CN110452235A - Fluorine isoxazole class compound and preparation method thereof, pharmaceutical composition and purposes - Google Patents

Fluorine isoxazole class compound and preparation method thereof, pharmaceutical composition and purposes Download PDF

Info

Publication number
CN110452235A
CN110452235A CN201810431514.0A CN201810431514A CN110452235A CN 110452235 A CN110452235 A CN 110452235A CN 201810431514 A CN201810431514 A CN 201810431514A CN 110452235 A CN110452235 A CN 110452235A
Authority
CN
China
Prior art keywords
base
group
methyl
substituted
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201810431514.0A
Other languages
Chinese (zh)
Other versions
CN110452235B (en
Inventor
柳红
李佳
周宇
臧奕
李亚洲
孙丹丹
李俊友
茹弘博
高立信
蒋华良
陈凯先
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201810431514.0A priority Critical patent/CN110452235B/en
Priority to PCT/CN2019/086068 priority patent/WO2019214656A1/en
Publication of CN110452235A publication Critical patent/CN110452235A/en
Application granted granted Critical
Publication of CN110452235B publication Critical patent/CN110452235B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to fluorine isoxazole class compound and preparation method thereof, pharmaceutical composition and purposes.Specifically, the invention discloses general formula I compound represented or its enantiomer or diastereomer or its officinal salts or their mixture.And disclosing above compound is the small molecule agonist for targeting FXR, can be used for treating the disease of FXR mediation.

Description

Fluorine isoxazole class compound and preparation method thereof, pharmaceutical composition and purposes
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, and in particular to fluorine isoxazole class compound, its Preparation method, the pharmaceutical composition containing such compound and as FXR agonist, especially prepare for treating non-alcoholic rouge Fat hepatopathy, liver fibrosis drug purposes.
Background technique
Non-alcohol fatty liver (NAFLD) refer in addition to alcohol and other specific damage liver factors caused by, with liver Intracellular fat over-deposit is the clinical pathology syndrome of main feature, is a kind of acquired metabolic stress hepatic injury, with Insulin resistance is closely related with genetic predisposition.Developed country's NAFLD illness rate in risky factor crowd about increases every year Add 2%, and onset gradually becomes younger, it has also become western countries' " the first big hepatopathy ", in China and common chronic liver disease class Type.NAFLD can also influence other Chronic Livers in addition to it can directly result in decompensated liver cirrhosis, hepatocellular carcinoma and liver transplantation and recur The progress of disease, and participate in the morbidity of diabetes B and atherosclerosis, it is considered to be the liver part of general metabolism syndrome Performance.
NAFLD mainly includes simple fatty liver (SFL) and nonalcoholic fatty liver disease (NASH), and wherein NASH is most A main seed type, patient's NASH cirrhosis incidence in 10 years are up to 25%.But it is regrettably ground in relation to NASH drug Study carefully it is slow with therapeutic advance, past NASH be considered as diabetes or obesity a kind of benign complication, the idea of this mistake People are caused to ignore to its timely diagnosing and treating.Currently, the research and development of NASH therapeutic agent specifically include that (1) selectivity Periphery Cannabined receptor (CB) hinders preparation；(2) peroxisome proliferation-activated receptors (PPAR) agonist；(3) half Guang days Winter enzyme (Caspase) inhibitor；(4) phosphodiesterase 4 (PDE4) inhibitor；(5) method Buddhist nun ester derivant X receptor (FXR) excitement Agent；(6) the double target spot inhibitor of CC chemokine receptor-5/chemokine receptor-2 (CCR5/CCR2)；(7) apoptotic signal, which is adjusted, swashs Enzyme -1 (ASK1) inhibitor etc..In these target spots and its medicament research and development, it has been found that method Buddhist nun's ester derivant X receptor (FXR) is made For bile acid receptor, internal bile acid stable state is not only controlled, and also there is important regulation to make lipid and glycometabolism With, be regulate and control metabolic syndrome patient's metabolic disorder important target spot.
