl dimidazoles.

" DMF " refers to DMF.

" DMAP " refers to DMAP.

" DIPEA " refers to DIPEA.

" EDCI " refers to 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides.

" IBX " refers to 2- iodosobenzoic acids.

“Pd(dppf)Cl₂" refer to [double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride.

“Pd₂(dba)₃" refer to three (dibenzalacetone) two palladium.

" TBAF " refers to tetrabutyl ammonium fluoride.

" X-phos " refers to 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyls.

" NCS " refers to N- chlorosuccinimides.

" BPin " refers to which alcohol borate of Knit-the-brows.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes The event or environment generation or not spot occasion.For example, " optionally by alkyl-substituted heterocyclic group " means that alkyl can be with But necessarily exist, the explanation includes heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.

" substituted " refers to one or more of group hydrogen atom and replaced independently of one another by the substituent of respective number.No Say and explain, substituent is only in their possible chemical position, and those skilled in the art can not pay what is excessively made great efforts In the case of determine (by experiment or theoretical) may or impossible substitution.For example, amino or hydroxyl and tool with free hydrogen The carbon atom for having unsaturated (such as olefinic) key is probably unstable when combining.

" pharmaceutical composition " represent containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or Pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.Medicine The purpose of compositions is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.

With reference to embodiment, the present invention is described in further detail and completely, but limits the present invention, the present invention by no means Also it is not intended to be limited to the content of embodiment.

The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or/and LC-MS chromatogram (LC-MS) 's.Nmr chemical displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).NMR measure is to use BrukerAVANCE-400 cores Magnetic instrument, measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterated methanol (CD₃) and deuterochloroform (CDCl OD₃) in be designated as Tetramethylsilane (TMS).

LC-MS chromatogram LC-MS measure Agilent1200InfinitySeries mass spectrographs.HPLC measure makes It is high with Agilent 1200DAD high pressure liquid chromatographs (SunfireC18150 × 4.6mm chromatographic columns) and Waters2695-2996 Pressure liquid chromatography instrument (GiminiC18150 × 4.6mm chromatographic columns).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that TLC is used is 0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.Column chromatography typically uses cigarette The mesh silica gel of platform Huanghai Sea silica gel 200~300 is carrier.

Initiation material in the embodiment of the present invention is known and can be commercially available, or can use or press Synthesized according to methods known in the art.

In the case of without specified otherwise, all reactions of the invention are under continuous magnetic agitation, in drying nitrogen Or carried out under argon atmospher, solvent is to dry solvent.

Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.Nitrogen atmosphere refers to instead Bottle is answered to connect the hydrogen balloon of an about 1L volume.

In the case of without specified otherwise, the solution in embodiment refers to the aqueous solution.The temperature of reaction is room temperature.Room temperature is Optimum reaction temperature, is 20 DEG C~30 DEG C.

The monitoring of reaction process in embodiment is reacted using thin-layered chromatography (TLC) or LC-MS chromatogram (LC-MS) Used solvent system has：Dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate System, acetone, the volume ratio of solvent can be adjusted according to the polarity difference of compound.The system bag of the eluant, eluent of column chromatography Include：A：Dichloromethane and methanol system, B：N-hexane and ethyl acetate system, C：Dichloromethane and ethyl acetate system, D：Second Acetoacetic ester and methanol, the volume ratio of solvent are adjusted according to the polarity difference of compound, can also add a small amount of ammoniacal liquor It is adjusted with acetic acid etc..

First, the synthesis of intermediate

1st, 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole I-1 synthesis

The first step：2,6- dichlorobenzonitrile I-1-a (10.0g, 58mmol) and ring the third formyl acetic acid ethyl ester I-1-b (9.2g, Toluene (200mL) 58mmol) is dissolved in, nitrogen protection is lower to be added dropwise SnCl₄(7mL, 58mmol), is stirred at room temperature 1h, and 80 DEG C are continued anti- Answer 2h.It is quenched after reaction completely with saturated sodium bicarbonate aqueous solution, ethyl acetate is extracted twice, organic phase is dry with anhydrous sodium sulfate It is dry, filter, concentration, column chromatography purifying obtains compound I-1-c (13.0g, yield：68%).

LC-MS:t_R=2.76min, [M+H]⁺=328.0.

Second step：Compound I-1-c (13.0g, 40mmol) is dissolved in toluene with tetrachloroquinone (9.8g, 40mmol) (150mL), stirring is lower to add P₂S₅(26.6g, 120mmol), is heated to reflux 1h.TLC monitoring reactions are complete, filter, concentration, post Chromatographic purifying, obtains compound I-1-d (5.8g, yield：42%).

LC-MS:t_R=3.27min, [M+H]⁺=342.0.

3rd step：Compound I-1-d (2.8g, 8.2mmol) is dissolved in anhydrous tetrahydro furan (30mL), and ice-water bath is cooled down, to System adds Lithium Aluminium Hydride (0.4g, 10.6mmol), reacts at room temperature 1h.TLC monitoring reactions are complete, and add water (0.4mL), hydrogen-oxygen respectively Change sodium water solution (0.4mL, 15%) and water (1.2mL), then add anhydrous magnesium sulfate stirring 0.5h, filtering is concentrated to give compound I-1-e (2.4g, yield：97%).

LC-MS:t_R=2.67min, [M+H]⁺=300.0.

4th step：Compound I-1-e (2.4g, 8.0mmol) is dissolved under dichloromethane (20mL), ice-water bath to be added to system Thionyl chloride (1.7mL, 24mmol), reacts at room temperature 1h.TLC monitoring reactions are complete.Concentration, column chromatography purifying, obtains 4- (chloromethanes Base) -5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole I-1 (1.4g, yield：55%).

LC-MS:t_R=3.23min, [M+H]⁺=318.0.

2nd, 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyls) isoxazole I-2 synthesis

The first step：Compound I-2-a (10g, 57.1mmol) and sodium hydroxide (2.7g, 68.5mmol) are dissolved in ethanol In (100mL) and water (50mL), add and 2h stirred at hydroxylamine hydrochloride (4.7g, 68.5mmol), 90 DEG C, cooled down after reaction completely, It is diluted with water, ethyl acetate extraction.Organic phase sodium sulphate is dried, and is spin-dried for, is obtained compound I-2-b (10.5g).

Second step：Compound I-2-b (10g, 52.6mmol) and NCS (9.2g, 69.0mmol) are dissolved in DMF, room temperature 2h is stirred, is added water and methyl tertiary butyl ether(MTBE) extraction, sodium sulphate is dried after organic phase is washed with water twice, is spin-dried for, is obtained compound I-2-c (10.5g)。

3rd step：Compound I-2-c (10.5g, 47.8mmol) and I-1-b (10.3g, 71.7mmol) are blended in triethylamine In (40mL), it is stirred overnight at room temperature.Water and ethyl acetate extraction are added, organic phase sodium sulphate is dried, is spin-dried for, ethyl acetate (20m) is beaten, filtering, obtains white solid I-2-d (7.5g).

4th step：Compound I-2-d (0.5g, 1.53mmol) is dissolved in tetrahydrofuran, addition lithium aluminium hydride reduction (65mg, 1.68mmol), 2h is stirred at room temperature.Add ethyl acetate after water quenching is gone out to extract, organic phase is spin-dried for, and obtains compound I-2-e (0.5g).

5th step：Compound I-2-e (0.5g, 1.75mmol) is dissolved in dichloromethane, adds thionyl chloride (0.16mL), stirs 2h at room temperature, then adds water quenching and goes out, ethyl acetate is extracted, and is spin-dried for, is obtained compound I-2 (0.6g).

3rd, 4- (chloromethyl) -3- (2,6- dichlorophenyls) -5- (trifluoromethyl) isothiazole I-3 synthesis

The first step：2,6- dichlorobenzonitriles I-3-a (1.72g, 10mmol) is weighed in 100mL there-necked flasks, dry THF is added (13mL).Solution is flowed back under blanket of nitrogen, activated zinc powder (1.3g) is then added portionwise.In bromine second is slowly added dropwise under reflux state Acetoacetic ester (1.7mL), back flow reaction 1h.Solution is cooled to 0 DEG C, and n-BuLi (6.8mL, 1.6M) and trifluoroacetic acid are added dropwise successively Acid anhydride (1.8mL).Completion of dropping, which is warmed to room temperature, to be stirred overnight.Saturated ammonium chloride solution is quenched after reaction, and ethyl acetate has been extracted Machine layer, organic phase concentration, column chromatography for separation obtains compound I-3-b (1.25g, yield：35%, cis-trans-isomer ratio is about 1:3)。

LC-MS:t_R=2.826min, 2.926min.

Second step：Above-claimed cpd I-3-b is dissolved in toluene (20mL), tetrachloroquinone (0.87g) and five are sequentially added Vulcanize two phosphorus (2.4g).Back flow reaction 30min.Reaction solution cooled and filtered.Filtrate concentrates, and column chromatography for separation obtains compound I-3-c (0.76g, yield：58%)

LC-MS:t_R=3.410min；

¹HNMR(400MHz,CDCl₃) δ 7.44-7.39 (m, 2H), 7.35 (dd, J=9.3,6.5Hz, 1H), 4.22 (q, J =7.1Hz, 2H), 1.12 (t, J=7.1Hz, 3H).

3rd step：Above-claimed cpd I-3-c is dissolved in dry THF (8mL), ice-water bath cooling, and Lithium Aluminium Hydride is added in batches (93mg).30min is stirred at room temperature.Reaction solution is quenched with sal glauberi.Filtering, filtrate concentration, crude product through column chromatography for separation, Obtain compound I-3-d (475mg, yield：70%).

LC-MS:t_R=2.929min；

¹HNMR(400MHz,CDCl₃) δ 7.45 (dd, J=7.9,1.2Hz, 2H), 7.38 (dd, J=9.3,6.6Hz, 1H), 4.60 (d, J=0.7Hz, 2H).

4th step：Above-claimed cpd I-3-d is dissolved in dry CH₂Cl₂(5mL), sequentially adds SOCl₂(1.2mL) and DMAP (21mg).Back flow reaction 4h.Cooling, concentration, column chromatography for separation obtains compound I-3 (425mg, yield：85%).

LC-MS:t_R=3.428min；

¹HNMR(400MHz,CDCl₃) δ 7.46 (dd, J=7.9,1.4Hz, 2H), 7.41 (dd, J=9.5,6.3Hz, 1H), 4.48(s,2H)。

4th, 4- (3- carbonyls cyclobutyl) methyl benzoate I-4 synthesis

The first step：I-4-b (5.6g, 36.64mmol) is weighed in 250mL single port bottles, mixed solvent THF/H is added₂O (80mL, v/v=9:1) m-iodobenzoic acid methyl esters I-4-a (8.0g, 30.53mmol), is sequentially added, cesium carbonate (29.8g, 91.59mmol), triphenylphosphine (1.68g, 6.41mmol), palladium chloride (379mg, 2.14mmol).Substitute gas, nitrogen protection Under be heated to reflux, be stirred overnight.Filtered, and washed 3 times with ethyl acetate by diatomite after question response cooling, filtrate is through extraction After take organic layer to be dried with sodium sulphate, concentrate, column chromatography for separation obtains compound I-4-c (4.3g, yield 87%).

LC-MS:t_R=2.799min；

¹HNMR(400MHz,CDCl₃) δ 8.08 (t, J=1.7Hz, 1H), 7.97-7.89 (m, 1H), 7.63-7.57 (m, 1H), 7.40 (t, J=7.7Hz, 1H), 6.75 (dd, J=17.6,10.9Hz, 1H), 5.83 (dd, J=17.6,0.6Hz, 1H), 5.33 (d, J=10.9Hz, 1H), 3.93 (s, 3H).

Second step：Weigh Compound I-4-c (3.6g, 22.20mmol) adds dry ether in 500mL there-necked flasks (108mL), adds ultrasonic half an hour under zinc powder (4.4g, 66.60mmol), blanket of nitrogen afterwards.Ultrasound is slowly added dropwise simultaneously afterwards Dissolved with trichloro-acetic chloride (10.1g, 55.49mmol) diethyl ether solution (36mL).After adding, the lower ultrasound 2h of backflow.Question response Water (40mL) is added dropwise after liquid cooling to be quenched.Filtered after reaction solution stirring 15min through diatomite, and with a small amount of ether filter wash.Filtrate Organic phase washed with water (40mL), saturated sodium bicarbonate solution (40mL), saturated common salt water washing, sodium sulphate is dried.Filtering, it is dense Contracting, obtains grease (6.2g).This grease is dissolved in acetic acid (40mL), zinc powder (3.3g) is added.The lower 120 DEG C of heating of blanket of nitrogen 4h.Diluted after cooling with ethyl acetate (40mL).Dilution is concentrated after being filtered through diatomite.Grease is obtained after concentration and is dissolved in acetic acid Ethyl ester (50mL), successively with water (50mL), saturated sodium bicarbonate solution (50mL), saturated common salt water washing, sodium sulphate is dried.Cross Filter, concentration, column chromatography for separation (PE/EA, EA:0~15%), obtain compound I-4 (2.3g, yield：55%).

LC-MS:t_R=2.453min；

¹HNMR(400MHz,CDCl₃) δ 7.99 (s, 1H), 7.93 (d, J=7.6Hz, 1H), 7.50 (d, J=7.8Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 3.93 (s, 3H), 3.79-3.69 (m, 1H), 3.59-3.48 (m, 2H), 3.33-3.23 (m,2H)。

5th, 4- (3- carbonyls cyclobutyl) methyl benzoate I-5 synthesis

4- (3- carbonyls cyclobutyl) methyl benzoate I-5 synthesis reference compound I-4 preparation method.

LC-MS:t_R=2.437min；

¹HNMR(400MHz,CDCl₃) δ 8.06-7.98 (m, 2H), 7.37 (d, J=8.1Hz, 2H), 3.92 (s, 3H), 3.80-3.67(m,1H),3.60-3.49(m,2H),3.34-3.22(m,2H)。

6th, the fluoro- 5- of 2- (3- carbonyls cyclobutyl) methyl benzoate I-6 synthesis.

The fluoro- 5- of 2- (3- carbonyls cyclobutyl) methyl benzoate I-6 synthesis reference compound I-4 preparation method.

¹HNMR(400MHz,CDCl₃) δ 7.79 (dd, J=6.7,2.5Hz, 1H), 7.42-7.34 (m, 1H), 7.07 (dd, J =10.3,8.6Hz, 1H), 3.87 (s, 3H), 3.62 (m, 1H), 3.52-3.39 (m, 2H), 3.24-3.10 (m, 2H).

7th, the fluoro- 5- of 3- (3- carbonyls cyclobutyl) methyl benzoate I-7 synthesis

The fluoro- 5- of 3- (3- carbonyls cyclobutyl) methyl benzoate I-7 synthesis reference compound I-4 preparation method.

¹HNMR(400MHz,CDCl₃) δ 7.78 (s, 1H), 7.61 (ddd, J=8.9,2.4,1.4Hz, 1H), 7.20 (ddd, J=9.2,2.9,1.2Hz, 1H), 3.94 (s, 3H), 3.73 (dt, J=16.2,8.3Hz, 1H), 3.59-3.50 (m, 2H), 3.31-3.23(m,2H)。

8th, 4- (3- carbonyls cyclobutyl) repefral I-8 synthesis

The first step：3- bromobenzoic acid acid anhydride I-8-a (5675mg, 25.0mmol) are dissolved in H₂SO₄/ MeOH (100mL, 1%), plus Heat backflow, reaction is stayed overnight.Room temperature is cooled to, the NaOH aqueous solution is added and neutralizes.Concentration, removes methanol, ethyl acetate extraction.Cross Filter, concentration, obtains compound I-8-b (5886mg, yield：86%).

¹HNMR(400MHz,CDCl₃) δ 7.84 (d, J=1.9Hz, 1H), 7.67 (dd, J=8.3,1.9Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H).

Second step：Weigh Compound I-8-b (5886mg, 21.6mmol) and I-4-b (4980mg, 32.3mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (100mL), nitrogen protection is lower to add Pd (dppf) Cl₂(1577mg, 2.16mmol) and Cs₂CO₃(14.0g, 43.1mmol), 100 DEG C of reactions are heated to stay overnight.Room temperature is cooled to after reaction completely, is filtered, EtOAc washings.Filtrate concentrates, slightly Product obtain compound I-8-c (4.3g, 90%) through column chromatography for separation.

¹HNMR(400MHz,CDCl₃) δ 7.73 (d, J=8.0Hz, 1H), 7.70 (d, J=1.8Hz, 1H), 7.54 (dd, J =8.0,1.8Hz, 1H), 6.73 (dd, J=17.6,10.9Hz, 1H), 5.88 (d, J=17.6Hz, 1H), 5.42 (d, J= 11.0Hz,1H),3.92(s,3H),3.90(s,3H)。

3rd step：Compound I-8-c (1101mg, 5.0mmol) is dissolved in dry ether (25mL), add Zn (981mg, 15.0mmol), ultrasonic agitation 30min.It is dissolved in dry ether (10mL) Cl₃COCl (2273mg, 12.5mmol) is added dropwise to instead System is answered, 10min is added.Continue ultrasound, back flow reaction 5h.Add water and be quenched, EtOAc extractions.Organic phase is concentrated, and crude product is dissolved in second Sour (10mL), adds Zn (719mg, 11.0mmol).120 DEG C of reaction 2h of heating.It is cooled to room temperature.EtOAc is extracted, and is used successively Water, saturation NaHCO₃With the washing of the saturation NaCl aqueous solution.Organic phase is concentrated, and crude product obtains compound I-8 through column chromatography for separation (580mg, yield：44%).

LC-MS:t_R=2.336min, [M+H]⁺=263.2.

9th, simultaneously [d] thiazole -6- carboxylate methyl esters I-9 is synthesized the bromo- 4- fluorobenzene of 2-

The first step：The fluoro- 4- nitrobenzene methyls I-9-a (3983mg, 20mmol) of compound 3- are dissolved in 40mL EtOAc/ MeOH(1:1) in mixed liquor, Pd/C (400mg) is added, normal temperature and pressure hydrogenation, reaction is stayed overnight.LC-MS is monitored, and reaction is complete.Cross Filter, filtrate concentration, obtains crude product I-9-b and is directly used in the next step.

LC-MS：t_R=2.226min, [M+H]⁺=170.2.

Second step：Compound I-9-b (20mmol) and NaSCN (6486mg, 80mmol) adds 20mL acetic acid, and ice-water bath is cold But；Br₂(1mL, 20.0mmol) is dissolved in acetic acid (10mL), then is slowly added dropwise into reaction system, adds within about 20 minutes.Heating 40 DEG C reaction 5 hours, LC-MS monitorings, reaction is complete.Room temperature is cooled to, the dilution of 50mL water is added.Filtering, is washed, vacuum drying, Obtain compound I-9-c (4090mg, 90%).

LC-MS：t_R=2.161min, [M+H]⁺=227.1.

3rd step：CuBr₂Solid (1340mg, 6.0mmol) adds acetonitrile (20mL), and ice-water bath cooling is lower to be added dropwise tBuONO (1.1mL, 9.2mmol), adds compound I-9-c (905mg, 4.0mmol).Recover room temperature, reaction is stayed overnight.Add acetic acid second Ester is extracted, washing, the washing of the saturation NaCl aqueous solution, anhydrous Na₂SO₄Dry, filter, concentration, crude product is through column chromatography for separation (PE/EA 10:1) compound I-9 (230mg, 20%), is obtained.

LC-MS：t_R=2.904min.

10th, simultaneously [d] thiazole -6- carboxylate methyl esters I-10 is synthesized 2- bromobenzenes

The first step：Compound I-10-a (10mmol) and NaSCN (3243mg, 40mmol) adds acetic acid (10mL), frozen water Bath cooling；Br₂(0.5mL, 10.0mmol) is dissolved in acetic acid (5mL), then is slowly added dropwise into reaction system, adds within about 5 minutes.Plus Hot 40 DEG C of reactions are stayed overnight, and LC-MS monitorings, reaction is complete.Room temperature is cooled to, water (20mL) dilution is added, ammoniacal liquor is neutralized.Filtering, Washing, vacuum drying obtains compound I-10-b (2100mg, quantitative).