FXR receptor is a kind of Farnesoid X receptor, and the activation of FXR controls the processes such as synthesis, the transhipment of bile acid.FXR is A member of hormone nuclear receptor superfamily has typical nuclear receptor structure, has now been found that there are FXR α 1, FXR α 2,3 and of FXR α Totally 4 hypotypes of FXR α 4.FXR ligand mainly passes through the activation small heterodimer companion receptor (SHP) of FXR and FXR target gene, suppression Hepatic stellate cells (HSC) expression processed reduces extracellular matrix (ECM) and generates and increase ECM removing, to reduce ECM deposition； FXR ligand can also increase HSC to the sensibility of apoptosis, keep HSC increasing apoptosis more, and the nuclear factor phase of liver fibrosis is reversed with other Interaction reverses liver fibrosis, to play treatment fibrosis effect.
In recent years, multiple FXR agonists subsequently enter clinical research, the compound L JN-452 found such as Novatis With good bioactivity and selectivity, 0.2nM is reached to the EC50 of FXR, comes into II clinical trial phase use at present In the treatment of NASH and primary biliary cholangitis (PBC)；The FXR agonist PX-104 developed by Gilead company once entered II phase clinical research is used for the treatment of NASH, but regrettably not up to expected clinical endpoint is forced to terminate.Other several chemical combination Object is expected to alleviate the still unsatisfied huge clinical demand of NASH if LY-2562175 and INT-767 also enter clinical research. Wherein, shellfish cholic acid (OCA) difficult to understand goes through to list as first FXR agonist, for treating the candidate new medicine of PBC and NASH Object does not have abundant response or intolerable patient mainly for ursodesoxycholic acid.Its mechanism mainly pass through exciting FXR by Body adjusts related gene, influences synthesis, secretion, transhipment and the absorption of bile acid.In January, 2015, FDA authorize OCA treatment with The breakthrough drug qualification of the NASH of liver fibrosis, the fast traffic lane status for treating PBC, the Orphan drug status for treating PBC and PSC, And ratify to list in 27 Nikkei U.S. FDA May in 2016.Global Medicine market projecting body EvaluatePharma publication " global bio-pharmaceuticals later period pipeline weight pound drug TOP 15 " list predicts that OCA will be up to 30 in the global marketing volume of the year two thousand twenty Hundred million dollars.However, it can but be promoted low close although shellfish cholic acid difficult to understand has played positive effect in terms of reducing hepatic fibrosis-renal tubular ectasia syndrome It spends lipoprotein cholesterol (LDL) and reduces high-density lipoprotein cholesterol (HDL), indicate that there may be increases to suffer from painstaking effort for the drug The risk of pipe disease, while the side effects such as itch that can also cause patient body, this limits it to a certain extent and is widely used.
Therefore, the still unsatisfied clinical demand of NASH is faced, there is an urgent need to for the novel target spot exploitation innovation of NASH NASH therapeutic agent, fills up gaps in market, meets clinical application demand.
Summary of the invention
The object of the present invention is to provide the small molecule agonists and its preparation method and application of a kind of novel targeting FXR.
First aspect present invention provide it is a kind of with the fluorine-containing isoxazole class compound of structure shown in following general formula I or its Enantiomer or diastereomer or its officinal salt or their mixture:
Wherein:
M is 0,1,2 or 3；
N is 0,1 or 2；
P is 0,1 or 2；
Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member aromatic ring yl, Substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from by 1,2,3 or 4 The substituent group of the following group replaces: deuterium (D), tritium (T), halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6 Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitre Base, amino, amido (preferably C1-C6Amido), hydroxyl, carboxyl, C1-C6Ester group, C6-C10Aryl, C6-C10Aryloxy ,-X4- CO2R5、C1-C6Alkyl hydroxy ,-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6, 3-12 member it is miscellaneous Ring group and 3-12 circle heterocyclic ring base oxygroup；Wherein, described q, r, s, y1 and y2 may respectively be 1,2,3 or 4；The heteroaromatic Base, aromatic ring yl or heterocycle contain 1~4 hetero atom in oxygen, sulphur and nitrogen each independently；X4For key, C1-C6 alkylene Base, C1-2Alkylene, cyclopropyl or epoxy ethyl；
R1Be selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, replaces substituted or unsubstituted 6-20 member aromatic ring yl Or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from the group by 1,2,3 or 4 Substituent group replace: deuterium, tritium, halogen, C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O (CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitro, amino, amido (preferably C1-C6 Amido), hydroxyl, methylol, carboxyl, C6-C10Aryl, C6-C10Aryloxy, 3-12 circle heterocyclic ring base and 3-12 circle heterocyclic ring base oxygen Base；Wherein, described q, r and s may respectively be 1,2,3 or 4；Aromatic heterocyclic, aryl or the heterocycle contains each independently There is 1~4 hetero atom in oxygen, sulphur and nitrogen；
R2It can be independently selected from the substituent group of 1,2,3 or 4 the following group: hydrogen, halogen, substituted or unsubstituted C1-C6Alkyl, Substituted or unsubstituted C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3- C8Cycloalkyloxy, cyano, nitro, amino, amido (preferably C1-C6Amido), hydroxyl, methylol, carboxyl；Wherein, described to take In generation, refers to that the hydrogen atom on group is replaced by 1,2,3 or 4 substituent group selected from the group below: hydrogen, halogen, nitro, cyano, fluoroform Base, trifluoroethyl, trifluoro propyl, trifluoromethoxy, trifluoro ethoxy, amino, amido (preferably C1-C6Amido), hydroxyl, hydroxyl Methyl, carboxyl, sulfydryl and sulfonyl；
R3And R4It is each independently selected from the following group: hydrogen, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogen For C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyanogen Base, nitro, amino, amido (preferably C1-C6Amido), hydroxyl, methylol and carboxyl；Or R3And R4It links together common Form C1-C6Alkylidene；
R5And R6For from independently hydrogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring Base.
In another preferred example, 0,1 or 2 m；Preferably 0 or 1.
In another preferred example, n is 0 or 1.
In another preferred example, p is 0 or 1.
In another preferred example,Ring is selected from the group: phenyl, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, benzo thiophene Oxazolyl, benzo [d] isothiazolyl, imidazo [1,2-a] pyridyl group, quinolyl, 1H- indyl, pyrrolo- [1,2-b] pyridazine Base, benzofuranyl, benzo [b] thiophenyl, 1H- indazolyl, benzo [d] isoxazolyl, thiazolinyl, 1H- pyrrolo- [3,2- C] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazoles [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyrrole radicals；Above-mentioned group is It is substituted or unsubstituted；Wherein, the substitution refers to that the hydrogen atom on group is taken by 1,2,3 or 4 substituent group selected from the group below Generation: D, T, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O (CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitro, amino, amido (preferably C1-C6 Amido), hydroxyl, carboxyl, C1-C6Ester group, C6-C10Aryl, C6-C10Aryloxy ,-X4-CO2R5、C1-C6Alkyl hydroxy ,-X4- CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6, 3-12 circle heterocyclic ring base and 3-12 circle heterocyclic ring base oxygen Base；
Wherein, described q, r, s, y1 and y2 may respectively be 1,2,3 or 4；
Heteroaromatic, aryl or heterocycle contain 1~4 hetero atom in oxygen, sulphur and nitrogen each independently；
X4For key, C1-C6 alkylidene, C1-2Alkylene, cyclopropyl, epoxy ethyl；
R5And R6It is each independently hydrogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring Base.
In another preferred example,It is selected from the group:
Wherein,
R8It is selected from the group: hydrogen, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkoxy carbonyl, Halogenated C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Naphthenic base, cyano, nitro, amino, hydroxyl, methylol, carboxyl, Sulfydryl, sulfonyl, C6-C10Aryl and 3-12 circle heterocyclic ring base；
T is 0,1,2,3,4 or 5；
XlAnd X2It is each independently N, CH or CR8；
X3For O or S；
R9For-X4-CO2R5、C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Hydroxyl ,-X4-CONR5R6、-X4-CONR5 (CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6；Y1 and y2 is each independently 1,2,3 or 4；X4For key, C1-C6 alkylidene, C1-2Alkylene, cyclopropyl or epoxy ethyl；
R5And R6It is each independently hydrogen, C1-6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring Base；
R10For hydrogen, C1-C6Alkyl hydroxy, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkoxy carbonyl Base, halogenated C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl or C3-C8Naphthenic base.
In another preferred example,It is selected from the group:Wherein, R8、R9、R10And t It is as defined above.
In another preferred example, R1It is selected from the group: phenyl, pyridyl group, pyridine 1-oxide base, cyclohexyl, cyclopenta, cyclopropyl Base；Above-mentioned group is substituted or unsubstituted；Wherein, the substitution refers to that the hydrogen atom on group is selected from down by 1,2,3 or 4 The substituent group of group replaces: hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoro propyl, trifluoromethoxy, trifluoro second Oxygroup, phenyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, C1-6Alkyl, Cl-6Naphthenic base, C1-6Alkoxy, Cl-6Ring Alkoxy, cyclopropyl.