LC-MS：t_R=1.966min, [M+H]⁺=209.1.

Second step：CuBr₂Solid (1340mg, 6.0mmol) adds acetonitrile (20mL), and ice-water bath cooling is lower to be added dropwise tBuONO (1.1mL, 9.2mmol), then compound I-10-b (833mg, 4.0mmol) is added portionwise.Recover room temperature, reaction is stayed overnight.Add Ethyl acetate is extracted, washing, the washing of the saturation NaCl aqueous solution, anhydrous Na₂SO₄Dry, filter, concentration, crude product is through column chromatography for separation (PE/EA10:1) compound I-10 (865mg, 79%), is obtained.

LC-MS：t_R=2.871min.

11st, 2- chloro-4-methoxies benzo [d] thiazole -6- carboxylate methyl esters I-11 is synthesized

The first step：NaSCN (1.62g, 20.0mmol) HOAc (4mL) solution is prepared in 50mL three-necked bottles.In at 0 DEG C 4- amino -3- methoxyl methyl benzoates I-11-a (0.9g, 5.0mmol) HOAc (4mL) solution is added dropwise, then Br is added dropwise₂ HOAc (1.2mL) solution of (0.88g, 5.5mmol).The solution of acquisition is stirred 1 hour at room temperature, 50 DEG C are stirred overnight, Then diluted with water (20mL).The pH of solution is adjusted to pH=8 using sodium carbonate.Solid is collected by filtration, under reduced pressure in temperature Dried in the baking oven of heat, obtain compound I-11-b (1.0g), yield 84%.

LC-MS:t_R=2.012min, [M+H]⁺=239.1.

Second step：The H dissolved with compound I-11-b (1.0g, 4.2mmol) is added into 50mL three-necked bottles₃PO₄(8mL) is molten Liquid.NaNO is added dropwise thereto in 0 DEG C₂Water (10mL) solution of (0.9g, 12.6mmol).The solution of acquisition is stirred into 1h in 0 DEG C. Then CuSO is added portionwise in 0 DEG C₄(3.4g, 21.0mmol), with the water that NaCl (3.7g, 63.0mmol) is added dropwise after 0 DEG C (10mL) solution.The solution of acquisition is stirred into 1h at room temperature, then diluted with water (20mL).The aqueous solution is extracted with dichloromethane Take, merge organic phase, concentration.Crude product is separated through silica gel column chromatography, and obtaining compound I-11, (23%) 250mg, yield is.

LC-MS:t_R=2.764min；

¹H NMR(400MHz,CDCl₃) δ 8.11 (d, J=1.3Hz, 1H), 7.59 (d, J=1.3Hz, 1H), 4.09 (s, 3H),3.97(s,3H)。

12nd, the bromo- 1- Methyl-1H-indoles -3- carboxylate methyl esters I-12 synthesis of 6-

The first step：Compound I-12-a (8g, 50mmol) is dissolved in acetic acid (100mL), and bromine (8.4g) is slowly added dropwise at room temperature Acetum, drip off stirring reaction and stay overnight.Filtering, washing, dry compound I-12-b (6.2g, yield：51.2%).

LC-MS:t_R=2.25min, [M-H]^-=238.0.

Second step：Methanol (60mL) is placed in 250mL single port bottles, and chloroacetic chloride (6.2g) is slowly added dropwise under ice-water bath cooling, Compound I-12-b (6.2g, 26mmol), back flow reaction 16h are added after dripping off.Cooling, is filtered, washing, dry compound I- 12-c (4.9g, yield：75.0%).

LC-MS:t_R=2.66min, [M-H]^-=251.9.

3rd step：Compound I-12-c (2.13g, 8.4mmol) is dissolved in acetonitrile (30mL), add potassium carbonate (2.3g, 16.8mmol) with MeI (2.1mL, 33.7mmol), in stirring reaction 3h at 50 DEG C.It is dilute with water (20mL) after the cooling of question response liquid Release, ethyl acetate merges organic phase after extracting 3 times.Organic phase after merging is washed once with saturated common salt, and sodium sulphate is dried.Cross Filter, concentration, column chromatography for separation (PE/EA 5~15%) obtains compound I-12 (2.1g, yield：93%).

LC-MS:t_R=2.88min.

13rd, 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) phenyl) azete Pyridine -1- carboxylic acid tert-butyl esters I-13

The first step：Compound I-13-a (150mg, 0.75mmol), which is dissolved at dichloromethane (3mL), -78 DEG C, to be slowly added dropwise Boron tribromide (4N) solution, drop, which finishes, is warmed to room temperature stirring 20min.Methanol is added to be quenched and stir 30min under ice-water bath, ethyl acetate Extraction, organic phase merging is washed once with saturated common salt, and sodium sulphate is dried.Filtering, concentration, it is anti-that crude product is directly used in bottom Should.

Second step：Above-mentioned crude product is placed in 100mL single port bottles, is added methylene chloride successively (5mL), triethylamine (0.8mL) With di-tert-butyl dicarbonate (180mg), 2h is stirred at room temperature.Extraction, is dried, and concentration directly throws next step without purifying.

3rd step：Above-claimed cpd is placed in 50mL single port bottles, compound I-2, DMF (3mL) and potassium carbonate are added successively (414mg), 50 DEG C of stirring reactions are stayed overnight, and reaction is complete.Column chromatography for separation after concentration, obtains compound I-13 (180mg, yield 43%).

LC-MS:t_R=3.59min, [M-100]⁺=449.0.

14th, 7- bromoquinolines -3- carboxylic acid, ethyl esters I-14

The first step：Compound I-14-a (1.17g, 5.0mmol) is dissolved in ethanol (15ml), add activation iron powder (1.68g, 30.0mmol) with 1M HCl (5ml), back flow reaction 2h.It is cooled to after room temperature and filters.Dissolved after filtrate concentration through ethyl acetate, And saturated aqueous sodium carbonate, water, brine It are used successively.Organic layer is concentrated after drying, and residue is through silica gel column chromatography point From obtaining compound I-14-b (760mg, yield：76%).

LC-MS:t_R=2.512min, [M+H]⁺=200.0；

¹H NMR (400MHz, DMSO) δ 9.79 (s, 1H), 7.48 (d, J=8.3Hz, 1H), 7.26 (s, 2H), 6.99 (d, J=1.8Hz, 1H), 6.79 (dd, J=8.3,1.9Hz, 1H).

Second step：Compound I-14-b (560mg, 2.8mmol) is dissolved in toluene (14ml), adds 3- ethoxy-c olefin(e) acids Ethyl ester I-14-c (484mg, 3.4mmol) ,-hydration p-methyl benzenesulfonic acid (53mg, 0.28mmol) and MgSO₄(560mg).Mixing Liquid return stirring 5.5h.Ethyl acetate after normal temperature is cooled to dilute and filter.Through silica gel chromatography after filtrate concentration Compound I-14 (478mg, yield：61%).

LC-MS:t_R=2.962min, [M+H]⁺=280.0；

¹H NMR(400MHz,CDCl₃) δ 9.46 (d, J=2.0Hz, 1H), 8.85 (d, J=1.4Hz, 1H), 8.40 (s, 1H), 7.83 (d, J=8.7Hz, 1H), 7.74 (dd, J=8.7,1.8Hz, 1H), 4.49 (q, J=7.1Hz, 2H), 1.46 (t, J =7.1Hz, 3H).

2nd, the synthesis of specific embodiment compound

The 3- of embodiment 1 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) benzene Base) -3- hydroxycyclobutyls) benzoic acid (1)

The first step：Compound 1-a (468mg, 1.45mmol) is dissolved in dry THF (6mL), and stirred under nitrogen atmosphere, In dropwise addition n-BuLi (1.6M, 1.0mL) at -70~-78 DEG C.Add and stir 45min at this temperature.Then it is added dropwise dissolved with change Compound I-4 (270mg, 1.32mmol) dry THF solution (0.5mL).Add and stir 1h after this temperature.It is slowly increased to room Temperature, and use saturation NH₄Cl (5mL) is quenched, ethyl acetate extraction.Organic phase is dried, concentration, column chromatography for separation (PE/EA, EA:0 ~15%), obtain compound 1-b (246mg, yield：42%).

LC-MS:t_R=3.825min, [M-OH]⁺=429.1；

¹HNMR(400MHz,CDCl₃) δ 7.97 (s, 1H), 7.88 (d, J=7.7Hz, 1H), 7.48 (dd, J=16.4, 8.1Hz, 2H), 7.39 (t, J=7.7Hz, 1H), 6.96 (d, J=2.5Hz, 1H), 6.78 (dd, J=8.5,2.5Hz, 1H), 3.92 (s, 3H), 3.25-3.17 (m, 2H), 3.04 (dt, J=17.7,9.1Hz, 1H), 2.59 (td, J=9.7,2.7Hz, 2H),0.99(s,9H),0.23(s,6H)。

Second step：Compound 1-b (246mg, 0.55mmol) is dissolved in THF (2.5mL), add TBAF (1.1mL, 1.10mmol,1.0MinTHF).15min is stirred at room temperature.Add saturated sodium bicarbonate solution (2mL) to be quenched, ethyl acetate extraction, Aqueous phase is extracted with ethyl acetate 2 times again after layering, and organic phase merging is washed with saturated common salt, and sodium sulphate is dried.Filtering, concentration, Column chromatography for separation (PE/EA, EA:20~30%), obtain compound 1-c (160mg, yield：87%).

LC-MS:t_R=2.578min, [M-OH]⁺=315.1；

¹HNMR(400MHz,CDCl₃) δ 7.97 (s, 1H), 7.88 (d, J=7.7Hz, 1H), 7.48 (t, J=9.2Hz, 2H), 7.39 (t, J=7.7Hz, 1H), 6.98 (d, J=2.6Hz, 1H), 6.78 (dd, J=8.5,2.6Hz, 1H), 5.43 (s, 1H), 3.92 (s, 3H), 3.26-3.16 (m, 2H), 3.09-2.98 (m, 1H), 2.59 (td, J=9.7,2.7Hz, 2H).

3rd step：Compound 1-c (160mg, 0.48mmol) is dissolved in dry DMF (2.5mL).Add intermediate compound I -1 (184mg, 0.57mmol) and potassium carbonate (133mg, 0.96mmol).It is stirred overnight under blanket of nitrogen in 60 DEG C.Question response liquid is cooled down Diluted afterwards with water (15mL), ethyl acetate merges organic phase after extracting 3 times.Organic phase is washed once with saturated common salt, sodium sulphate Dry.Filtering, concentration, column chromatography for separation (PE/EA, EA:10~25%), obtain compound 1-d (178mg, yield：60%).

LC-MS:t_R=3.528min, [M+H]⁺=614.0.

4th step：Compound 1-d (178mg, 0.29mmol) is dissolved in methanol (2mL).The addition NaOH aqueous solution (2mL, 1.0M).60 DEG C of reaction 3h.PH=4 is acidified to after cooling with 1N hydrochloric acid, ethyl acetate is extracted 3 times, and organic layer is dried.Filtering, Concentration, column chromatography obtains compound 1 (117mg) after purification.

LC-MS:t_R=3.218min, [M+H]⁺=600.0；

¹HNMR(400MHz,CDCl₃) δ 8.02 (s, 1H), 7.95 (d, J=7.6Hz, 1H), 7.55 (d, J=7.4Hz, 1H), 7.50-7.34 (m, 4H), 7.32-7.26 (m, 1H), 6.91 (d, J=2.4Hz, 1H), 6.75 (dd, J=8.6,2.5Hz, 1H), 4.91 (d, J=16.0Hz, 2H), 3.30-3.10 (m, 2H), 3.08-2.95 (m, 1H), 2.59 (dd, J=12.0, 9.6Hz, 2H), 2.28 (ddd, J=13.4,8.3,5.0Hz, 1H), 1.26 (t, J=6.2Hz, 2H), 1.00-0.88 (m, 2H).

The 3- of embodiment 2 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- methoxies Phenyl) -3- hydroxycyclobutyls) benzoic acid (2)

The first step：Preparation method of the compound 2-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.465min, [M-OH]⁺=592.0；

¹HNMR(400MHz,CDCl₃)δ7.98-7.93(m,1H),7.89-7.84(m,1H),7.53-7.44(m,1H), 7.41-7.35(m,3H),7.33-7.27(m,2H),6.48-6.35(m,2H),4.92(s,2H),3.91(s,3H),3.85(s, 3H),3.05-2.89(m,3H),2.54-2.47(m,2H),2.34-2.25(m,1H),1.33-1.26(m,2H),0.98-0.92 (m,2H)。

Second step：Compound 2-a (30mg, 0.05mmol) is dissolved in THF/MeOH (1mL, 1:1).Add the NaOH aqueous solution (1.0M,1mL).Reaction solution is stirred overnight in 60 DEG C.PH=5 is acidified to after cooling with 3NHCl, then ethyl acetate is extracted 2 times. Organic phase is dried, concentration, PTLC purifying, obtains compound 2 (3.0mg)；

LC-MS:t_R=3.139min, [M-OH]⁺=578.0；

¹HNMR (400MHz, MeOD) δ 7.95 (s, 1H), 7.84 (d, J=7.6Hz, 1H), 7.55-7.32 (m, 6H), 6.44 (d, J=8.0Hz, 2H), 5.00 (s, 2H), 3.80 (s, 3H), 3.09 (d, J=9.4Hz, 2H), 2.97 (dd, J= 16.8,8.9Hz, 1H), 2.41 (ddd, J=9.9,8.9,3.4Hz, 3H), 1.31 (dd, J=5.5,2.8Hz, 2H), 0.95- 0.89(m,2H)。

The 3- of embodiment 3 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- methyl Phenyl) -3- hydroxycyclobutyls) benzoic acid (3)

The first step：Preparation method of the compound 3-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.514min, [M+H]⁺=594.1.

Second step：Compound 3-a (8mg, 0.013mmol) is dissolved in tetrahydrofuran (1mL), sodium hydrate aqueous solution is added (1mL, 1N), 60 DEG C of reaction 4h.Watery hydrochloric acid is added after reaction completely and is acidified to faintly acid, ethyl acetate extraction.Organic phase is dried, Concentration, PTLC separation, obtains compound 3 (4mg, 53%).

LC-MS:t_R=3.2min, [M-OH]⁺=580.0,582.1；

¹HNMR(400MHz,CDCl₃) δ 7.95 (s, 1H), 7.87 (d, J=7.8Hz, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.7Hz, 1H), 7.33-7.28 (m, 3H), 7.25-7.21 (m, 1H), 6.65 (d, J=2.5Hz, 1H), 6.58 (dd, J=8.5,2.7Hz, 1H), 4.85 (s, 2H), 3.16-3.05 (m, 2H), 3.01-2.89 (m, 1H), 2.54-2.43 (m, 2H),2.36(s,3H),2.28-2.20(m,1H),1.20-1.12(m),0.90-0.80(m)。

The 3- of embodiment 4 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- trifluoros Aminomethyl phenyl) -3- hydroxycyclobutyls) benzoic acid (4)

The first step：Preparation method of the compound 4-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.544min, [M+H]⁺=648.1；

¹HNMR(400MHz,CDCl₃) δ 7.90 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7.50-7.42 (m, 2H), 7.37-7.27 (m, 2H), 7.24-7.21 (m, 1H), 7.11 (d, J=2.7Hz, 1H), 6.89 (dd, J=8.7,2.7Hz, 1H), 4.91 (s, 2H), 3.85 (s, 3H), 3.18-3.00 (m, 2H), 2.56 (dd, J=11.4,7.8Hz, 2H), 2.20 (ddd, J= 8.3,5.0,3.3Hz,1H),1.24-1.15(m,2H),0.92-0.84(m,2H)；

¹⁹FNMR(376MHz,CDCl₃)δ-56.74。

Second step：Compound 4-a (8mg, 0.013mmol) is dissolved in methanol (1mL), sodium hydrate aqueous solution is added (1mL, 1N), 60 DEG C of reaction 6h.Watery hydrochloric acid is added after reaction completely and is acidified to faintly acid, ethyl acetate extraction.Organic phase is dried, Concentration, PTLC separation, obtains compound 4 (4mg, 53%).

LC-MS:t_R=3.2min, [M-OH]⁺=634.0,636.0；

¹HNMR(400MHz,CDCl₃) δ 7.97 (s, 1H), 7.88 (d, J=7.8Hz, 1H), 7.50 (d, J=7.7Hz, 1H), 7.46 (d, J=8.7Hz, 1H), 7.36 (t, J=7.7Hz, 1H), 7.33-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.11 (d, J=2.7Hz, 1H), 6.89 (dd, J=8.7,2.6Hz, 1H), 4.91 (s, 2H), 3.19-3.03 (m, 3H), 2.62- 2.50(m,2H),2.22-2.13(m,1H),1.33-1.05(m),0.95-0.72(m)；

¹⁹FNMR(376MHz,CDCl₃)δ-56.74。

The 3- of embodiment 5 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) benzene Base) -3- hydroxycyclobutyls) -5- fluobenzoic acids (5)

The first step：Preparation method of the compound 5-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.581min, [M+H]⁺=631.9；

¹HNMR(400MHz,CDCl₃) δ 7.74 (s, 1H), 7.55 (ddd, J=8.9,2.4,1.4Hz, 1H), 7.45-7.36 (m, 3H), 7.29 (dd, J=8.9,7.1Hz, 1H), 7.24-7.18 (m, 1H), 6.91 (d, J=2.6Hz, 1H), 6.74 (dd, J =8.6,2.6Hz, 1H), 4.93 (s, 2H), 3.92 (s, 3H), 3.25-3.13 (m, 2H), 3.06-2.95 (m, 1H), 2.60- 2.51 (m, 2H), 2.27 (ddt, J=12.0,8.8,4.4Hz, 1H), 1.26 (dd, J=4.5,2.1Hz, 2H), 0.94 (dt, J =6.7,4.9Hz, 2H).

Second step：Compound 5-a (53mg, 0.08mmol) is dissolved in THF/MeOH (2mL, 1:1) the NaOH aqueous solution, is added (1.0M,1mL).60 DEG C of stirring reaction 3h.PH=4 is acidified to after solution cooling with 3NHCl, ethyl acetate is extracted 2 times.Organic phase Dry, concentration, PTLC separation purifies to obtain compound 5 (11.2mg).

LC-MS:t_R=3.270min, [M+H]⁺=618.0；

¹HNMR (400MHz, MeOD) δ 7.73 (s, 1H), 7.47 (t, J=20.3Hz, 5H), 7.20 (s, 1H), 6.89 (s, 1H), 6.79 (s, 1H), 5.00 (s, 2H), 3.27-3.18 (m, 2H), 2.94 (s, 1H), 2.44 (d, J=32.8Hz, 3H), 1.31(s,2H),0.92(s,2H)。

The 3- of embodiment 6 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- (three Methyl fluoride) phenyl) -3- hydroxycyclobutyls) -5- fluobenzoic acids (6)

The first step：Preparation method of the compound 6-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.584min, [M+H]⁺=666.0.

Second step：Compound 6-a (60mg, 0.08mmol) is dissolved in THF/MeOH (2mL, 1:1) the NaOH aqueous solution, is added (1.0M,2mL).60 DEG C of stirring reaction 3h.PH=4 is acidified to after solution cooling with 3NHCl, ethyl acetate is extracted 2 times.Organic phase Dry, concentration, PTLC separation purifies to obtain compound 6 (40.8mg).