In another preferred example, the compound is selected from the group:
Second aspect of the present invention provides a kind of pharmaceutical composition, contains described in the first aspect it includes therapeutically effective amount Fluorine isoxazole class compound or its enantiomer or diastereomer or its officinal salt or their mixture, and Pharmaceutically acceptable carrier.
Third aspect present invention provides a kind of FXR agonist, and it includes the fluorine-containing isoxazole class described in first aspect Close object or its enantiomer or diastereomer or its officinal salt or their mixture.
Fourth aspect present invention provide fluorine-containing isoxazole class compound or its enantiomter described in first aspect or The purposes of diastereoisomer or its officinal salt or their mixture is used to prepare prevention or treats what FXR was mediated The drug of disease.
In another preferred example, the disease is selected from the group: non-alcoholic fatty liver disease, nonalcoholic fatty liver disease, Fatty liver, liver fibrosis, primary biliary cirrhosis, hyperlipemia, dyslipidemia.
Fifth aspect present invention provides the preparation method of fluorine-containing isoxazole class compound described in first aspect,
(a) the method includes the steps:
Wherein,R1、R2、R3、R4, n, m and p define it is identical as the definition in general formula I above-mentioned；X be halogen or Nitro；
Step j: in organic solvent, in the presence of 18- crown ether -6 and alkali, intermediate 12 and intermediate 9 are reacted, shape At intermediate 13；
Step k: in organic solvent, intermediate 13 is subjected to deprotection reaction, forms intermediate 14；
Step l: under nitrogen protection, in organic solvent, in the presence of alkali, palladium catalyst and ligand, intermediate 14 It is reacted with intermediate 15, forms final product I；Or
Step m: under nitrogen protection, in organic solvent, in the presence of a base, intermediate 14 and intermediate 15 react, shape At final product I；
Or
(b) the method includes the steps:
Wherein, R1、R2、R3、R4, n, m and p define it is identical as the definition in general formula I above-mentioned；X is halogen or nitro；
Step j: in organic solvent, in the presence of 18- crown ether -6 and alkali, intermediate 12 and intermediate 9 are reacted, shape At intermediate 13；
Step k: in organic solvent, intermediate 13 is subjected to deprotection reaction, forms intermediate 14；
Step l: under nitrogen protection, in organic solvent, in the presence of alkali, palladium catalyst and ligand, intermediate 14 It is reacted with intermediate 15, forms intermediate compound I '；Or
Step m: under nitrogen protection, in organic solvent, in the presence of a base, intermediate 14 and intermediate 15 react, shape At intermediate compound I '；With
Step e: in organic solvent, intermediate compound I ' and HNR5R6、HNR5(CH2)y1CO2R6Or HNR5(CH2)y2SO3R6Into Row reaction, forms final product I；
Wherein,Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member virtue Ring group, substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to the hydrogen atom on group by 1,2,3 or 4 Substituent group selected from the group below replaces :-X4-CO2R5；Wherein, X4、R5It is as defined above
Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member aromatic ring yl, Substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from by 1,2,3 or 4 The substituent group of the following group replaces :-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6；Wherein, X4、 R5、R6, y1, y2 it is as defined above.
The present invention provides a kind for the treatment of methods, apply fluorine-containing isoxazole class chemical combination of the present invention to the object of needs Object or its enantiomer or diastereomer or its officinal salt or their mixture or pharmaceutical composition of the invention Object or FXR agonist.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows influence of the compounds of this invention to serum levels of ALP.
Fig. 2 shows influence of the compounds of this invention to α-SMA and Col1 α 1mRNA.
Fig. 3 shows influence of the compounds of this invention to collagen content.
Fig. 4 shows influence of the compounds of this invention to TC, TG, HDL, LDL concentration in serum.
Fig. 5 shows influence of the compounds of this invention to liver coefficient.
Specific embodiment
The present inventor's in-depth study by long-term, design are prepared for the fluorine-containing isoxazole class chemical combination of a kind of structure novel Object.The compound can be effectively targeted to ground excitement FXR.Based on above-mentioned discovery, inventor completes the present invention.
Term
In the present invention, unless otherwise indicated, term used is with well known to a person skilled in the art general senses.