LC-MS:t_R=3.305min, [M+H]⁺=651.8；

¹HNMR(400MHz,CDCl₃) δ 7.83 (s, 1H), 7.64-7.59 (m, 1H), 7.50 (d, J=8.7Hz, 1H), 7.39 (d, J=1.1Hz, 2H), 7.29 (dt, J=8.0,5.6Hz, 2H), 7.17 (d, J=2.7Hz, 1H), 6.96 (dd, J= 8.7,2.7Hz, 1H), 4.98 (s, 2H), 3.18 (dq, J=24.7,8.5Hz, 3H), 2.63 (dd, J=10.8,6.3Hz, 2H), 2.27 (tt, J=8.3,5.1Hz, 1H), 1.29-1.22 (m, 2H), 0.94 (dt, J=6.7,4.9Hz, 2H)；

¹⁹FNMR(376MHz,CDCl₃)δ-56.78(s),-112.27(s)。

The 5- of embodiment 7 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) benzene Base) -3- hydroxycyclobutyls) -2- fluobenzoic acids (7)

The first step：Preparation method of the compound 7-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.50min, [M+H]⁺=631.9.

Second step：Compound 7-a (67mg, 0.1mmol) is dissolved in methanol (1mL) and water (1mL), sodium hydroxide is added (16mg,0.4mmol).40 DEG C of stirring 2h.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid precipitation.Filtering Crude product is obtained after drying, crude by column chromatography purifying obtains compound 7 (20mg, yield：30%).

LC-MS:t_R=3.20min, [M+H]⁺=618.0；

¹HNMR(400MHz,MeOD-d₄) δ 7.79 (dd, J=6.9,2.3Hz, 1H), 7.54 (d, J=8.7Hz, 1H), 7.51-7.38 (m, 4H), 7.10 (dd, J=10.5,8.5Hz, 1H), 6.91 (d, J=2.6Hz, 1H), 6.79 (dd, J=8.6, 2.6Hz,1H),5.02(s,2H),3.29-3.19(m,2H),2.98-2.84(m,1H),2.53-2.33(m,3H),1.34- 1.29(m,2H),0.96-0.89(m,2H)；

¹⁹FNMR(400MHz,MeOD-d₄)δ-117.2。

The 5- of embodiment 8 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- (three Methyl fluoride) phenyl) -3- hydroxycyclobutyls) -2- fluobenzoic acids (8)

The first step：Preparation method of the compound 8-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.51min, [M+H]⁺=666.0.

Second step：Compound 8-a (66mg, 0.1mmol) is dissolved in methanol (1mL) and (1mL) water, sodium hydroxide is added (16mg,0.4mmol).Reaction solution stirs 2h in 40 DEG C.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid Separate out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 8 (20mg, yield after purification：31%).

LC-MS:t_R=3.25min, [M+H]⁺=652.0；

¹HNMR(400MHz,MeOD-d₄) δ 7.80 (d, J=5.1Hz, 1H), 7.67 (d, J=8.7Hz, 1H), 7.54- 7.28 (m, 4H), 7.10 (dd, J=17.8,8.8Hz, 3H), 5.09 (s, 2H), 3.17-2.92 (m, 3H), 2.53 (m, 2H), 2.47-2.31(m,1H),1.30(m,2H),0.93(m,2H)；

¹⁹FNMR(400MHz,MeOD-d₄)δ-57.9,-117.1。

The 4- of embodiment 9 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) benzene Base) -3- hydroxycyclobutyls) benzoic acid (9)

The first step：Compound 1-a (160mg, 0.50mmol) is dissolved in dry tetrahydrofuran (2mL), nitrogen is protected, in- N-BuLi (1.6M tetrahydrofuran solution, 0.38mL) is added dropwise at 70~78 DEG C, 45min is stirred.Compound I-5 is added dropwise The tetrahydrofuran solution of (102mg, 0.50mmol), stirs 1h.Reaction solution is warmed to room temperature, and saturated ammonium chloride solution (5mL) is quenched, Ethyl acetate is extracted.Organic phase is dried, concentration, column chromatographic isolation and purification (EA/PE:0~15%), obtain compound 9-a (120mg, yield：53%).

LC-MS:t_R=3.82min, [M-OH]⁺=429.1.

Second step：Compound 9-a (120mg, 0.27mmol) is dissolved in tetrahydrofuran (1.5mL), stirring is lower to be added dropwise TBAF Tetrahydrofuran solution (0.54mL, 1M, 0.54mmol).20min is stirred at room temperature.Add a small amount of water after reaction completely, and use acetic acid Ethyl ester (2 × 10mL) is extracted, and organic phase uses saturated common salt water washing after merging, and anhydrous sodium sulfate drying is filtered, concentration, post layer Analysis purifying (EA/PE:20~30%) obtain compound 9-b (50mg, yield：55%).

LC-MS:t_R=2.58min, [M-OH]⁺=315.1.

3rd step：Compound 9-b (50mg, 0.15mmol) and I-1 (52mg, 0.165mmol) are dissolved in dry DMF (1mL), adds potassium carbonate (28mg, 0.20mmol), is stirred overnight in 60 DEG C.Add ethyl acetate after the cooling of question response liquid (20mL), is washed with water and saturated common salt successively, and anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying (PE/EA:10~ 25%) compound 9-c (50mg, yield, are obtained：54%).

LC-MS:t_R=3.53min, [M+H]⁺=614.0.

4th step：Compound 9-c (50mg, 0.08mmol) is dissolved in methanol (1mL) and (1mL) water, sodium hydroxide is added (10mg,0.24mmol).Reaction solution stirs 2h in 40 DEG C.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid Separate out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 9 (25mg, yield after purification：51%).

LC-MS:t_R=3.19min, [M+H]⁺=600.0；

¹HNMR(400MHz,CDCl₃):δ 7.97 (d, J=8.2Hz, 2H), 7.37 (d, J=8.7Hz, 1H), 7.30 (m, 4H), 7.20 (dd, J=9.3,1.9Hz, 1H), 6.84 (d, J=2.5Hz, 1H), 6.67 (dd, J=8.6,2.5Hz, 1H), 4.86(s,2H),3.16-3.04(m,2H),3.00-2.88(m,1H),2.55-2.46(m,2H),2.20(m,1H),1.17- 1.10(m,2H),0.87-0.82(m,2H)。

The 4- of embodiment 10 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- first Base phenyl) -3- hydroxycyclobutyls) benzoic acid (10)

The first step：Preparation method of the compound 10-a synthesis with reference to the step of embodiment 9 first step~the 3rd.

LC-MS:t_R=3.49min, [M+H]⁺=594.0.

Second step：Compound 10-a (20mg, 0.03mmol) is dissolved in methanol (1mL) and (1mL) water, sodium hydroxide is added (13mg,0.3mmol).Reaction solution stirs 2h in 40 DEG C.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid Separate out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 10 (9mg, yield after purification：46%).

LC-MS:t_R=3.16min, [M+H]⁺=580.0；

¹HNMR(400MHz,MeOD-d₄) δ 7.97 (d, J=8.3Hz, 2H), 7.48 (dd, J=8.0,1.0Hz, 2H), 7.44-7.37 (m, 4H), 6.68 (d, J=2.5Hz, 1H), 6.64 (dd, J=8.4,2.7Hz, 1H), 4.98 (s, 2H), 3.19- 3.08 (m, 2H), 2.97 (d, J=8.2Hz, 1H), 2.49 (td, J=10.0,2.6Hz, 2H), 2.41-2.39 (m, 4H), 1.32-1.29(m,2H),0.95-0.89(m,2H)。

The 4- of embodiment 11 (3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) -2- (three Methyl fluoride) phenyl) -3- hydroxycyclobutyls) benzoic acid (11)

The first step：Preparation method of the compound 11-a synthesis with reference to the step of embodiment 9 first step~the 3rd.

LC-MS:t_R=3.52min, [M+H]⁺=648.1.

Second step：Compound 11-a (80mg, 0.12mmol) is dissolved in methanol (1mL) and (1mL) water, adds sodium hydroxide (15mg,0.36mmol).Reaction solution stirs 2h in 40 DEG C.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid Separate out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 11 (10mg, yield after purification：13%).

LC-MS:t_R=3.23min, [M+H]⁺=634.0；

¹HNMR(400MHz,DMSO-d₆) δ 12.80 (bs, 1H), 7.88 (d, J=8.0Hz, 2H), 7.65 (d, J= 7.7Hz, 1H), 7.56 (m, 2H), 7.46 (m, 3H), 7.10 (d, J=8.7Hz, 2H), 5.64 (s, 1H), 5.05 (s, 2H), 3.00(m,3H),2.48-2.39(m,3H),1.35-1.22(m,2H),0.87(m,2H)；

¹⁹FNMR(400MHz,DMSO-d₆)δ-55.3。

The 3- of embodiment 12 (3- (the chloro- 4- of 2- ((3- (2,6- dichlorophenyls) -5- isopropyls thiazole-4-yl) methoxyl group) Phenyl) -3- hydroxycyclobutyls) -5- fluobenzoic acids (12)

The first step：Preparation method of the compound 12-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.65min, [M+H]⁺=634.0.

Second step：Compound 12-a (10mg, 0.015mmol) is dissolved in methanol (1mL) and (1mL) water, hydroxide is added Sodium (6mg, 0.15mmol).Reaction solution stirs 2h in 40 DEG C.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid Body is separated out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 12 (6mg, yield after purification：61%).

LC-MS:t_R=3.34min, [M+H]⁺=619.9；

¹HNMR(400MHz,MeOD-d₄) δ 7.77 (s, 1H), 7.55 (d, J=8.7Hz, 1H), 7.50 (ddd, J=9.1, 4.9,0.9Hz, 3H), 7.41 (dd, J=9.2,6.8Hz, 1H), 7.25 (d, J=9.6Hz, 1H), 6.89 (d, J=2.6Hz, 1H), 6.79 (dd, J=8.6,2.6Hz, 1H), 4.94 (s, 2H), 3.61 (dt, J=13.7,6.9Hz, 1H), 3.31-3.19 (m, 2H), 3.04-2.82 (m, 1H), 2.51 (td, J=9.8,2.7Hz, 2H), 1.53-1.43 (m, 6H)；

¹⁹FNMR(400MHz,MeOD-d₄)δ-115.8。

The 3- of embodiment 13 (3- (the chloro- 4- of 2- ((3- (2,6- dichlorophenyls) -5- (trifluoromethyl) isothiazole -4- bases) methoxies Base) phenyl) -3- hydroxycyclobutyls) -5- fluobenzoic acids (13)

The first step：Preparation method of the compound 13-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.729min, [M-OH]⁺=642.1；

¹HNMR(400MHz,CDCl₃) δ 7.74 (s, 1H), 7.55 (ddd, J=8.9,2.4,1.4Hz, 1H), 7.38 (ddd, J=15.9,8.9,4.2Hz, 4H), 7.21 (dd, J=9.4,1.7Hz, 1H), 6.80 (d, J=2.6Hz, 1H), 6.68 (dd, J =8.6,2.6H z, 1H), 5.01 (s, 2H), 3.92 (s, 3H), 3.23-3.12 (m, 2H), 3.06-2.95 (m, 1H), 2.61- 2.50(m,2H)。

Second step：Compound 13-a (50mg .08mmol) is dissolved in MeOH (1mL) and THF (1mL).Add the NaOH aqueous solution (1.0M,1mL).60 DEG C of stirring reaction 2h.PH=4 is acidified to after cooling with 1N hydrochloric acid, ethyl acetate is extracted 3 times, organic phase Dry, filter, concentration, column chromatography for separation obtains compound as white solid 13 (14.9mg) after purification.

LC-MS:t_R=3.443min, [M-H]^-=644.0；

¹HNMR (400MHz, MeOD) δ 7.77 (s, 1H), 7.66-7.40 (m, 5H), 7.24 (d, J=9.8Hz, 1H), 6.85 (s, 1H), 6.78 (d, J=8.6Hz, 1H), 5.10 (s, 2H), 3.31-3.22 (m, 2H), 3.03-2.93 (m, 1H), 2.51 (t, J=10.4Hz, 2H)；

¹⁹FNMR(376MHz,MeOD)δ-56.76(s),-115.96(s)。

The 4- of embodiment 14 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) phthalandione (14)

The first step：Compound 1-a (320mg, 0.55mmol) is dissolved in dry tetrahydrofuran (10mL), nitrogen is protected, in- N-BuLi (1.6M tetrahydrofuran solution, 0.4mL) is added dropwise at 70~78 DEG C.Add stirring 45min.Compound I-8 is added dropwise The tetrahydrofuran solution of (131mg, 0.50mmol).Add stirring 1h.Reaction solution is warmed to room temperature, and is quenched with saturated ammonium chloride solution Go out, ethyl acetate extraction.Organic layer dries concentration rear pillar chromatographic purifying (EA/PE:0~15%), obtain compound 14-a (40mg, Yield：20%).

LC-MS:t_R=3.64min, [M-OH]⁺=487.0.

Second step：Compound 14-a (40mg, 0.08mmol) is dissolved in tetrahydrofuran (1mL), stirring is lower to be added dropwise TBAF's Tetrahydrofuran solution (1M, 0.24mL, 0.24mmol).Be stirred at room temperature after 20min, system adds a small amount of water, with ethyl acetate (2 × 210mL) extract, organic phase uses saturated common salt water washing after merging, anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying (EA/PE:20~30%) obtain compound 14-b (120mg, yield：62%).

LC-MS:t_R=2.46min, [M-OH]⁺=373.0.

3rd step：Compound 14-b (30mg, 0.07mmol) and I-1 (30mg, 0.09mmol) are dissolved in dry DMF (3mL), adds potassium carbonate (50mg, 0.35mmol), is stirred overnight in 60 DEG C.Add ethyl acetate after the cooling of question response liquid (20mL), successively with water and saturated common salt water washing, anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying (PE/EA:10 ~25%), obtain compound 14-c (30mg, yield：64%).

LC-MS:t_R=3.41min, [M+H]⁺=672.1.

4th step：Compound 14-c (10mg, 0.015mmol) is dissolved in methanol (1mL) and water (1mL), hydroxide is added Sodium (3mg, 0.075mmol).40 DEG C of stirring 2h.It is 5~6 that question response, which finishes and pH is acidified to 1N hydrochloric acid, there is white solid analysis Go out.Crude product is obtained after filtration drying, crude by column chromatography obtains compound 14 (4mg, yield after purification：40%).

LC-MS:t_R=2.91min, [M-OH]⁺=626.0；

¹HNMR(400MHz,MeOD-d₄) δ 8.04 (d, J=8.1Hz, 1H), 8.00 (d, J=1.6Hz, 1H), 7.45 (d, J =8.7Hz, 1H), 7.39 (m, 3H), 7.30 (dd, J=9.2,6.7Hz, 1H), 6.79 (d, J=2.6Hz, 1H), 6.68 (dd, J =8.6,2.6Hz, 1H), 5.03 (s, 2H), 3.19-3.07 (m, 2H), 2.93-2.79 (m, 1H), 2.43 (td, J=9.8, 2.7Hz, 2H), 2.30 (tt, J=8.3,5.1Hz, 1H), 1.24-1.17 (m, 2H), 0.83-0.76 (m, 2H).

The 5- of embodiment 15 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) -2- hydroxyisoindolin -1,3- diketone (15)

The first step：Compound 14 (64mg, 0.1mmol) and EDCI (38mg, 0.2mmol) are dissolved in DMF (5mL), and Stirred under nitrogen atmosphere 2h.Add ethyl acetate (30mL) in the completely backward system of TLC monitorings reaction, successively with water and saturated common salt Water washing, anhydrous sodium sulfate drying, filtering is concentrated to give compound 15-a (50mg, yield：80%).

LC-MS:t_R=3.38min, [M+H]⁺=625.9.

Second step：Compound 15-a (50mg, 0.08mmol) and hydroxylamine hydrochloride (200mg) are dissolved in pyridine (6mL), flowed back React 3h.TLC monitoring reactions are complete.Add ethyl acetate (30mL) into system, washed successively with water and saturated common salt, anhydrous sulphur Sour sodium is dried, and is filtered, concentration, column chromatography purifying, obtains compound 15 (13mg, yield：30.7%).

LC-MS:t_R=3.12min, [M+H]⁺=640.9；

¹HNMR(400MHz,DMSO-d₆) δ 10.76 (s, 1H), 7.87 (s, 1H), 7.74 (q, J=7.7Hz, 2H), 7.62- 7.54 (m, 2H), 7.54-7.44 (m, 2H), 6.94 (d, J=2.6Hz, 1H), 6.79 (dd, J=8.6,2.6Hz, 1H), 5.54 (s, 1H), 4.97 (s, 2H), 3.23-3.11 (m, 2H), 3.09-2.94 (m, 1H), 2.50-2.37 (m, 3H), 1.29 (dt, J= 6.5,4.6Hz, 2H), 0.87 (dt, J=6.8,4.7Hz, 2H).

The 5- of embodiment 16 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) isoindoline -1,3- diketone (16)

By compound 15-a (50mg, 0.08mmol) and NH₄OAc (200mg) is placed in 50mL round-bottomed flasks, and stirring is lower to be added Heat reacts 2h to molten condition.Add ethyl acetate (30mL) in the completely backward system of TLC monitorings reaction, eaten successively with water and saturation Salt is washed, anhydrous sodium sulfate drying, is filtered, concentration, column chromatography purifying, obtains compound 16 (15mg, yield：30%).

LC-MS:t_R=3.20min, [M+H]⁺=624.8；

¹HNMR(400MHz,DMSO-d₆) δ 11.25 (s, 1H), 7.84 (s, 1H), 7.74 (s, 2H), 7.59 (d, J=8.3H Z, 2H), 7.55-7.43 (m, 2H), 6.94 (s, 1H), 6.79 (d, J=8.6Hz, 1H), 5.54 (s, 1H), 4.97 (s, 2H), 3.17 (d, J=10.4Hz, 2H), 3.10-2.97 (m, 1H), 2.44 (m, 3H), 1.29 (m, 2H), 0.88 (m, 2H).

The 4- of embodiment 17 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) phthalandione (17)

The first step：Preparation method of the compound 17-a synthesis with reference to the step of embodiment 14 first step~the 3rd.

LC-MS:t_R=3.298min, [M-OH]⁺=638.0,640.0.

Second step：Compound 17-a (13mg, 0.020mmol) is dissolved in tetrahydrofuran (2mL), 1N sodium hydroxide water is added Solution (2mL), 50 DEG C of reaction 2h.Reaction is complete, adds watery hydrochloric acid acidifying, ethyl acetate extraction, organic phase saturated aqueous common salt Washing, anhydrous sodium sulfate drying.Filtering, concentration, crude product is separated through PTLC, obtains compound 17 (9mg, yield：73%).

LC-MS:t_R=2.82min, [M+H]⁺=626.0,628.0；

¹HNMR (400MHz, MeOD) δ 8.06 (d, J=7.9Hz, 1H), 8.01 (s, 1H), 7.44-7.29 (m, 5H), 6.81 (d, J=2.5Hz, 1H), 6.66 (dd, J=8.6,2.5Hz, 1H), 4.79 (s, 2H), 3.16 (t, J=10.1Hz, 2H), 2.97-2.84 (m, 1H), 2.46 (dd, J=12.0,9.9Hz, 2H), 2.22-2.08 (m, 1H), 1.21-1.07 (m, 4H).

The 5- of embodiment 18 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) -2- hydroxyisoindolin -1,3- diketone (18)

The first step：Compound 17 (80mg, 0.127mmol) is dissolved in dry DMF (1.5mL), stirring is lower to add EDCI (38mg).Reaction 3h is stirred at room temperature.It is diluted with water, ethyl acetate is extracted 3 times.Merge organic phase, then use saturated common salt water washing, Dry, concentration obtains crude product 18-a (68mg, yield：88%).

LC-MS:t_R=3.275min, [M+H]⁺=not appearance.

Second step：Compound 18-a (34mg, 0.056mmol) is dissolved in pyridine (2mL), hydroxylamine hydrochloride (40mg) is added. Return stirring 2h.Reaction solution is cooled to room temperature, is diluted with ethyl acetate, dries concentration, purifying after washing and salt washing successively After obtain compound 18 (14.6mg, yield：42%).

LC-MS:t_R=2.999min. [M-OH]⁺=606.8；

¹HNMR (400MHz, DMSO) δ 10.86 (s, 1H), 7.86 (s, 1H), 7.73 (q, J=7.8Hz, 2H), 7.66- 7.61 (m, 2H), 7.59-7.49 (m, 2H), 6.92 (d, J=2.6Hz, 1H), 6.77 (dd, J=8.6,2.6Hz, 1H), 5.55 (s, 1H), 4.92 (s, 2H), 3.23-3.14 (m, 2H), 3.02 (dt, J=17.2,8.7Hz, 1H), 2.45 (t, J=9.9Hz, 3H), 1.19 (dd, J=7.8,2.9Hz, 2H), 1.16-1.11 (m, 2H).

The 5- of embodiment 19 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) Phenyl) -3- hydroxycyclobutyls) isoindoline -1,3- diketone (19)

Compound 18-a (34mg, 0.056mmol) and ammonium acetate (1.0g) are heated to 130 DEG C of reaction 2h.It is cooled to room It is diluted with water after temperature, ethyl acetate is extracted 2 times.Merge organic phase, dry, concentration, through column chromatographic isolation and purification, obtains compound 19 (9mg, 26%).

LC-MS:t_R=3.081min. [M-OH]⁺=591.0；

¹HNMR (400MHz, DMSO) δ 11.25 (s, 1H), 7.84 (s, 1H), 7.74 (d, J=8.0Hz, 2H), 7.68- 7.60 (m, 2H), 7.59-7.49 (m, 2H), 6.92 (d, J=2.5Hz, 1H), 6.77 (dd, J=8.7,2.5Hz, 1H), 5.54 (s, 1H), 4.92 (s, 2H), 3.18 (t, J=10.0Hz, 2H), 3.03 (dd, J=17.3,8.8Hz, 1H), 2.45 (dd, J= 15.1,6.8Hz, 3H), 1.16 (ddd, J=17.5,6.8,3.7Hz, 4H).

The 3- of embodiment 20 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) Phenyl) azetidine -1- bases) -5- fluobenzoic acids (20)

The first step：Compound 20-a (2215mg, 10.0mmol) is dissolved in dry THF (20mL), dry ice-ethanol bath is cold But, BuLi (6.9mL, 11.0mmol, 1.6M hexane solution), low-temp reaction 30min is added dropwise.Ketone 20-b (856mg, Dry THF (10mL) 5.0mmol) is dissolved in, reaction system is added.It is to slowly warm up to close to 0 DEG C of reaction 2h.Added after reaction completely Saturation NH₄The Cl aqueous solution is quenched, ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, concentration, post layer Analysis separation (PE/EA3:1) compound 20-c (1040mg, yield, are obtained：66%).

LC-MS:t_R=2.69min, [M+H-Boc]⁺=214.1.

Second step：Compound 20-c (1040mg, 3.31mmol) is dissolved in dry CH₂Cl₂(20mL, ice-water bath cooling, according to Secondary addition Et₃SiH (5.3mL, 33.1mmol) and BF₃·Et₂O (5.0mL, 39.8mmol).Low temperature is kept, 2h is reacted.React The NaOH aqueous solution is added after complete and adjusts pH to alkalescent.Concentration, crude product adds ethyl acetate, and being stirred vigorously makes product fully molten Solution.Filtering, ethyl acetate washing.Filtrate concentrates, and obtains crude Compound 20-d (955mg, yield：100%).

LC-MS:t_R=1.69min, [M+H]⁺=198.1.

3rd step：By compound 20-d (89mg, 0.45mmol), 20-e (70mg, 0.30mmol), X-phos (29mg, 0.06mmol) and Cs₂CO₃(195mg, 0.60mmol) adds dioxane (4mL), takes out ring gas, and nitrogen protection is lower to add Pd₂ (dba)₃(27mg, 0.03mmol), 100 DEG C of reactions are stayed overnight.Reaction is complete, is cooled to room temperature, adds saturated common salt water washing, second Acetoacetic ester is extracted.Crude product column chromatography for separation after concentration, obtains compound 20-f (80mg, yield：76%).

LC-MS:t_R=3.45min, [M+H]⁺=350.0.

4th step：Compound 20-f (80mg, 0.23mmol) is dissolved in dichloromethane (2mL), ice-water bath cooling is added BBr₃/CH₂Cl₂(0.9mL, 0.91mmol, 1M), 0 DEG C of reaction 1h.Add methanol to be quenched, dichloromethane extraction.Compound 20-g Crude product is directly used in the next step.

LC-MS:t_R=3.05min, [M+H]⁺=336.0.

5th step：Compound 20-g (40mg, 0.12mmol) and I-2 (36mg, 0.12mmol) are dissolved in dry DMF (2mL), adds K₂CO₃(33mg, 0.24mmol), 50 DEG C of reactions are stayed overnight.Concentrated after reaction completely, PTLC separation obtains compound 20-h (14mg, 19%).

LC-MS:t_R=3.74min, [M+H]⁺=601.0,603.1.

6th step：Compound 20-h (14mg, 0.023mmol) is dissolved in tetrahydrofuran (1mL), 1NNaOH is added (1mL) aqueous solution.50 DEG C of reactions are stayed overnight.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is passed through after concentration PTLC is separated, and obtains compound 20 (11.4mg, yield：83%).

LC-MS:t_R=3.42min, [M+H]⁺=586.9,589.0；

¹HNMR(400MHz,CDCl₃) δ 7.41 (d, J=1.5Hz, 1H), 7.39 (s, 1H), 7.32 (dd, J=9.1, 6.9Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 7.16-7.11 (m, 1H), 7.01-6.94 (m, 1H), 6.83 (d, J= 2.6Hz, 1H), 6.72 (dd, J=8.6,2.6Hz, 1H), 6.37 (dt, J=10.4,2.2Hz, 1H), 4.79 (s, 2H), 4.36 (t, J=7.6Hz, 2H), 4.30-4.19 (m, 1H), 3.87 (t, J=6.7Hz, 2H), 2.15 (tt, J=8.4,5.1Hz, 1H), 1.30-1.23 (m, 2H), 1.15 (ddd, J=11.5,7.1,4.5Hz, 2H)；

¹⁹FNMR(376MHz,CDCl₃)δ-111.79。

The 3- of embodiment 21 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -5- fluobenzoic acids (21)

The first step：Preparation method of the compound 21-a synthesis with reference to the step of embodiment 20 first step~the 5th.

LC-MS:t_R=3.901min, [M+H]⁺=617.0,619.0.

Second step：Compound 21-a (15mg, 0.024mmol) is dissolved in tetrahydrofuran (1mL), 1NNaOH is added (1mL) aqueous solution.50 DEG C of reactions are stayed overnight.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is passed through after concentration PTLC is separated, and obtains compound 21 (10.0mg, yield：68%).

LC-MS:t_R=3.53min, [M+H]⁺=603.0,605.0；

¹HNMR(400MHz,CDCl₃) δ 7.38 (d, J=1.1Hz, 1H), 7.36 (s, 1H), 7.31-7.23 (m, 2H), 7.17-7.11 (m, 1H), 7.01-6.95 (m, 1H), 6.84 (d, J=2.6Hz, 1H), 6.72 (dd, J=8.6,2.6Hz, 1H), 6.38 (dt, J=10.3,2.2Hz, 1H), 4.90 (s, 2H), 4.36 (t, J=7.6Hz, 2H), 4.31-4.20 (m, 1H), 3.88 (t, J=6.7Hz, 2H), 2.31-2.21 (m, 1H), 1.29-1.20 (m, 2H), 0.92 (dt, J=6.7,4.9Hz, 2H)；

¹⁹FNMR(376MHz,CDCl₃)δ-111.78。

The 2- of embodiment 22 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxyazetidinium -1- bases) 4-Picolinic acid (22)

The first step：Compound 22-a (1900mg, 8.8mmol) and 22-b (1440mg, 13.2mmol) are dissolved in Isosorbide-5-Nitrae-two The ring of oxygen six (30mL), adds Cs successively₂CO₃(8600mg, 26.3mmol), BINAP (1100mg, 1.76mmol) and Pd (OAc)₂ (400mg, 1.76mmol), the lower backflow 16h of nitrogen protection.TLC monitoring reactions are complete, filtering, concentration rear pillar chromatographic purifying (EA/ PE:20%~50%) obtain compound 22-c (500mg, yield：28%).

Second step：Compound 22-c (500mg, 2.5mmol) is dissolved in dichloromethane (30mL), stirring is lower to add DMP (2120mg, 5mmol).2h, plus saturation NaHCO is stirred at room temperature₃Reaction is quenched in the aqueous solution, and is extracted with ethyl acetate (2 × 30mL) Take, organic phase uses saturated common salt water washing after merging, anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying obtains compound 22-d (230mg, yield：29%).

LC-MS:t_R=1.58min, [M+H]⁺=207.1.

3rd step：By compound 1-a (300mg, 0.93mmol)) dry tetrahydrofuran (5mL) is dissolved in, nitrogen is protected, in- N-BuLi (1.6M tetrahydrofuran solution, 0.7mL) is added dropwise at 70~78 DEG C.Stir 45min.Compound 22-d is added dropwise The tetrahydrofuran solution of (175mg, 0.85mmol), stirs 1h.Reaction solution is warmed to room temperature, and is quenched with saturated ammonium chloride solution, Ethyl acetate is extracted.Organic layer is dried, concentration, column chromatography purifying, obtains compound 22-e (30mg, yield：7%).

LC-MS:t_R=3.35min, [M-OH]⁺=449.2.

4th step：Compound 22-e (30mg, 0.06mmol) is dissolved in tetrahydrofuran (1mL), stirring is lower to be added dropwise TBAF's Tetrahydrofuran solution (1M, 0.18mL, 0.18mmol).It is stirred at room temperature after 20min, is added water into system, and with ethyl acetate (2 × 10mL) extraction, saturated common salt water washing is used after organic phase merging, anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying (EA/PE:20~30%), obtain compound 22-f (18mg, yield：90%).

LC-MS:t_R=2.10min, [M+H]⁺=335.0.

5th step：Compound 22-f (15mg, 0.04mmol) and I-1 (19mg, 0.06mmol) are dissolved in dry DMF (2mL), adds K₂CO₃(20mg, 0.16mmol), 60 DEG C of stirring reactions are stayed overnight.Add ethyl acetate after the cooling of question response liquid (10mL), is washed with water and saturated common salt successively, and anhydrous sodium sulfate drying is filtered, concentration, column chromatography purifying (PE/EA:10~ 25%) compound 22-g (20mg, yield, are obtained：75%).

LC-MS:t_R=3.10min, [M+H]⁺=616.0.

6th step：Compound 22-g (20mg, 0.03mmol) is dissolved in methanol (1mL) and water (1mL), NaOH is added (4mg,0.010mmol).40 DEG C of stirring 2h.Question response is finished, and it is 5~6 that pH is acidified to 1N hydrochloric acid, there is solid precipitation.Cross Be filtered dry it is dry after crude product, crude by column chromatography purifying, obtain compound 22 (6mg, yield：30.7%).

LC-MS:t_R=2.57min, [M+H]⁺=602.0；

¹HNMR(400MHz,MeOD-d₄) δ 8.11 (d, J=5.4Hz, 1H), 7.50-7.43 (m, 2H), 7.43-7.32 (m, 2H), 7.17 (d, J=5.0Hz, 1H), 7.02 (s, 1H), 6.89 (d, J=2.5Hz, 1H), 6.80 (dd, J=8.7,2.5Hz, 1H), 5.01 (s, 2H), 4.60 (d, J=9.4Hz, 2H), 4.33 (d, J=9.3Hz, 2H), 2.47-2.32 (m, 1H), 1.26 (m,2H),0.91(m,2H)。

The 5- of embodiment 23 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxyazetidinium -1- bases) Nicotinicum Acidum (23)

The first step：Preparation method of the compound 22-a synthesis with reference to the step of embodiment 21 first step~the 5th.

LC-MS:t_R=3.096min, [M+H]⁺=616.0.

Second step：Compound 23-a (30mg, 0.05mmol) is dissolved in MeOH/THF (2mL, 1:1) NaOH, is added water-soluble Liquid (1mL, 1.0M).60 DEG C of stirring reaction 1.5h.PH=4 is acidified to after cooling with 1N hydrochloric acid, ethyl acetate is extracted 3 times, had Machine layer is dried, and is filtered, and concentration, crude product is isolated and purified through PTLC, obtains compound 23 (12.3mg).

LC-MS:t_R=2.658min, [M+H]⁺=602.0；

¹HNMR (400MHz, MeOD) δ 8.47 (s, 1H), 8.02 (s, 1H), 7.77-7.22 (m, 5H), 6.85 (d, J= 34.7Hz, 2H), 5.01 (s, 2H), 4.48 (d, J=8.2Hz, 2H), 4.29 (d, J=7.9Hz, 2H), 2.48-2.33 (m, 1H),1.31(s,2H),0.93(s,2H)。

The 3- of embodiment 24 (1- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -3- bases) benzoic acid (24)

The first step：Compound 24-a (1.31g, 5.0mmol) is dissolved in dry THF (20mL), stirred under nitrogen atmosphere, In dropwise addition i-PrMgCl (2.0M, 3mL) at -70~78 DEG C.1h is stirred, compound 20-b (1.28g, 7.5mmol) THF is added dropwise (8mL) solution.Add and be slowly increased to that 1h is stirred at room temperature.Use saturation NH₄The Cl aqueous solution (20mL) is quenched, ethyl acetate extraction.Have Machine layer is dried, and concentration, column chromatography for separation obtains compound 24-b (1.5g, yield：90%).

LC-MS:t_R=2.592min, [M-Boc]⁺=208.1；

¹HNMR(400MHz,CDCl₃) δ 8.18 (t, J=1.7Hz, 1H), 8.05-7.93 (m, 1H), 7.77-7.67 (m, 1H), 7.48 (t, J=7.8Hz, 1H), 4.23 (dd, J=26.2,9.5Hz, 4H), 3.93 (s, 3H), 1.46 (s, 9H).

Second step：Compound 24-b (153mg, 0.50mmol) is dissolved in dry methylene chloride (4mL), DIPEA is added (0.17mL, 1.00mmol), stirring is lower to be added dropwise MsCl (0.05mL, 0.65mmol).Mixture is stirred overnight at room temperature.Add water (5mL), dichloromethane is extracted 2 times.Organic phase is mixed, is dried, concentration, rapid column chromatography obtains crude product compound 24-c (180mg, purity is about 45%).

LC-MS:t_R=2.764min.

3rd step：Compound 24-c (180mg, 0.46mmol) is dissolved in methanol (5mL), Pd/C (10mg) is added.Hydrogen It is stirred overnight at room temperature under atmosphere.Reacting liquid filtering, filtrate concentration, column chromatographic isolation and purification obtains compound 24-d (60mg).

LC-MS:t_R=2.927min, [M-Boc]⁺=192.1；

¹HNMR(400MHz,CDCl₃) δ 7.98 (t, J=1.7Hz, 1H), 7.93 (dt, J=7.6,1.4Hz, 1H), 7.54- 7.48 (m, 1H), 7.43 (t, J=7.7Hz, 1H), 4.35 (t, J=8.7Hz, 2H), 3.99 (dd, J=8.7,6.0Hz, 2H), 3.93(s,3H),1.47(s,9H)。

4th step：Compound 24-d (60mg, 0.20mmol) is dissolved in 1,4- dioxane (3mL).Add hydrochloric acid dioxy Six ring solution (3mL, 6.0M).2h is stirred at room temperature.47mg compounds 24-e hydrochloride is concentrated to give, crude product is directly used in down Step reaction.

5th step：Compound 24-e (47mg, 0.20mmol) is dissolved in dry Isosorbide-5-Nitrae-dioxane (5mL), afterwards successively Add compound 24-f (127mg, 0.27mmol), Cs₂CO₃(205mg, 0.63mmol), X-phos (30mg, 0.06mmol) and Pd₂(dba)₃(29mg,0.03mmol).Nitrogen is protected, and 105 DEG C of stirring reactions are stayed overnight.Diatomite is filtered after question response cooling, and Washed with ethyl acetate 3 times.Filtrate takes organic layer to be dried with sodium sulphate after extraction, and concentration, column chromatography for separation obtains compound 24-g (30mg, yield：25%).

LC-MS:t_R=3.634min, [M+H]⁺=583.0；

¹HNMR(400MHz,CDCl₃) δ 7.99 (s, 1H), 7.94 (d, J=7.8Hz, 1H), 7.57 (d, J=7.6Hz, 1H), 7.46-7.39 (m, 4H), 7.36-7.30 (m, 1H), 6.80 (d, J=2.6Hz, 1H), 6.70-6.65 (m, 1H), 4.76 (s, 2H), 4.62-4.52 (m, 2H), 4.15-4.04 (m, 3H), 3.92 (s, 3H), 2.14 (tt, J=8.4,5.1Hz, 1H), 1.27 (tt, J=7.1,5.1H z, 2H), 1.15 (ddd, J=11.5,7.1,4.4Hz, 2H).

6th step：Compound 24-g (20mg, 0.034mmol) is dissolved in MeOH/THF (2mL, v/v=1:1).Add The NaOH aqueous solution (1.0M, 1mL).50 DEG C of stirring reaction 3h.PH=5, ethyl acetate extraction 3 are acidified to after cooling with 1N hydrochloric acid Secondary, organic layer is dried, and is filtered, and concentration, column chromatography for separation purifies to obtain compound 24 (9.6mg).

LC-MS:t_R=3.312min, [M+H]⁺=569.0；

¹HNMR (400MHz, MeOD) δ 7.95 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7.54 (d, J=7.1Hz, 1H), 7.43-7.33 (m, 4H), 6.61 (t, J=2.3Hz, 1H), 6.58 (dd, J=8.8,2.8Hz, 1H), 6.50 (d, J= 8.8Hz,1H),4.72(s,2H),4.34-4.22(m,2H),3.85-3.74(m,3H),2.23-2.14(m,1H),1.26- 1.17 (m, J=18.3Hz, 2H), 1.10-1.04 (m, 2H).

The 3- of embodiment 25 (1- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) -3- hydroxyazetidinium -3- bases) benzoic acid (25)

The first step：Compound 22-b (1.64g, 15.0mmol) is dissolved in dry Isosorbide-5-Nitrae-dioxane (100mL), 1- is added A (3.21g, 10.0mmol), Cs₂CO₃(11.4g, 35.0mmol), X-phos (953mg, 2.0mmol), Pd₂(dba)₃ (916mg,1.0mmol).Nitrogen is protected, and 100 DEG C of stirring reactions are stayed overnight.Diatomite is filtered after question response cooling, and uses acetic acid second Ester is washed.Filtrate takes organic layer to be dried with sodium sulphate after extraction, concentration, column chromatography for separation, obtains compound 25-a (160mg, production Rate：5%).

LC-MS:t_R=3.372min. [M+H]⁺=314.0；

¹HNMR(400MHz,CDCl₃) δ 6.79 (d, J=2.7Hz, 1H), 6.65 (dd, J=8.7,2.7Hz, 1H), 6.46 (d, J=8.7Hz, 1H), 4.71-4.62 (m, 1H), 4.31-4.24 (m, 2H), 3.70-3.65 (m, 2H), 0.96 (s, 9H), 0.16(s,6H)。

Second step：Compound 25-a (160mg, 0.50mmol) is dissolved in ethyl acetate (10mL), add IBX (217mg, 0.78mmol).Mixture return stirring 2h.Reaction solution, which is cooled to after room temperature, uses ethyl acetate dilute filtration, and filtrate is washed successively Concentration is dried with after salt washing, compound 25-b (60mg, yield are obtained after purification：37%).

LC-MS:t_R=3.612min；

¹HNMR(400MHz,CDCl₃) δ 6.88 (d, J=2.7Hz, 1H), 6.71 (dd, J=8.7,2.7Hz, 1H), 6.60 (d, J=8.8Hz, 1H), 4.74 (s, 4H), 0.97 (s, 9H), 0.18 (s, 6H).

3rd step：Compound 24-a (60mg, 0.23mmol) is dissolved in dry THF (3mL), in dropwise addition at -70~78 DEG C I-PrMgCl (2.0M, 0.13mL).1h is stirred after adding at this temperature.- 70 DEG C be added dropwise dissolved with compound 25-b (60mg, Dry THF solution (1mL) 0.20mmol).Add and stir 1h after this temperature.Reaction solution is warmed to room temperature stirring 1h.Use saturation NH₄Cl (5mL) is quenched, ethyl acetate extraction.Organic layer dries column chromatography for separation after concentration, obtains compound 25-c (35mg, production Rate：40%).

LC-MS:t_R=3.728min, [M+H]⁺=448.1.

4th step：Compound 25-c (35mg, 0.08mmol) is dissolved in THF (1mL), add TBAF (0.16mL, 0.16mmol,1.0MinTHF).30min is stirred at room temperature.Saturated sodium bicarbonate aqueous solution (2mL) and ethyl acetate (2mL) are added, Aqueous phase is extracted 2 times with ethyl acetate (2mL) after layering, organic phase merging brine It, sodium sulphate dry filter.After concentration PTLC is separated, and obtains compound 25-d (19mg, yield：73%).

LC-MS:t_R=2.467min, [M+H]⁺=334.0.

5th step：Compound 25-d (19mg, 0.057mmol) is dissolved in dry DMF (2mL).Addition I-2 (21mg, 0.068mmol) and K₂CO₃(16mg, 0.110mmol), 65 DEG C of stirring reactions are stayed overnight.It is dilute with water (15mL) after the cooling of question response liquid Release, ethyl acetate is extracted 3 times, merge organic phase.Organic phase is washed once with saturated common salt, and sodium sulphate is dried, and is filtered, concentration, Column chromatography for separation (PE/EA, EA:10~25%), obtain compound 25-e (32mg, yield：94%).

LC-MS:t_R=3.356min, [M+H]⁺=599.0；

¹HNMR(400MHz,CDCl₃) δ 8.27 (t, J=1.7Hz, 1H), 8.04-7.95 (m, 1H), 7.88-7.81 (m, 1H), 7.48 (t, J=7.8Hz, 1H), 7.43-7.37 (m, 2H), 7.32 (dd, J=9.1,6.9Hz, 1H), 6.76 (d, J= 2.7Hz, 1H), 6.69-6.63 (m, 1H), 6.53 (d, J=8.9Hz, 1H), 4.74 (s, 2H), 4.35 (d, J=8.6Hz, 2H), 4.19 (d, J=8.6Hz, 2H), 3.92 (s, 3H), 2.14 (ddd, J=10.1,6.8,4.2Hz, 1H), 1.29-1.25 (m, 2H), 1.14 (ddd, J=11.5,7.1,4.4Hz, 2H).

6th step：Compound 25-e (15mg, 0.025mmol) is dissolved in MeOH/THF (2mL, v/v=1:1).Add The NaOH aqueous solution (1.0M, 1mL).50 DEG C of stirring reaction 2h.PH=5, ethyl acetate extraction 3 are acidified to after cooling with 1N hydrochloric acid Secondary, organic layer dry filter concentration, column chromatographic isolation and purification obtains compound 25 (9.5mg).

LC-MS:t_R=3.050min, [M+H]⁺=585.0；

¹HNMR(400MHz,CDCl₃) δ 8.34 (d, J=1.6Hz, 1H), 8.06 (d, J=7.8Hz, 1H), 7.91 (d, J= 8.3Hz, 1H), 7.52 (dd, J=10.2,5.5Hz, 1H), 7.43-7.36 (m, 2H), 7.32 (dd, J=9.1,6.9Hz, 1H), 6.77 (d, J=2.7Hz, 1H), 6.66 (dd, J=8.8,2.8Hz, 1H), 6.54 (d, J=8.9Hz, 1H), 4.75 (s, 2H), 4.35 (d, J=8.5Hz, 2H), 4.21 (d, J=8.4Hz, 2H), 2.14 (tt, J=8.4,5.1Hz, 1H), 1.29-1.23 (m, 2H), 1.14 (ddd, J=11.5,7.1,4.5Hz, 2H).

The 5- of embodiment 26 (3- (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxies Base) phenyl) -3- hydroxycyclobutyls) phenyl) -1,3,4- oxadiazoles -2 (3H) -one (26)

The first step：Preparation method of the compound 26-a synthesis with reference to the step of embodiment 1 first step~the 3rd.

LC-MS:t_R=3.428；[M-OH]⁺=580.0；

¹HNMR(400MHz,CDCl₃) δ 7.95 (s, 1H), 7.88 (dt, J=7.7,1.3Hz, 1H), 7.50-7.33 (m, 6H), 6.90 (d, J=2.6Hz, 1H), 6.75 (dd, J=8.6,2.6Hz, 1H), 4.83 (s, 2H), 3.92 (s, 3H), 3.24- 3.10 (m, 2H), 3.05-2.94 (m, 1H), 2.58 (td, J=9.7,2.7Hz, 2H), 2.17 (ddd, J=8.4,6.8, 4.2Hz,1H),1.29-1.25(m,2H),1.20-1.14(m,2H)。

Second step：Compound 26-a (60mg, 0.10mmol) is dissolved in ethanol (2.5mL), add hydrazine hydrate (0.75mL, 85%).Reaction solution backflow 1.5h.Compound 26-b (60mg, yield are obtained after reaction solution concentration：100%).

LC-MS:t_R=2.847min, [M-OH]⁺=580.0.

3rd step：Compound 26-b (60mg, 0.10mmol) is dissolved in tetrahydrofuran (3mL).Add CDI (24mg).75℃ Stir 45min.Reaction solution is concentrated, and column chromatography for separation obtains compound 26 (12mg, yield：19%).

LC-MS:t_R=3.151min, [M-OH]⁺=606.0；

¹HNMR(400MHz,CDCl₃) δ 8.76 (s, 1H), 7.77 (s, 1H), 7.69 (dt, J=6.8,1.8Hz, 1H), 7.48-7.39 (m, 5H), 7.34 (dd, J=9.1,6.9Hz, 1H), 6.91 (d, J=2.6Hz, 1H), 6.75 (dd, J=8.6, 2.6Hz, 1H), 4.83 (s, 2H), 3.25-3.15 (m, 2H), 3.09-2.92 (m, 2H), 2.59 (td, J=9.6,2.6Hz, 2H), 2.17 (tt, J=8.4,5.1H z, 1H), 1.31 (dt, J=6.6,4.6Hz, 2H), 1.17 (ddd, J=11.6,7.1, 4.5Hz,2H)。

The 4- of embodiment 27 (2- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) cyclopropyl) benzoic acid (27)

The first step：Compound 27-a (10g, 43.6mmol) and triethoxy phosphine Hybrid Heating are stirred into 4h to 175 DEG C.It is cold But to room temperature, it is concentrated under reduced pressure, removes triethoxy phosphine, obtain crude product compound 27-b (13g).

Second step：Compound 27-b (2.2g, 16.9mmol) is dissolved in tetrahydrofuran, addition NaH (630mg, 15.8mmol), half an hour is stirred at room temperature, then adds compound 27-c (1.8g, 10.4mmol), is stirred overnight at room temperature.Add Water and ethyl acetate extraction, organic phase are spin-dried for, and obtain compound 27-d (1.5g).

3rd step：By Et₂Zn (64mL, 2M) is added in dichloromethane, is added trifluoroacetic acid (5mL), is cooled to -78 DEG C, 30min is stirred, temperature is raised to -30 DEG C, adds CH₂I₂(8mL), continuation stirring 30min, addition compound 27-d (2g, 6.6mmol), room temperature reaction is stayed overnight.Add saturated aqueous ammonium chloride to be quenched, ethyl acetate extraction.Organic phase dry, filtering, Concentration, column chromatography for separation obtains compound 28-e (1.0g).

4th step：Compound 27-e (1.0g, 3.3mmol) is dissolved in dichloromethane, Boron tribromide solution (1mL) is added, 1h is stirred at room temperature.Add methanol to be quenched, organic phase concentration, column chromatography for separation obtains compound 28-f (300mg).

5th step：Compound I-1 (40mg, 0.126mmol) and 27-f (38mg, 0.126mmol) are dissolved in dry DMF (2mL), adds potassium carbonate (17mg, 0.126mmol), 60 DEG C of stirring 24h.Add water, ethyl acetate extraction.Crude product column chromatography point From obtaining compound 27-g (13mg).

6th step：Compound 27-g (13mg, 0.022mmol) is dissolved in methanol (1mL), 3N sodium hydroxide solutions are added (1mL), back flow reaction are stayed overnight.Cooling, ethyl acetate extraction.Crude product column chromatography for separation, obtains compound 27 (6.5mg).

LC-MS:t_R=3.446min, [M+H]⁺=570.1；

¹HNMR(400MHz,CDCl₃) δ 7.94 (d, J=8.4Hz, 2H), 7.34-7.27 (m, 2H), 7.24-7.21 (m, 1H), 7.17 (d, J=8.4Hz, 2H), 6.88 (d, J=8.6Hz, 1H), 6.77 (d, J=2.6Hz, 1H), 6.60 (dd, J= 8.6,2.6Hz,1H),4.81(s,2H),2.38-2.27(m,1H),2.25-2.10(m,1H),2.02-1.88(m,1H), 1.64-1.51(m,2H),1.43-1.33(m,2H),0.90-0.77(m,2H)。

The 3- of embodiment 28 (1- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isoxazole -4- bases) methoxyl group) Phenyl) azetidine -3- bases) -5- fluobenzoic acids (28)

The first step：Preparation method of the compound 28-a synthesis with reference to the step of embodiment 24 first step~the 5th.

¹H NMR(400MHz,CDCl₃) δ 7.79 (s, 1H), 7.61 (dd, J=8.9,1.4Hz, 1H), 7.44-7.39 (m, 2H), 7.36-7.29 (m, 2H), 6.78 (d, J=2.5Hz, 1H), 6.67 (dd, J=13.0,5.5Hz, 2H), 4.75 (s, 2H), 4.49(s,2H),4.01(s,3H),3.93(s,3H),2.17–2.10(m,1H),1.31–1.26(m,2H),1.17–1.09(m, 2H)。

Second step：Compound 28-a (90mg, 0.034mmol) is dissolved in 4mL MeOH/THF (v/v=1:1).Into solution Add the NaOH aqueous solution (1.0M, 2mL), 60 DEG C of stirring reactions 3 hours.Ph=5, acetic acid second are acidified to after cooling with 1N hydrochloric acid Ester is extracted 3 times, the concentration of organic layer dry filter, and through column chromatography for separation, compound 28 (33mg) is obtained after purification.

LC-MS:t_R=3.344min, [M+H]⁺=587.0；

¹H NMR (400MHz, MeOD) δ 7.88 (s, 1H), 7.58 (d, J=9.0Hz, 1H), 7.53-7.39 (m, 4H), 6.72 (d, J=2.7Hz, 1H), 6.68 (dd, J=8.8,2.8Hz, 1H), 6.60 (d, J=8.8Hz, 1H), 4.82 (s, 2H), 4.37 (s, 2H), 3.90 (d, J=3.0Hz, 3H), 2.30 (dt, J=16.1,6.9Hz, 1H), 1.29 (s, 2H), 1.19 (d, J =3.2Hz, 2H)；

¹⁹F NMR(376MHz,MeOD)δ-114.82(s)。

The 5- of embodiment 29 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isoxazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) benzo [d] isothiazole -3 (2H) -one 1,1- dioxies (29)

The first step：By compound 20-d (59mg, 0.30mmol), 29-a (88mg, 0.30mmol), X-phos (57mg, 0.12mmol) and Cs₂CO₃(195mg, 0.60mmol) adds dioxane (5mL), takes out ring gas, and nitrogen protection is lower to add Pd₂ (dba)₃(55mg, 0.06mmol), 90 DEG C of reactions are stayed overnight.Reaction is complete, is cooled to room temperature, adds saturated common salt water washing, second Acetoacetic ester is extracted.Crude product column chromatography for separation after concentration, obtains compound 29-b (10mg).

LC-MS:t_R=2.696min, [M-H]^-=377.0.

Second step：Compound 29-b (10mg, 0.026mmol) is dissolved in dichloromethane (2mL), ice-water bath cooling is added BBr₃/CH₂Cl₂(13 μ L, 0.053mmol, 4M), 0 DEG C of reaction 1h.Add methanol to be quenched, dichloromethane extraction.Crude product is through PTLC Separation, obtains compound 29-c (5mg).

LC-MS:t_R=2.285min, [M-H]^-=363.1.

3rd step：By compound 29-c (5mg, 0.0137mmol) be dissolved in 1mL dry DMF, add NaH (2.4mg, 0.06mmol), it is stirred at room temperature 20 minutes, adds tetrabutylammonium iodide (1mg) and I-2 (5mg, 0.0151mmol), 50 DEG C anti- Answer 2 hours.Concentrated after reaction completely, add saturation NH₄The Cl aqueous solution, EtOAc is extracted 3 times.Dry, filter, concentration, crude product PTLC is separated, and purifies to obtain compound 29 (2.4mg).

LC-MS:t_R=3.172min, [M-H]^-=628.0,630.0.

¹H NMR (400MHz, MeOD) δ 7.45 (d, J=8.3Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (dd, J= 9.4,6.5Hz, 1H), 7.27 (d, J=8.6Hz, 1H), 6.74 (d, J=2.6Hz, 1H), 6.72-6.66 (m, 2H), 6.60 (dd, J=8.3,2.1Hz, 1H), 4.80 (s, 2H), 4.31 (t, J=7.9Hz, 2H), 4.22-4.08 (m, 1H), 3.90-3.80 (m, 2H), 2.23 (tt, J=7.4,6.0Hz, 1H), 1.64-1.48 (m, 2H), 1.15-1.05 (m, 2H).

The 2- of embodiment 30 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) benzo [d] thiazole -6- carboxylic acids (30)

The first step：Compound I-13 (44mg, 0.08mmol) is dissolved in dry CH₂Cl₂(2mL), ice-water bath cooling is lower to be added TFA (0.5mL), 0 DEG C is reacted 30 minutes.Reaction is complete, concentration, drains.Crude product 30-a is directly used in the next step.

LC-MS：t_R=2.509min；[M+H]⁺=449.0,451.0.

Second step：Compound 30-a and I-9 (22mg, 0.08mmol) are dissolved in dry DMA (2mL), then Add Cs₂CO₃(65mg, 0.20mmol), heats 50 DEG C and reacts 1 hour.LC-MS is monitored, and reaction is complete.EtOAc dilutions are added, The saturation NaCl aqueous solution is washed, anhydrous Na₂SO₄Dry.Filtering, concentration, crude product is through column chromatography for separation (PE/EA=3:1), obtain Compound 30-b (47.6mg, 93%).

LC-MS：t_R=3.609min；[M+H]⁺=640.0,642.0.

3rd step：Compound 30-b (45mg, 0.07mmol) is dissolved in THF/MeOH (4/2mL), add the KOH aqueous solution (3N, 1mL), 70 DEG C are heated to react 1 hour.Reaction is complete, is cooled to room temperature, and watery hydrochloric acid is added dropwise and neutralizes.EtOAc is extracted, saturation NaCl The aqueous solution is washed, anhydrous Na₂SO₄Dry.Filtering, concentration, crude product separates (PE/EA=1 through PTLC:1) product 30, is obtained (28mg, 64%).

LC-MS：t_R=3.248min；[M+H]⁺=625.9,628.0；

¹H NMR (400MHz, DMSO) δ 8.40 (d, J=1.7Hz, 1H), 7.87 (dd, J=8.5,1.8Hz, 1H), 7.66-7.61 (m, 2H), 7.58-7.45 (m, 3H), 6.96 (d, J=2.6Hz, 1H), 6.82 (dd, J=8.6,2.6Hz, 1H), 4.92 (s, 2H), 4.56 (t, J=8.3Hz, 2H), 4.43-4.28 (m, 1H), 4.28-4.15 (m, 2H), 2.49-2.40 (m, 1H),1.22–1.06(m,4H)。

The 2- of embodiment 31 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -4- fluorobenzene simultaneously [d] thiazole -6- carboxylic acids (31)

Compound 31-a synthesis is with reference to the first step of embodiment 30 to second step.

Compound 31-a：LC-MS:t_R=3.653min；[M+H]⁺=658.0,660.0.

Compound 31-a (50mg, 0.076mmol) is dissolved in THF/MeOH (4/2mL), adds the KOH aqueous solution (3N, 1mL), 70 DEG C of heating is reacted 1 hour.Reaction is complete, is cooled to room temperature, and watery hydrochloric acid is added dropwise and neutralizes.EtOAc is extracted, the saturation NaCl aqueous solution Washing, anhydrous Na₂SO₄Dry.Filtering, concentration, crude product separates (PE/EA=1 through PTLC:1), obtain product 31 (34mg, 69%).

LC-MS:t_R=3.309min；[M+H]⁺=644.0,645.8；

¹H NMR(400MHz,DMSO)δ13.02(s,1H),8.27(s,1H),7.70–7.40(m,4H),6.96(s, 1H), 6.82 (d, J=7.8Hz, 1H), 4.93 (s, 2H), 4.59 (t, J=7.4Hz, 2H), 4.34 (m, 1H), 4.31-4.17 (m,2H),1.35–1.05(m,4H)；

¹⁹F NMR(376MHz,DMSO)δ-126.26。

The 2- of embodiment 32 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -4- methoxyl groups benzo [d] thiazole -6- carboxylic acids (32)

Compound 32-a synthesis is with reference to the first step of embodiment 30 to second step.

LC-MS:t_R=3.589min, [M+H]⁺=670.0.

Compound 32-a (25mg, 0.037mmol) is dissolved in the addition 3M KOH aqueous solution in MeOH/THF (2/4ml) solution (1ml), heats 75 DEG C of stirring 1h.Reaction solution is cooled down, pH=6 is acidified to 2N HCl, is then extracted with ethyl acetate, organic layer Dry, concentration, silica gel column chromatography separation obtains compound 32 (15mg, yield：60%).

LC-MS:t_R=3.243min, [M+H]⁺=655.9；

¹H NMR(400MHz,CDCl₃) δ 8.06 (d, J=1.1Hz, 1H), 7.56 (s, 1H), 7.44-7.35 (m, 2H), 7.32 (dd, J=9.0,7.0Hz, 1H), 7.24 (s, 1H), 6.84 (d, J=2.5Hz, 1H), 6.73 (dd, J=8.6,2.4Hz, 1H), 4.80 (s, 2H), 4.66 (t, J=8.1Hz, 2H), 4.34 (ddd, J=24.8,14.4,6.9Hz, 3H), 4.05 (s, 3H), 2.15 (ddd, J=13.5,8.4,5.1Hz, 1H), 1.29 (dt, J=6.5,4.6Hz, 2H), 1.15 (td, J=7.0, 4.4Hz,2H)。

The 2- of embodiment 33 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) benzo [d] thiazole -6- carboxylic acids (33)

Compound 33-a synthesis is with reference to the first step of embodiment 30 to second step.

LC-MS:t_R=3.617min, [M+H]⁺=656.0；

¹H NMR(400MHz,CDCl₃) δ 8.32 (d, J=1.6Hz, 1H), 8.03 (d, J=8.5Hz, 1H), 7.64 (d, J =8.5Hz, 1H), 7.57-7.48 (m, 2H), 7.38 (t, J=7.6Hz, 2H), 7.28 (d, J=12.2Hz, 1H), 6.85 (d, J =2.5Hz, 1H), 6.75 (dd, J=8.5,2.3Hz, 1H), 4.86 (s, 2H), 4.69 (s, 2H), 4.48-4.25 (m, 3H), 3.92 (s, 3H), 2.18-2.09 (m, 1H), 1.25 (tt, J=6.5,3.2Hz, 4H), 1.13 (dt, J=7.6,4.5Hz, 2H)；

¹⁹F NMR(376MHz,CDCl3)δ-57.36。

Compound 33-a (53mg, 0.081mmol) is dissolved in THF/MeOH (4/2mL), adds the KOH aqueous solution (3N, 1mL), 70 DEG C of heating is reacted 1 hour.Reaction is complete, is cooled to room temperature, and watery hydrochloric acid is added dropwise and neutralizes.EtOAc is extracted, the saturation NaCl aqueous solution Washing, anhydrous Na₂SO₄Dry.Filtering, concentration, crude product separates (PE/EA=1 through PTLC:2), obtain product 33 (15mg, 29%).

LC-MS:t_R=3.275min；[M+H]⁺=642.0；

¹H NMR (400MHz, DMSO) δ 12.69 (s, 1H), 8.40 (s, 1H), 7.87 (d, J=8.0Hz, 1H), 7.71- 7.45 (m, 6H), 7.02 (s, 1H), 6.87 (d, J=8.1Hz, 1H), 4.96 (s, 2H), 4.57 (t, J=8.1Hz, 2H), 4.41-4.28 (m, 1H), 4.22 (t, J=7.1Hz, 2H), 2.42 (m, 1H), 1.19-1.01 (m, 4H)；

¹⁹F NMR(376MHz,DMSO)δ-56.37。

The 2- of embodiment 34 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -4- fluorobenzene simultaneously [d] thiazole -6- carboxylic acids (34)

Compound 34-a synthesis is with reference to the first step of embodiment 30 to second step.

LC-MS:t_R=3.659min, [M+H]⁺=674.0.

Compound 34-a (46mg, 0.068mmol) is dissolved in THF/MeOH (4/2mL), adds the KOH aqueous solution (3N, 1mL), 70 DEG C of heating is reacted 1 hour.Reaction is complete, is cooled to room temperature, and watery hydrochloric acid is added dropwise and neutralizes.EtOAc is extracted, the saturation NaCl aqueous solution Washing, anhydrous Na₂SO₄Dry.Filtering, concentration, crude product separates (PE/EA=1 through PTLC:2), obtain product 34 (28mg, 62%).

LC-MS:t_R=3.335min；[M+H]⁺=660.0；

¹H NMR (400MHz, DMSO) δ 12.98 (s, 1H), 8.27 (d, J=1.4Hz, 1H), 7.74-7.58 (m, 3H), 7.58-7.47 (m, 3H), 7.02 (d, J=2.5Hz, 1H), 6.87 (dd, J=8.7,2.5Hz, 1H), 4.96 (s, 2H), 4.60 (t, J=8.3Hz, 2H), 4.35 (dt, J=14.8,7.4Hz, 1H), 4.30-4.22 (m, 2H), 2.45-2.37 (m, 1H), 1.19–1.07(m,4H)；

¹⁹F NMR(376MHz,DMSO)δ-56.36,-126.29。

The 2- of embodiment 35 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -4- methoxyl groups benzo [d] thiazole -6- carboxylic acids (35)

Compound 35-a synthesis is with reference to the first step of embodiment 30 to second step.

LC-MS:t_R=3.598min, [M+H]⁺=686.0.

¹H NMR(400MHz,CDCl₃) δ 7.91 (d, J=1.3Hz, 1H), 7.51-7.41 (m, 3H), 7.31 (t, J= 7.6Hz, 2H), 7.21 (s, 1H), 6.77 (d, J=2.5Hz, 1H), 6.66 (dd, J=8.6,2.5Hz, 1H), 4.78 (s, 2H), 4.59 (t, J=8.0Hz, 2H), 4.34-4.18 (m, 3H), 3.97 (s, 3H), 3.85 (s, 3H), 2.06 (ddd, J=13.5, 8.4,5.1Hz, 1H), 1.22-1.16 (m, 2H), 1.06 (dt, J=7.6,4.5Hz, 2H).

Compound 35-a (45mg, 0.066mmol) is dissolved in the addition 3M KOH aqueous solution in MeOH/THF (2/4ml) solution (1ml), heats 75 DEG C of stirring 1h.Reaction solution is cooled down, pH=6 is acidified to 2N HCl, is then extracted with ethyl acetate, organic layer Dry, concentration, silica gel column chromatography separation obtains compound 35 (14mg, yield：31%).

LC-MS:t_R=3.267min, [M+H]⁺=672.0；

¹H NMR(400MHz,CDCl₃) δ 8.06 (s, 1H), 7.61-7.46 (m, 3H), 7.38 (t, J=7.7Hz, 2H), 7.29 (s, 1H), 6.84 (s, 1H), 6.74 (d, J=7.5Hz, 1H), 4.86 (s, 2H), 4.68 (m, 2H), 4.44-4.25 (m, 3H),4.05(s,3H),2.13(m,1H),1.25(m,2H),1.13(m,2H)。

The 2- of embodiment 36 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (difluoro-methoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -4- fluorobenzene simultaneously [d] thiazole -6- carboxylic acids (36)

Compound 36-a synthesis is with reference to the first step of embodiment 30 to second step.

LC-MS:TR=3.53min, [M+H] +=656.0.

Compound 36-a (70mg, 0.11mmol) is dissolved in tetrahydrofuran (2mL), adds 1 milliliter of 1N NaOH aqueous solution, 50 DEG C of stirring 2h.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is separated through PTLC after concentration, must be changed Compound 36 (7mg, yield：10%).

LC-MS:t_R=3.18min, [M+H]⁺=642.0；

¹H NMR(400MHz,CDCl₃) δ 8.18 (s, 1H), 7.79 (d, J=10.8Hz, 1H), 7.49 (dd, J=14.5, 7.5Hz, 2H), 7.37-7.27 (m, 3H), 6.86 (s, 1H), 6.76 (d, J=8.6Hz, 1H), 6.44 (t, J=73.9Hz, 1H), 4.88 (s, 2H), 4.67 (t, J=7.9Hz, 2H), 4.46-4.18 (m, 3H), 2.13 (d, J=4.8Hz, 1H), 1.28 (m,2H),1.13(m,2H)；

¹⁹F NMR (376MHz, CDCl3) δ -81.14, -125.23.

The 6- of embodiment 37 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -1- Methyl-1H-indole -3- carboxylic acids (37)

The first step：Weigh Compound I-12 (300mg, 1.12mmol) adds Isosorbide-5-Nitrae-dioxane in 100mL single port bottles Solution (15mL), sequentially adds compound 20-d (197mg, 1.0mmol), cesium carbonate (980mg, 3mmol), Pd afterwards₂(dba)₃ (137mg, 0.15mmol) and X-phos (143mg, 0.3mmol), displacement nitrogen three times.Heating reflux reaction is stayed overnight.Question response Filtered, and washed 3 times with EA by diatomite after cooling.Filtrate takes organic layer to be dried with sodium sulphate after extraction, concentration, post layer Analysis separates to obtain compound 37-a (160mg, yield 41.6%).

LC-MS:t_R=3.25min, [M+H]⁺=385.0.

Second step：Compound 37-a (160mg, 0.41mmol), which is dissolved at dichloromethane (5mL), -78 DEG C, is slowly added dropwise three Boron bromide (4N) solution, is warmed to room temperature stirring 20min after dripping off.Methanol is added to be quenched and stir 30min under ice-water bath, ethyl acetate Extraction, organic phase merging is washed once with saturated common salt, and sodium sulphate is dried.Filtering, is concentrated to give compound 37-b (110mg, production Rate：71%).

LC-MS:t_R=2.79min, [M+H]⁺=371.0.

3rd step：Compound 37-b (110mg, 0.3mmol) and I-2 (100mg, 0.33mmol) are dissolved in dry DMF (3mL), adds K₂CO₃(83mg, 0.6mmol), 50 DEG C of stirring reactions are stayed overnight.Concentrated after reaction completely, PTLC separation must be changed Compound 37-c (100mg, 53%).

LC-MS：t_R=3.60min, [M+H]⁺=636.0.

4th step：Compound 37-c (100mg, 0.16mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL), adds 1N NaOH (1mL) aqueous solution, back flow reaction is stayed overnight.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is passed through after concentration PTLC is separated, and obtains compound 37 (44mg, yield：45%).

LC-MS:t_R=3.29min, [M+H]⁺=622.0；

¹H NMR(400MHz,DMSO)δ11.79(s,1H),7.80(m,2H),7.66–7.57(m,2H),7.53(dd,J =9.1,7.0Hz, 1H), 7.39 (d, J=8.6Hz, 1H), 6.94 (d, J=2.5Hz, 1H), 6.79 (dd, J=8.7,2.5Hz, 1H), 6.57-6.38 (m, 2H), 4.91 (s, 2H), 4.29 (t, J=7.5Hz, 2H), 4.21-4.07 (m, 1H), 3.83-3.66 (m, 5H), 2.45 (td, J=8.3,4.2Hz, 1H), 1.22-1.06 (m, 4H).

The 6- of embodiment 38 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -1- cyclopropyl -1H- indole -3-carboxylic acids (38)

The first step：Dichloroethanes (30mL) is placed in 250mL three-necked flasks, addition compound I-12-c (760mg, 3.0mmol), cyclopropylboronic acid (516mg, 6.0mmol) and sodium carbonate (640mg, 6.0mmol).By copper acetate (600mg, Dichloroethanes (15mL) solution 3.0mmol) is placed in 2,2- bipyridyls (470mg, 3.0mmol), is heated to being in suspension, by this Hanging drop is added in above-mentioned reaction solution, 70 DEG C of open stirring 5h.Reaction is complete, cooling, plus appropriate watery hydrochloric acid, dichloromethane extraction Take, dry, concentration, column chromatography for separation obtains compound 38-a (450mg, yield：51.2%).

LC-MS:t_R=3.11min.

Second step：Weigh Compound 38-a (450mg, 1.5mmol) adds Isosorbide-5-Nitrae-dioxane in 100mL single port bottles Solution (15mL), sequentially adds 20-d (300mg, 1.5mmol), cesium carbonate (1476mg, 4.5mmol), Pd afterwards₂(dba)₃ (140mg, 0.15mmol) and X-phos (143mg, 0.3mmol), displacement nitrogen three times, heating reflux reaction is stayed overnight.Question response Filtered, and washed 3 times with EA by diatomite after cooling.Filtrate is extracted, and sodium sulphate is dried, and is filtered, and concentration, column chromatography for separation is obtained Compound 38-b (276mg, yield 44.5%).

LC-MS:t_R=3.44min, [M+H]⁺=411.1.

3rd step：Compound 38-b (100mg, 0.24mmol), which is dissolved at dichloromethane (5mL), -78 DEG C, is slowly added dropwise three Bromination B solution (4N, 0.24mL), drips off and is warmed to room temperature stirring 20min.Add methanol to be quenched under ice-water bath, stir 30min, acetic acid Ethyl ester is extracted, and organic phase merging is washed once with saturated common salt, and sodium sulphate is dried.Filtering, be concentrated to give compound 38-c (50mg, Yield：52%).

LC-MS:t_R=2.99min, [M+H]⁺=397.1.

4th step：Compound 38-c (50mg, 0.12mmol) and I-2 (40mg, 0.13mmol) are dissolved in dry DMF (3mL), Add K₂CO₃(50mg, 0.36mmol), 50 DEG C of stirring reactions are stayed overnight.Concentrated after reaction completely, PTLC separation obtains compound 38-d (50mg, 60%).

LC-MS:t_R=3.72min, [M+H]⁺=662.0.

5th step：Compound 38-d (50mg, 0.075mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL), adds 1N NaOH (1mL) aqueous solution, flow back 48h.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is through PTLC after concentration Separation, obtains compound 38 (10mg, yield：20%).

LC-MS:t_R=3.42min, [M+H]⁺=648.0；

¹H NMR (400MHz, MeOD) δ 8.48 (s, 1H), 7.96 (d, J=8.6Hz, 1H), 7.39 (ddd, J=15.9, 10.7,8.2Hz, 3H), 7.28 (d, J=8.6Hz, 1H), 6.75 (d, J=2.5Hz, 1H), 6.69 (dd, J=8.6,2.6Hz, 1H), 6.59 (d, J=1.8Hz, 1H), 6.46 (dd, J=8.5,2.0Hz, 1H), 4.82 (s, 2H), 4.28 (t, J=7.3Hz, 2H), 4.14 (t, J=7.3Hz, 1H), 3.74 (t, J=6.9Hz, 2H), 2.29-2.20 (m, 1H), 1.76-1.70 (m, 1H), 1.25–1.21(m,2H),1.13–1.11(m,2H),1.01–0.99(m,2H),0.89–0.87(m,2H)。

The 5- of embodiment 39 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) -1- Methyl-1H-indole -3- carboxylic acids (39)

The first step：Compound 39-a (0.46g, 1.8mmol) is dissolved in acetonitrile (20mL), add potassium carbonate (0.75g, 5.4mmol) and MeI (0.4mL, 6.3mmol), in stirring 3h at 50 DEG C.Diluted after the cooling of question response liquid with water (20mL), acetic acid Merge organic phase after ethyl ester extraction.Organic phase after merging is washed once with saturated common salt, and sodium sulphate is dried.Filtering, concentration, post Chromatography (PE/EA:5~15%), obtain compound 39-b (0.4g, yield：83%).

LC-MS:t_R=2.83min.

Second step：Weigh Compound 39-b (200mg, 0.75mmol) adds Isosorbide-5-Nitrae-dioxane in 100mL single port bottles Solution (15mL), sequentially adds 20-d (150mg, 0.75mmol), cesium carbonate (740mg, 2.25mmol), Pd afterwards₂(dba)₃ (70mg, 0.075mmol) and X-phos (70mg, 0.15mmol), displacement nitrogen three times.It is heated to reflux, reaction is stayed overnight.Question response Filtered, and washed 3 times with EA by diatomite after cooling.Filtrate takes organic layer to be dried with sodium sulphate after extraction, concentration, post layer Analysis separates to obtain compound 39-c (55mg, yield 20%).

LC-MS:t_R=3.24min, [M+H]⁺=385.0.

3rd step：Compound 39-c (55mg, 0.14mmol), which is dissolved at dichloromethane (5mL), -78 DEG C, is slowly added dropwise tribromo Change boron (4N) solution, stirring 20min is warmed to room temperature after dripping off.Add methanol to be quenched under ice-water bath, stir 30min, ethyl acetate extraction Take, organic phase merging is washed once with saturated common salt, sodium sulphate is dried.Filtering, is concentrated to give compound 39-d (45mg, yield： 85%).

LC-MS:t_R=2.65min, [M+H]⁺=371.0.

4th step：Compound 39-d (45mg, 0.12mmol) and I-2 (40mg, 0.13mmol) are dissolved in dry DMF (3mL), Add K₂CO₃(50mg, 0.36mmol), 50 DEG C of stirring reactions are stayed overnight.Concentrated after reaction completely, PTLC separation obtains compound 39-e (60mg, 78%).

LC-MS:t_R=3.55min, [M+H]⁺=636.0.

5th step：Compound 39-e (60mg, 0.094mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL), adds 1N NaOH (1mL) aqueous solution, back flow reaction is stayed overnight.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is passed through after concentration PTLC is separated, and obtains compound 39 (12mg, yield：20%).

LC-MS:t_R=3.29min, [M+H]⁺=622.0；

¹H NMR(400MHz,CDCl₃)δ7.78(s,1H),7.46–7.12(m,6H),6.82(s,1H),6.65(m,2H), 4.78(s,2H),4.40(m,2H),4.25(m,1H),3.83(m,5H),2.14(m,1H),1.27(m,2H),1.14(m,2H)。

The 7- of embodiment 40 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) quinoline-3-carboxylic acid (40)

The first step：Compound I-13 (70mg, 0.13mmol) is dissolved in DCM (3ml), and ice-water bath cooling is lower to be added dropwise TFA (1mL), maintains low-temp reaction 1h.Solution concentration removes solvent and obtains compound 30-a, is directly used in the next step.

Second step：Compound I-14 (45mg, 0.17mmol), Pd are added into above-mentioned crude product₂(dba)₃(17mg, 0.02mmol) with X-Phos (18mg, 0.04mmol), toluene (6mL) is dissolved in.Substitute gas, nitrogen protection.It is heated to 100 DEG C instead Answer 6h.Reaction solution is cooled down, and is extracted with ethyl acetate/water, organic layer dries silica gel chromatography after concentration and obtains compound 40- A (59mg, yield：71%).

LC-MS:t_R=3.337min, [M+H]⁺=648.1.

3rd step：Compound 40-a (59mg, 0.09mmol) is dissolved in MeOH/THF (2/4mL), adds the 3M KOH aqueous solution (1mL), heats 75 DEG C of stirring 1h.Reaction solution is cooled down, pH=6 is acidified to 2N HCl, is then extracted, had with ethyl acetate/water Machine layer is dried, concentration, silica gel column chromatography separation, obtains compound 40 (20mg, yield：33%).

LC-MS:t_R=2.837min, [M+H]⁺=620.0；

¹H NMR(400MHz,CDCl₃) δ 9.41 (s, 1H), 8.80 (s, 1H), 7.74 (d, J=8.0Hz, 1H), 7.44- 7.27 (m, 4H), 7.01 (d, J=14.1Hz, 1H), 6.95-6.66 (m, 3H), 4.79 (s, 2H), 4.52 (s, 2H), 4.31 (s, 1H), 4.08 (s, 2H), 2.19-2.11 (m, 1H), 1.26 (d, J=4.6Hz, 2H), 1.14 (d, J=5.7Hz, 2H).

The 7- of embodiment 41 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) quinoline-3-carboxylic acid (41)

Compound 41-a is prepared with reference to the first step of embodiment 40 to second step.

LC-MS:t_R=3.372min, [M+H]⁺=664.0.

Compound 41-a (40mg, 0.06mmol) is dissolved in MeOH/THF (2/4mL), adds the 3M KOH aqueous solution (1mL), 75 DEG C of stirring 1h of heating.Reaction solution is cooled down, pH=6 is acidified to 2N HCl, is then extracted with ethyl acetate/water, organic layer is done It is dry, filter, concentration, silica gel column chromatography separation obtains compound 41 (30mg, yield：75%).

LC-MS:t_R=2.859min, [M+H]⁺=636.1；

¹H NMR(400MHz,CDCl₃) δ 9.42 (s, 1H), 8.79 (s, 1H), 7.69 (s, 1H), 7.49 (dd, J=19.9, 7.6Hz, 2H), 7.33 (dd, J=17.6,9.9Hz, 3H), 6.98 (s, 1H), 6.85-6.65 (m, 3H), 4.82 (s, 2H), 4.46(s,2H),4.27(s,1H),4.04(s,2H),2.15–2.07(m,1H),1.26-1.21(m,2H),1.12-1.07(m, 2H)。

The 5- of embodiment 42 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -1- Methyl-1H-indole -3- carboxylic acids (42)

Compound 42-a is prepared with reference to the first step of embodiment 40 to second step.

LC-MS:t_R=3.56min, [M+H]⁺=652.2.

Compound 42-a (40mg, 0.06mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL), adds 1N NaOH (1mL) water-soluble Liquid, 100 DEG C of stirring 48h.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is separated through PTLC after concentration, Obtain compound 42 (10mg, yield：25%).

LC-MS:t_R=3.29min, [M+H]⁺=638.0；

¹H NMR(400MHz,CDCl₃) δ 7.79 (s, 1H), 7.51 (dd, J=17.4,7.7Hz, 2H), 7.40-7.26 (m, 4H), 7.28-7.14 (m, 1H), 6.82 (d, J=2.3Hz, 1H), 6.79-6.49 (m, 2H), 4.84 (s, 2H), 4.42 (t, J= 7.3Hz, 2H), 4.32-4.18 (m, 1H), 3.89 (t, J=6.6Hz, 2H), 2.12 (td, J=8.3,4.2Hz, 1H), 1.24 (m,2H),1.13–1.02(m,2H)；

¹⁹F NMR(376MHz,CDCl3)δ-57.34。

The 3- of embodiment 43 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -5- fluobenzoic acids (43)

Compound 43-a is prepared with reference to the first step of embodiment 40 to second step.

LC-MS:t_R=3.73min, [M+H]⁺=617.0.

Compound 43-a (40mg, 0.06mmol) is dissolved in tetrahydrofuran (2mL), adds 1N NaOH (1mL) aqueous solution, 50 DEG C of stirring 2h.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is separated through PTLC after concentration, must be changed Compound 43 (18mg, yield：46%).

LC-MS:t_R=3.42min, [M+H]⁺=603.0；

¹H NMR(400MHz,CDCl₃) δ 7.58-7.46 (m, 2H), 7.38 (t, J=7.5Hz, 2H), 7.29 (s, 1H), 7.14 (d, J=8.8Hz, 1H), 6.98 (s, 1H), 6.83 (d, J=2.5Hz, 1H), 6.72 (dd, J=8.6,2.5Hz, 1H), 6.39 (d, J=10.3Hz, 1H), 4.85 (s, 2H), 4.37 (t, J=7.5Hz, 2H), 4.28 (d, J=7.7Hz, 1H), 3.89 (t, J=6.6Hz, 2H), 2.13 (dd, J=9.2,4.1Hz, 1H), 1.29-1.23 (m, 2H), 1.13 (m, 2H)；

¹⁹F NMR(376MHz,CDCl3)δ-57.35,-111.75。

The 3- of embodiment 44 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (difluoro-methoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) -5- fluobenzoic acids (44)

Compound 44-a is prepared with reference to the first step of embodiment 40 to second step.

LC-MS:t_R=3.60min, [M+H]⁺=599.0；

¹H NMR(400MHz,CDCl₃) δ 7.42 (dd, J=14.5,7.6Hz, 2H), 7.28-7.09 (m, 4H), 7.05 (s, 1H), 6.76 (s, 1H), 6.66 (s, 1H), 6.51 (d, J=8.5Hz, 1H), 6.31 (t, J=73.6Hz, 1H), 4.40 (m, 2H),4.27(m,1H),3.92(m,2H),3.83(s,3H),2.11–1.98(m,1H),1.20–1.12(m,2H),1.07– 0.99(m,2H)；

¹⁹F NMR(376MHz,CDCl3)δ-81.15,-110.83。

Compound 44-a (56mg, 0.09mmol) is dissolved in tetrahydrofuran (2mL), adds 1N NaOH (1mL) aqueous solution, 50 DEG C of stirring 2h.Add watery hydrochloric acid after reaction completely to neutralize, ethyl acetate extraction.Crude product is separated through PTLC after concentration, must be changed Compound 44 (14mg, yield：26%).

LC-MS:t_R=3.29min, [M+H]⁺=585.0；

¹H NMR(400MHz,CDCl₃) δ 7.49 (td, J=9.4,1.7Hz, 2H), 7.35-7.23 (m, 3H), 7.14 (d, J =8.4Hz, 1H), 6.98 (s, 1H), 6.84 (d, J=2.5Hz, 1H), 6.73 (dd, J=8.6,2.6Hz, 1H), 6.43 (t, J =74Hz, 1H), 6.40 (dd, J=10.4,2.2Hz, 1H), 4.87 (s, 2H), 4.37 (t, J=7.6Hz, 2H), 4.32-4.18 (m, 1H), 3.89 (t, J=6.7Hz, 2H), 1.27-1.21 (m, 2H), 1.12 (dt, J=7.6,4.4Hz, 2H)；

¹⁹F NMR(376MHz,CDCl3)δ-81.15,-111.72。

The 5- of embodiment 45 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) benzo [d] isothiazole -3- carboxylic acids (45)

The first step：Compound 45-a (50mg, 0.088mmol) is dissolved in dichloromethane (2mL), trifluoro is added under ice bath Acetic acid (1mL), reaction is stirred 1 hour under ice bath, and LCMS display reactions are complete, and reaction solution concentration obtains compound 45-b (40mg) is directly used in subsequent reactions.

Second step：Compound 45-c (5.0g, 26.4mmol) is dissolved in anhydrous methylene chloride (30mL), added at room temperature Oxalyl chloride (11.0g, 79.34mmol).Reaction is stirred at room temperature 16 hours.Reaction solution is spin-dried for, and obtains compound 45-d.Should Solid is dissolved in carbon disulfide (10mL), and aluminum trichloride (anhydrous) (10.0g, 79.34mmol) is slowly added portionwise at room temperature.With Alchlor is added, and reaction solution is in peony, and reaction is stirred at room temperature 16 hours.Afterwards, reaction solution is quenched to frozen water (about In 50g), organic phase is washed with saturated sodium bicarbonate (3X 20mL), is dried, and is filtered, concentration.Obtain crude Compound 45-e (3.0g).Product is directly used in next step, without being further purified.

3rd step：45-e (3.0g) is dissolved in methanol (20mL), ammoniacal liquor (25~28%, 10mL) is added.Reaction solution becomes Faint yellow, reaction is stirred at room temperature 16 hours, afterwards, adds H₂O₂(30%, 3mL), reaction solution turns white suspension immediately, Reaction continues to stir 2 hours at room temperature.Filtering, filter cake, which is washed with water, obtains crude white solid 45-f (2.0g).Product is direct For next step, without being further purified.

4th step：Crude product 45-f (2.0g, 7.78mmol) is dissolved in methanol (20mL) and H₂In O (20mL), hydrogen-oxygen is added Change sodium (1.5g, 39.0mmol).Reaction is heated to backflow, is kept for 3 hours.LCMS display reactions are complete, will be reacted with 6N hydrochloric acid Liquid adjusts pH=5~6.Filtering, after filter cake is washed with water, is dissolved in methanol (20mL), and the concentrated sulfuric acid (0.5mL) is added dropwise.Reaction heating To flowing back, kept for 3 hours.LCMS display reactions are complete, and reaction solution is adjusted into pH=6~7 with saturated sodium carbonate solution.Will reaction Liquid is concentrated.Residue obtains product 45-g (150mg, 10%) by the purifying of Flash silica post.

5th step：By compound 45-b (40mg, 0.088mmol), 45-g (48mg, 0.18mmol), Pd₂(dba)₃ (10mg), X-phos (20mg) and cesium carbonate (150mg, 0.44mmol) are dissolved in dioxane (10mL), and reaction is protected in nitrogen 110 DEG C are heated under shield and is kept for 5 hours, LCMS display reactions are complete and have partial hydrolysate, and reaction solution is directly spin-dried for, Add methanol (10mL), H₂O (10mL) and sodium hydroxide (40mg, 1.0mmol).Reaction is stirred at room temperature 3 hours, and LCMS shows Show that reaction is complete, reaction solution is adjusted into pH=5~6 with 6N hydrochloric acid.Reacting liquid filtering, filtrate is extracted with dichloromethane (3X 5mL) Take, merge organic phase, dry, filter, concentration.Residue obtains compound 45 (20.2mg, 35%) with thick preparative separation.

¹H NMR (400MHz, DMSO) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.72-7.62 (m, 1H), 7.59 (d, J= 7.5Hz, 1H), 7.56-7.50 (m, 2H), 7.50-7.43 (m, 1H), 6.99 (s, 2H), 6.84 (d, J=8.2Hz, 1H), 4.94 (s,2H),4.35(s,2H),4.18(s,1H),3.86(s,2H),2.06–1.95(m,1H),1.19–1.05(m,4H)；

LC-MS:m/z 642.1。

The 5- of embodiment 46 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) benzo [d] isothiazole -3- carboxylic acids (46)

By compound 30-a (40mg, 0.09mmol), 45-g (48mg, 0.18mmol), Pd₂(dba)₃(10mg)、X-phos (20mg) and cesium carbonate (150mg, 0.44mmol) are dissolved in dioxane (10mL), and reaction is heated to 110 under nitrogen protection DEG C and keep 5 hours, LCMS display reaction completely and have partial hydrolysate, reaction solution is directly spin-dried for, add methanol (10mL)、H₂O (10mL) and sodium hydroxide (40mg, 1.0mmol).Reaction is stirred at room temperature 3 hours, and LCMS displays have been reacted Entirely, reaction solution is adjusted into pH=5~6 with 6N hydrochloric acid.Reacting liquid filtering, filtrate is extracted with dichloromethane (3X 5mL), is associated with Machine phase, is dried, and is filtered, concentration.Residue obtains compound 46 (30.0mg, 52%) with thick preparative separation.

¹H NMR (400MHz, DMSO) δ 7.99 (s, 1H), 7.83 (s, 1H), 7.61 (d, J=7.7Hz, 2H), 7.55- 7.48 (m, 1H), 7.43 (d, J=8.1Hz, 1H), 6.94 (s, 2H), 6.79 (d, J=7.7Hz, 1H), 4.91 (s, 2H), 4.34 (s, 2H), 4.16 (s, 1H), 3.84 (s, 2H), 2.04-1.92 (m, 1H), 1.15 (dd, J=21.1,5.4Hz, 4H)；

LC-MS:m/z 625.9。

The 3- of embodiment 47 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isothiazole -4- bases) methoxies Base) phenyl) azetidine -1- bases) -5- fluobenzoic acids (47)

The first step：Sodium hydroxide (273mg, 6.825mmol) is dissolved in water (5ml), is cooled to 0 DEG C, adds hydroxylamine hydrochloride Water (5ml) solution of (459mg, 6.605mmol), stirs 10min.Compound 47-a (1.0g, 5.743mmol) ethanol is added dropwise (5ml) solution, stirs 1h.Added water (20ml), and ethyl acetate is extracted, and is dried, and is concentrated to dryness to obtain compound 47-b (1.022g, receipts Rate 94.1%).

Second step：Compound 47-b (1.022g, 5.403mmol) is dissolved in DMF (15ml), in batches plus NCS (808mg, 6.051mmol), 1h is stirred.Add water, ethyl acetate is extracted, dry, be concentrated to dryness to obtain compound 47-c (1.907g).

3rd step：Potassium carbonate (815mg, 5.897mmol) and THF (10ml) are cooled to -10 DEG C, add 3- cyclopropyl -3- oxygen For ethyl propionate (895mg, 5.731mmol)/THF (5ml), 30min is stirred.47-c (1.907g)/THF (5ml) solution is added dropwise, 1h is stirred at room temperature.Triethylamine (5ml) is added, is stirred overnight.Add water, ethyl acetate is extracted, salt washing is dried, is concentrated to dryness Compound 47-d (1.722g, two step yields 98.0%).

4th step：Lithium Aluminium Hydride (600mg) is added in dry THF (10ml), and -10 DEG C, drop are cooled under nitrogen protection Plus 47-d (1.722g)/THF (10ml) solution, drop, which finishes, stirs 30min.Ethyl acetate (3ml) and water (0.6ml) are added, is added dropwise 15% sodium hydroxide (1.8ml) solution.10min is stirred, filtering, ethyl acetate is washed.Filtrate is washed with salt, is dried, being concentrated to give Compound 47-e (1.218g, yield 81.2%).

5th step：47-e (1.218g, 4.300mmol) is dissolved in dichloromethane (10ml), thionyl chloride (2ml) is added dropwise, Drop finishes stirring 1h, is concentrated to dryness, column chromatography purifies to obtain compound 47-f (600mg, yield 46.3%).

6th step：By 47-f (200mg, 0.6629mmol), 47-g (170mg, 0.5991mmol), potassium carbonate (166mg, 1.201mmol) with the lower 50 DEG C of stirrings 1h of DMF (5ml) nitrogen protection, add water, ethyl acetate is extracted, dry, column chromatography is purified Compound 47-h (600mg).

7th step：By 47-h obtained in the previous step, 4M HCl/ methanol (8ml) stirs 1h, is concentrated to dryness and obtains at room temperature Compound 47-i (260mg, two step yields 89.4%).

8th step：By 47-i (180mg, 0.3709mmol), 47-j (130mg, 0.5578mmol), Pd₂(dba)₃(35mg, 0.0382mmol), X-Phos (36mg, 0.0756mmol), cesium carbonate (485mg, 1.4886mmol) and toluene (20ml) mixing, 100 DEG C, in stirred under nitrogen atmosphere 6h, are cooled to room temperature, and filtering, toluene is washed, and filtrate column chromatography purifies to obtain compound 47-k.

9th step：47-k, 5N sodium hydroxide (2ml) solution, THF (3ml) and methanol (3ml) mixing that upper step is obtained, 3h is stirred in 60 DEG C, cooling is added water and dichloromethane, and 2N salt acid for adjusting pH 5~6, point liquid, dichloromethane is extracted, and is dried, pure Change obtains compound 47 (137mg, two step yields 62.9%).

¹H NMR(400MHz,CDCl₃) δ 7.77 (d, J=7.4Hz, 1H), 7.57 (p, J=7.1Hz, 2H), 7.43 (d, J =6.6Hz, 1H), 7.30-7.16 (m, 1H), 7.10 (d, J=8.0Hz, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.71 (d, J=7.2Hz, 1H), 6.32 (d, J=9.5Hz, 1H), 4.72 (s, 2H), 4.29 (d, J=6.2Hz, 2H), 4.21 (d, J= 6.6Hz, 1H), 3.82 (s, 2H), 2.11 (ddd, J=13.3,8.4,5.1Hz, 1H), 1.25 (d, J=2.0Hz, 2H), 1.13 (dt, J=7.1,4.4Hz, 2H)；

LC-MS:t_R=3.393min；587.0；588.1.

The 2- of embodiment 48 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isothiazole -4- bases) methoxies Base) phenyl) azetidine -1- bases) -4- fluorobenzene simultaneously [d] thiazole -6- carboxylic acids (48)

The first step：By 47-i (80mg, 0.165mmol), I-9 (53mg, 0.183mmol), cesium carbonate (160mg, 0.491mmol) mixed with DMA (5ml), in the lower 60 DEG C of stirrings 6h of nitrogen protection, add water, dichloromethane is extracted, dry, purify Compound 48-a (70mg, yield 64.5%).

Second step：By 48-a (70mg, 0.1064mmol), 5N sodium hydroxides (2ml) solution, THF (3ml) and methanol (3ml) is mixed, and is stirred 2h in 60 DEG C, is added water and dichloromethane, and 2N salt acid for adjusting pH 5~6, point liquid, dichloromethane is extracted, and is done It is dry, purify to obtain compound 48 (46mg, yield 67.1%).

¹H NMR(400MHz,CDCl₃)δ8.17(s,1H),7.80(s,2H),7.60(s,2H),7.45(s,1H),7.28 (s, 1H), 6.81 (d, J=35.2Hz, 2H), 4.70 (d, J=27.1Hz, 4H), 4.35 (d, J=34.2Hz, 3H), 2.12 (s, 1H), 1.02 (d, J=109.5Hz, 4H)；

LC-MS:t_R=3.278min；644.0；645.0.

The 6- of embodiment 49 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isothiazole -4- bases) first Epoxide) phenyl) azetidine -1- bases) benzo [d] isothiazole -3- carboxylic acids (49)

The first step：Compound 49-a (5.0g, 26.4mmol) is dissolved in anhydrous methylene chloride (30mL), added at room temperature Oxalyl chloride (11.0g, 79.34mmol).Reaction is stirred at room temperature 16 hours.Reaction solution is spin-dried for, and obtains compound 49-b.Should Solid is dissolved in carbon disulfide (10mL), and aluminum trichloride (anhydrous) (10.0g, 79.34mmol) is slowly added portionwise at room temperature.With Alchlor is added, and reaction solution is in peony, and reaction is stirred at room temperature 16 hours.Afterwards, reaction solution is quenched to frozen water (about In 50g), organic phase is washed with saturated sodium bicarbonate (3X20mL), is dried, and is filtered, concentration.Obtain crude Compound 49-c (3.0g).Product is directly used in next step, without being further purified.

Second step：Compound 49-c (3.0g) is dissolved in methanol (20mL), ammoniacal liquor (25~28%, 10mL) is added.Instead Answer liquid to become faint yellow, reaction was stirred at room temperature after 16 hours, add H₂O₂(30%, 3mL), it is outstanding that reaction solution becomes white immediately Turbid liquid, reaction continues to stir 2 hours at room temperature.Filtering, filter cake, which is washed with water, obtains crude product 49-d (2.0g).Product is directly used in Next step, without being further purified.

3rd step：Crude product 49-d (2.0g, 7.78mmol) is dissolved in methanol (20mL) and H₂In O (20mL), hydrogen-oxygen is added Change sodium (1.5g, 39.0mmol).Reaction is heated to backflow, is kept for 3 hours.LCMS display reactions are complete, will be reacted with 6N hydrochloric acid Liquid adjusts pH=5~6.Filtering, after filter cake is washed with water, is dissolved in methanol (20mL), and the concentrated sulfuric acid (0.5mL) is added dropwise.Reaction heating To flowing back, kept for 3 hours.LCMS display reactions are complete, and reaction solution is adjusted into pH=6~7 with saturated sodium carbonate solution.Will reaction Liquid is concentrated.Residue obtains product 49-e (150mg, 10%) by the purifying of Flash silica post.

4th step：By 45-b (40mg, 0.088mmol), 49-e (48mg, 0.18mmol), Pd₂(dba)₃(10mg)、X- Phos (20mg) and cesium carbonate (150mg, 0.44mmol) are dissolved in dioxane (10mL), and reaction is heated under nitrogen protection 110 DEG C and keep 5 hours, LCMS display reaction completely and have partial hydrolysate, reaction solution is directly spin-dried for, add methanol (10mL)、H₂O (10mL) and sodium hydroxide (40mg, 1.0mmol).Reaction is stirred at room temperature 3 hours, and LCMS displays have been reacted Entirely, reaction solution is adjusted into pH=5~6 with 6N hydrochloric acid.Reacting liquid filtering, filtrate is extracted with dichloromethane (3X 5mL), is associated with Machine phase, is dried, and is filtered, concentration.Residue obtains 49 (18.0mg, 25%) with thick preparative separation.

¹H NMR (400MHz, DMSO) δ 8.61 (s, 2H), 7.65 (s, 1H), 7.59 (d, J=7.2Hz, 1H), 7.50 (t, J=18.8Hz, 2H), 7.00 (s, 2H), 6.86 (s, 1H), 6.76 (s, 1H), 4.95 (s, 2H), 4.38 (s, 2H), 4.20 (s, 1H), 3.94 (s, 2H), 2.00 (d, J=8.4Hz, 1H), 1.12 (d, J=17.8Hz, 4H)；

LC-MS:m/z 642.0。

The 6- of embodiment 50 (3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -1- bases) benzo [d] isothiazole -3- carboxylic acids (50)

By 30-a (40mg, 0.088mmol), 49-e (48mg, 0.18mmol), Pd₂(dba)₃(10mg), X-phos (20mg) and cesium carbonate (150mg, 0.44mmol) are dissolved in dioxane (10mL), and reaction is heated to 110 under nitrogen protection DEG C and keep 5 hours, LCMS display reaction completely and have partial hydrolysate, reaction solution is directly spin-dried for, add methanol (10mL)、H₂O (10mL) and sodium hydroxide (40mg, 1.0mmol).Reaction is stirred at room temperature 3 hours, and LCMS displays have been reacted Entirely, reaction solution is adjusted into pH=5~6 with 6N hydrochloric acid.Reacting liquid filtering, filtrate is extracted with dichloromethane (3X 5mL), is associated with Machine phase, is dried, and is filtered, concentration.Residue obtains compound 50 (8.0mg, 12%) with thick preparative separation.

¹H NMR (400MHz, DMSO) δ 8.54 (s, 1H), 7.61 (d, J=7.8Hz, 2H), 7.55 (s, 1H), 7.43 (s, 1H),7.02(s,1H),6.95(s,1H),6.81(s,2H),4.91(s,2H),4.38(s,2H),4.18(s,1H),3.92(s, 2H), 2.00 (d, J=6.8Hz, 1H), 1.15 (d, J=23.6Hz, 4H)；

LC-MS:m/z 625.9。

The 6- of embodiment 51 (1- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyls) isothiazole -4- bases) methoxyl group) Phenyl) azetidine -3- bases) -1- Methyl-1H-indole -3- carboxylic acids (51)

The first step：Compound I-12 (1.1g, 4.1mmol), NaI (1.85g, 12.3mmol), CuI (78mg, 0.4mmol) It is mixed in DMEDA (72mg, 0.8mmol) in 1,4- dioxane (10mL).It is anti-in 150 DEG C of microwaves under mixture nitrogen atmosphere Answer 6 hours.Ethyl acetate dilutes after reaction solution cooling.Dilution is filtered, and filtrate concentration rear pillar chromatographic purifying obtains compound 51- a(1.15g)。

LC-MS:t_R=2.955min.

Second step：Compound 51-a (1.0g, 3.17mmol) is dissolved in dry THF (20mL), and stirs under nitrogen atmosphere, In dropwise addition i-PrMgCl.LiCl (1.3M, 3.1mL) at 0 DEG C.Continue to stir 1h at this temperature after adding.0 DEG C is added dropwise dissolved with change Dry THF (3mL) solution of the compound tert-butyl group -3- carbonyl azetidine -1- carboxylates (815mg, 4.76mmol).Reacted after adding 0 DEG C of liquid is stirred 30 minutes, is risen to stirring at normal temperature and is stayed overnight.Use saturation NH₄Cl (20mL) is quenched, and ethyl acetate is extracted afterwards.It is organic Layer, which is dried to mix sample after concentration and cross post, obtains product Compound 51-b (570mg, yield：50%).

LC-MS:t_R=2.575min, [M-Boc]⁺=261.1；

¹H NMR (400MHz, CDCl3) δ 8.17 (d, J=8.4Hz, 1H), 7.79 (s, 1H), 7.48 (d, J=1.1Hz, 1H), 7.39 (dd, J=8.4,1.6Hz, 1H), 4.36 (d, J=9.8Hz, 2H), 4.24 (d, J=9.3Hz, 2H), 3.91 (s, 3H),3.85(s,3H),1.48(s,9H)。

3rd step:At 0 DEG C, BFEE (4.4mL) be added dropwise to 10mL contain compound 51-b (500mg, 1.39mmol) and in the dichloromethane solution of triethyl group silicon hydrogen (2.2mL), add rear solution stirring at normal temperature and stay overnight.Solution water Once, organic phase is concentrated after being alkalized through ammoniacal liquor for extraction, and the anti-phase purifying of concentrate obtains crude product, and crude product is again through normal phase column chromatography Purifying obtains compound 51-c (260mg).

LC-MS:t_R=1.704min, [M+H]⁺=245.1

¹H NMR (400MHz, MeOD) 1.1Hz, 1H), 7.39 (dd, J=8.4,1.6Hz, 1H), 4.36 (d, J= 9.8Hz, 2H), 4., 6H) J=8.4,1.6Hz, 1H), 4.36 (d, J=9.8Hz, 2H), 4.24).

4th step:Compound 51-c (24mg, 0.10mmol) is placed in 10mL microwave tubes, is added and is dried Isosorbide-5-Nitrae-dioxane (2mL), sequentially adds compound 24-f (62mg, 0.13mmol), cesium carbonate (66mg, 0.20mmol), X-phos afterwards (14mg, 0.03mmol) and Pd₂(dba)₃(14mg,0.015mmol).Taken a breath 1 minute under blanket of nitrogen, then 100 DEG C of microwaves 2 are small When.Diatomite is filtered after question response cooling, and is washed 3 times with EA.Filtrate takes organic layer to be dried with sodium sulphate after extraction, concentration TLC purifying afterwards obtains compound 51-d (20mg, yield：31%).

LC-MS:t_R=3.599min, [M+H]⁺=636.1.

5th step：Compound 51-d (20mg, 0.03mmol) is dissolved in dioxane (2mL).NaOH is added into solution The aqueous solution (5.0M, 1mL) and methanol (1mL).Reaction solution was in return stirring 72 hours.After cooling Ph=is acidified to 3N hydrochloric acid 5, ethyl acetate is extracted 3 times, organic layer dry filter concentration, through TLC purified compounds 51 (7.0mg).

LC-MS:t_R=3.296min, [M+H]⁺=622.0；

¹H NMR (400MHz, MeOD) M+H] +=622.0,7.39 (dd, J=8.4,1.6Hz, 1H), 4.36 (d, J= 9.8Hz, 2H), 4., 6H), J=9.3Hz, 2H) and, 3.91 (s, 3H), 3.85 (s, 3H), 1.48 (s, 9H) 4 (s, 2H), 2.126 (d, J=4.6Hz, 2H), 1.14 (d, J1.22 2), 2.34-2.25 (m, 1H), 1.22-1.14 (m, 4H).

Biological assessment

Experimental example 1：FXR receptor-binding activities test (time-resolved fluorescence detection method TR-FRET methods)

For the influence that test compound is combined to FXR acceptors, inventor is surveyed from commercialized FXR receptor-binding activities Examination kit carrys out influence (LBD domains are combined with SRC1 the fragments) (reagent of test compound to FXR protein fragments in connection Box supplier lifetechnologyInvitrogenCatalog：PV4835；cisbioCatalog：610SAXLA and 61GSTKLA).Specific method is shown in kit specification.Operation is as follows：

1st, the anti-GST of the FXR-LBD/ Eu mixed liquors of 2xGST labels are prepared to required volume, GST-FXR-LBD concentration For 6nM, Eu is 50nl/ holes；

2nd, SRC1/ streptomysins-allophycocyanin (SA-APC) mixed liquor to required volume, SRC1 of 2x biotin labelings is prepared Concentration is 1000nM, and streptomysin-allophycocyanin is 50nl/ holes；

3rd, by two kinds of mixed liquors 1 of 2xGST-FXR/Eu and SRC1/SA-APC：1 mixing；

4th, 20 μ lGST-FXR/Eu and SRC1/SA-APC mixed liquors are added to 384 orifice plates containing testing compound；

5th, 1000rpm centrifuges 1min；It is incubated at room temperature 180min；

6th, time-resolved fluorescence is detected：EnVision plate reader read plates.

7th, interpretation of result：

(1) numerical value at numerical value divided by 615nm at 665nm；

(2) exciting rate is calculated

Exciting rate=(X-Min)/(Max-Min) * 100%

■ X represent 665/615 value of each concentration；

■ Min represent 665/615 value for not adding compound；

■ Max represent 665/615 value of reference compound.

Experiment of the biochemical activity of the compounds of this invention more than is measured, and measures EC₅₀Value see the table below.

Conclusion：Compound of the embodiment of the present invention has significantly agonism to FXR activity.

Experimental example 2：(test of FXR reporter gene expressions)

In order to analyze influence of the test compound to the FXR gene expressions regulated and controled, inventor utilizes the double of Promega companies Luciferase Assay System (Promega#E1980) is transiently transfecting the HepG2 liver cancer cells of FXRGal4 reporter gene fragments Influence of the detection compound to FXR reporter genes in strain (ATCC#HB-8065).Specific experiment method is as follows：

1st, HepG2 cell culture and maintenance；

2nd, vitellophag and the cell of proper density is planted with 10mL complete mediums, then 37 DEG C of 5%CO₂Wet condition Lower culture 24h；

3rd, cell seeding and transfection, transfection reagent are FugeneHD (Promega#E231A)

(1) transfection mixture is prepared according to following table

PBIND-FXR (ng/ holes)	25
		PG5Luc (ng/ holes)	25
FuGENEHD (μ l/ holes)	0.15
		Serum free medium (μ l/ holes)	1.85
Total mixture (μ l/ holes)	2.5

(2) mixture in pipe is tempestuously mixed, 15min is incubated at room temperature；

(3) cell in digestion culture dish and counting；

(4) diluting cells suspension to density volume (the μ l/ holes of 96 orifice plate 100) for needed for 600,000/mL；

(5) transfection mixture of required volume is added in cell suspension, then 100 μ l/ holes bed board；

(6) 37 DEG C, 5%CO₂24h is incubated under wet condition.

4th, compound is handled

(1) 10mM compound stock solutions are prepared, then with DMSO3 times of serial dilution；

(2) plus 10 μ L compound to 90 μ L complete mediums (10x)；

(3) 5 μ l compound solution (21x) is added per hole；

(4) 37 DEG C, 5%CO₂18h is incubated under wet condition.

5th, Dual-Luciferase is detected

Firefly luciferase and renilla luciferase signal are detected by the Dual-Luciferase detecting system of Promega companies (Promega#E1980)。

6th, interpretation of result

Detect obtained numerical value by firefly luciferase signal (F) divided by renilla luciferase signal (R), i.e. F/R.This Plant data processing and eliminate the difference that cell quantity and transfection efficiency are brought.

7th, exciting rate is calculated, EC is calculated according to GraphPrism5.0₅₀：

Exciting rate=(X-Min)/(Max-Min) * 100%

■ X represent the F/R values of each concentration；

■ Min represent the F/R values for not adding compound；

■ Max represent the F/R values of reference compound.

Experiment of the biochemical activity of the compounds of this invention more than is measured, the EC measured₅₀Value see the table below.

Claims

Formula 1. (I) compound, its stereoisomer or its pharmaceutically-acceptable salts：

Wherein,

X is selected from S or O；

Y is selected from CR₆Or N；

Z is selected from CR₆, N or NO；

Ar is selected from C_5-10Aryl or 5-10 unit's heteroaryls, are optionally further selected from halogen, cyano group, nitro, nitrine by one or more Base, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 members are miscellaneous Ring group sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 Unit's heteroaryl sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、- C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced,

Optionally further it is selected from halogen, cyano group, nitro, azido, C by one or more again_1-8Alkyl, C_2-8Alkenyl, C_2-8Chain Alkynyl, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10 Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryl sulphur Base ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、- C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

R is selected from C_3-8Cycloalkyl or 3-8 circle heterocycles bases, are optionally further selected from halogen, cyano group, nitro, nitrine by one or more Base, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles Base epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 members Heteroaryl epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、- C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent Replaced；

R₁、R₂、R₃、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, cyano group, nitro, azido, C_1-8Alkyl, C_2-8Alkene Base, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8- S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O) NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈,

Optionally further it is selected from halogen, cyano group, nitro, azido, C by one or more_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkyne Base, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Virtue Base, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,- C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C (O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

R₇Selected from hydrogen, deuterium, C_1-8Alkyl, C_2-8Alkenyl, C_3-8Cycloalkyl, halogen substitution C_1-8Alkyl, phenyl, p-methylphenyl, ammonia Base, list C_1-8Alkyl amino, two C_1-8Alkyl amino or C_1-8Alkyl amido；

R₈Selected from hydrogen, deuterium, C_1-8Alkyl, C_3-8Cycloalkyl, halogen substitution C_1-8Alkyl or hydroxyl substitution C_1-8Alkyl；

R₉Selected from hydrogen, deuterium, C_1-8Alkyl, C_1-8Alkoxy, C_3-8Cycloalkyl, C_3-8Cycloalkyloxy, halogen substitution C_1-8Alkyl, halogen substitution C_1-8Alkoxy, hydroxyl substitution C_1-8Alkyl or hydroxyl substitution C_1-8Alkoxy；

R₁₀、R₁₁It is independently selected from hydrogen, deuterium, hydroxyl, amino, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, C_5-10Aryl, 5-10 unit's heteroaryls or C_1-8Alkanoyl,

Optionally further it is selected from halogen, hydroxyl, sulfydryl, cyano group, nitro, acetylamino, azido, sulphonyl by one or more Base, mesyl, C_1-8Alkyl, trifluoromethyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, C_1-8Alkane Epoxide, C_1-8Alkoxy carbonyl group, C_1-8Alkyl-carbonyl, C_1-8Alkyl carbonyl epoxide, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls Sulfenyl, amino, list C_1-8Alkyl amino or two C_1-8The substituent of alkyl amino is replaced；

M is 0,1 or 2；

R is 0,1 or 2.
2. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts according to claim 1, it is characterised in that Y is selected from CR₆；

Ar is selected from C_6-10Aryl or 6-10 unit's heteroaryls, optionally further by it is one or more selected from halogen, cyano group, nitro, Azido, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 Circle heterocycles base sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O) R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced,

Optionally further it is selected from halogen, cyano group, nitro, azido, C by one or more again_1-8Alkyl, C_2-8Alkenyl, C_2-8Chain Alkynyl, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10 Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryl sulphur Base ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、- C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent replaced；

R is selected from C_3-6Cycloalkyl or 3-6 circle heterocycles bases, are optionally further selected from halogen, cyano group, nitro, nitrine by one or more Base, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl group, halogen substitution C_1-8Alkyl, C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles Base epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 unit's heteroaryls, 5-10 members Heteroaryl epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8-C(O)R₈、- C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈Substituent Replaced；

R₁、R₂、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, cyano group, nitro, azido, C_1-8Alkyl, halogen substitution C_1-8Alkane Base, halogen substitution C_1-8Alkoxy, C_2-8Alkenyl, C_2-8Alkynyl group, C_3-8Cycloalkyl, halogen substitution C_3-8Cycloalkyl, 3-8 circle heterocycles base, 3-8 circle heterocycles bases epoxide, 3-8 circle heterocycles bases sulfenyl, C_5-10Aryl, C_5-10Aryloxy, C_5-10Artyl sulfo, 5-10 member heteroaryls Base, 5-10 unit's heteroaryls epoxide, 5-10 unit's heteroaryls sulfenyl ,-C_0-8-S(O)_rR₇、-C_0-8-O-R₈、-C_0-8-C(O)OR₈、-C_0-8- C(O)R₈、-C_0-8-O-C(O)R₉、-C_0-8-NR₁₀R₁₁、-C_0-8-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O) OR₈；

M is 0.
3. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts according to claim 1, it is characterised in that Y is selected from CR₆；

Ar is selected from following structure：

Optionally further it is selected from halogen, C by one or more_5-10Aryl, 5-10 unit's heteroaryls ,-C_0-8-O-R₈、-C_0-4-S(O)_rR₇、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉Or-C_0-4-C(O)NR₁₀R₁₁Substituent replaced, then appoint Choosing is further selected from halogen, C by one or more_5-10Aryl, 5-10 unit's heteroaryls ,-C_0-4-S(O)_rR₇、-C_0-4-C(O)OR₈、- C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉Or-C_0-4-C(O)NR₁₀R₁₁Substituent replaced；

R is selected from following structure：

Optionally further it is selected from halogen, sulfydryl ,-C by one or more_0-4-O-R₈Or-C_0-4-NR₁₀R₁₁Substituent replaced；

R₁、R₂、R₄、R₅、R₆It is independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halogen substitution C_1-4Alkyl, halogen substitution C_1-4Alcoxyl Base, C_2-4Alkenyl, C_2-4Alkynyl group, C_3-6Cycloalkyl, halogen substitution C_3-6Cycloalkyl, 3-6 circle heterocycles base, 3-6 circle heterocycles bases epoxide, 3-6 circle heterocycles bases sulfenyl ,-C_0-4-S(O)_rR₇、-C_0-4-O-R₈、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉、- C_0-4-NR₁₀R₁₁、-C_0-4-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈；

M is 0.
4. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts according to claim 1, it is characterised in that Selected from formula (II) compound：

Wherein, Ar is selected from following structure：

Optionally further by it is one or more selected from fluorine, chlorine, carboxyl, sulfonyl, mesyl, isopropylsulfonyl, methoxycarbonyl group, Carbethoxyl group, butyloxycarbonyl, acetyl group or the substituent selected from following structure are replaced：

R is selected from following structure：

Optionally further replaced by one or more substituents selected from hydroxyl, sulfydryl, methoxyl group, ethyoxyl or amino；

R₁Selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, pi-allyl, acetenyl, cyclopropyl, methoxyl group, ethyoxyl, Isopropoxy or amino；

R₂Selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, sulfydryl, methyl, ethyl, isopropyl, trifluoromethyl, pi-allyl, acetenyl, ring third Base, cyclobutyl, methoxyl group, ethyoxyl, isopropoxy or amino.

R₄、R₅It is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, methoxyl group or ethoxy Base.
5. according to any formula (I) compounds of claim 1-4, its stereoisomer or its pharmaceutically-acceptable salts, it is special Levy and be, selected from following compound：
6. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts according to claim 1, it is characterised in that Selected from formula (III) compound：

Wherein,

Ar is selected from following structure：

Optionally further it is selected from halogen, phenyl ,-C by one or more_0-8-O-R₈、-C_0-4-S(O)_rR₇、-C_0-4-C(O)OR₈、- C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉、-C_0-4-C(O)NR₁₀R₁₁Or the substituent selected from following structure is replaced；

R is selected from following structure：

Optionally further it is selected from halogen, sulfydryl ,-C by one or more_0-4-O-R₈Or-C_0-4-NR₁₀R₁₁Substituent replaced；

R₄、R₅It is independently selected from hydrogen, deuterium, halogen, C_1-4Alkyl, halogen substitution C_1-4Alkyl, halogen substitution C_1-4Alkoxy, C_2-4Chain Alkenyl, C_2-4Alkynyl group, C_3-6Cycloalkyl, halogen substitution C_3-6Cycloalkyl, 3-6 circle heterocycles base, 3-6 circle heterocycles bases epoxide, 3-6 members are miscellaneous Ring group sulfenyl ,-C_0-4-S(O)_rR₇、-C_0-4-O-R₈、-C_0-4-C(O)OR₈、-C_0-4-C(O)R₈、-C_0-4-O-C(O)R₉、-C_0-4- NR₁₀R₁₁、-C_0-4-C(O)NR₁₀R₁₁、-N(R₁₀)-C(O)R₉Or-N (R₁₀)-C(O)OR₈。
7. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts according to claim 6, it is characterised in that Selected from formula (III a), (III b), (III c) or (III d) compound：

Wherein, Ar is selected from following structure：

Optionally further it is selected from fluorine, chlorine, methoxyl group, ethyoxyl, carboxyl, sulfonyl, mesyl, isopropyl sulphur by one or more Acyl group, methoxycarbonyl group, carbethoxyl group, butyloxycarbonyl, acetyl group or the substituent selected from following structure are replaced：

R₄、R₅It is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy Base, cyclopropyl, methoxy or ethoxy.
8. formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, its feature according to claim 1,6 or 7 It is, selected from following compound：
9. pharmaceutical composition, any described formula (I) compounds of its claim 1-8 for including treatment effective dose, its solid Isomers or its pharmaceutically-acceptable salts and pharmaceutically useful carrier.
10. claim 1-8 any described formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, or right It is required that the pharmaceutical composition described in 9 is preparing the application in being used to preventing or treating the disease of FXR mediations or the medicine of situation；Institute The disease or situation for stating FXR mediations preferably are selected from angiocardiopathy, atherosclerosis, artery sclerosis, hypercholesterolemia, high fat of blood Chronic liver disease, chronic liver disease, gastrointestinal disease, nephrosis, angiocardiopathy, metabolic disease, cancer (such as colorectal cancer) or Neural sign such as apoplexy.
11. application according to claim 10, it is characterised in that the chronic liver disease is selected from hepatitis B, primary and hardened (PBC), the dirty property xanthomatosis (CTX) of brain, primary sclerosing cholangitis (PSC), drug induced cholestasia, pregnant liver inner bag Juice alluvial disease, parenteral absorption associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmunity liver Inflammation, chronic viral hepatitis, AML, NASH disease (NAFLD), nonalcoholic fatty liver disease (NASH), the anti-host disease of liver transfer operation related Graft, live donor liver transfer operation regeneration, congenital hepatic fibrosis, choledocholithiasis, meat Malignant tumour, Sjogren syndromes, sarcoidosis, Wilson's diseases, Gaucher's diseases, blood in or beyond bud hepatopathy, liver Color disease or the primary antibody membrane proteolytic enzyme deficiency diseases of α 1；The gastrointestinal disease preferably is selected from IBD (IBD) (including Crohn's diseases With routed characteristic of disease enteritis), IBS (IBS), bacterial overgrowth, nutrient absorption be bad, reflection postcolon is scorching or small Property colitis；The nephrosis preferably is selected from diabetic nephropathy, Focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, slow Property glomerulitis, chronic transplant glomerulopathy, arteriosclerotic kidney or polycystic kidney disease；The angiocardiopathy is preferably automated Arteries and veins sclerosis, artery sclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia；The metabolic disease preferably is selected from pancreas Island element resistance, type i diabetes, type ii diabetes or obesity.
12. a kind of disease or the method for situation prevented or treat FXR mediations, includes the claim 1- for applying therapeutically effective amount 8 any described formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, or the medicine group described in claim 9 Compound.