In the present invention, term " 6-20 circle heterocyclic ring base " refers to being selected from containing one or more with 6-20 annular atom The heteroatomic saturation or fractional saturation heterocycle of nitrogen and sulphur；Including but not limited to: morpholinyl, piperidyl, piperazinyl, hexamethylene Base and piperidyl etc..Other " heterocycle " terms have similar meaning.
In the present invention, term " 6-20 circle heterocyclic ring oxygroup " refers to 6-20 circle heterocyclic ring base-oxygen-.Other " heterocyclic oxy group " arts Language has similar meaning.
In the present invention, term " 6-20 member aromatic ring yl " refers to the aromatic ring yl with 6-20 annular atom；Including but it is unlimited In: phenyl, naphthalene, phenanthryl, anthryl etc..Other " aromatic ring yl " terms have similar meaning.
In the present invention, term " 6-20 member aromatic heterocyclic " refers to that the one or more that contains with 6-20 annular atom is selected From the heteroatomic aromatic heterocyclic of nitrogen and sulphur；Including but not limited to: tetrazole radical, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, Benzothiazolyl, benzo [d] isothiazolyl, imidazo [1,2-a] pyridyl group, quinolyl, 1H- indyl, pyrrolo- [1,2-b] Pyridazinyl, benzofuranyl, benzo [b] thiophenyl, 1H- indazolyl, benzo [d] isoxazolyl, thiazolinyl, 1H- pyrrolo- [3,2-c] pyridyl group, pyrazolo [1,5-a] pyrimidine radicals, imidazoles [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyrrole radicals etc..Its He has similar meaning by " aromatic heterocyclic " term.
In the present invention, term " C1-C6Alkyl " refers to the linear or branched alkyl group with 1 to 6 carbon atom, unrestricted Property include methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, amyl and base etc.；It is preferred that second Base, propyl, isopropyl, butyl, isobutyl group, sec-butyl and tert-butyl.
In the present invention, term " C1-C6Alkoxy " refers to the straight or branched alkoxyl with 1 to 6 carbon atom, non- It restrictively include methoxyl group, ethyoxyl, propoxyl group, isopropoxy and butoxy etc..
In the present invention, term " C2-C6Alkenyl " refers to the straight chain or branch containing a double bond with 2 to 6 carbon atoms Alkenyl includes vinyl, acrylic, cyclobutenyl, isobutenyl, pentenyl and hexenyl etc. without limitation.
In the present invention, term " C2-C6Alkynyl " refers to the straight chain or branch containing three keys with 2 to 6 carbon atoms Alkynyl group includes acetenyl, propinyl, butynyl, butynyl, pentynyl and hexin base etc. without limitation.
In the present invention, term " C3-C8Naphthenic base " refers to the cyclic alkyl on ring with 3 to 8 carbon atoms, non-limit It include property processed cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl and cyclodecyl etc..Other " naphthenic base " arts Language has similar meaning.
In the present invention, term " C3-C8Cycloalkyloxy " refers to the cyclic alkoxy on ring with 3 to 8 carbon atoms, It without limitation include cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, cycloheptyl oxygroup, ring octyloxy and ring decyloxy Deng.Other " cycloalkyloxy " terms have similar meaning.
In the present invention, term " C6-C10Aryl " refers on ring without the heteroatomic virtue with 6 to 10 carbon atoms Fragrant race's ring group, such as phenyl, naphthalene.Term " C6-C12Aryl " has similar meaning.
In the present invention, term " C1-C6Ester group " refers to 1-6 carbon atom and with the base of ester group (- O (C=O) -) Group.
In the present invention, term " C1-C6Amido " refers to 1-6 carbon atom and has group of the amino as end group.
In the present invention, the halogen is F, Cl, Br or I.What halogenated expression was optionally substituted by halogen.
Active constituent
The compound of the present invention is general formula I compound represented or its enantiomer or diastereomer or it can Pharmaceutical salts or their mixture.
The compounds of this invention is preferably following particular compound:
The compounds of this invention also includes the pharmaceutical salt of compound of Formula I, in particular compound of Formula I and inorganic acid Or organic acid reaction forms conventional officinal salt.For example, conventional officinal salt can by compound of Formula I and inorganic acid or Organic acid reaction is made, and the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid etc. and described Organic acid includes citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids, second sulphur Acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, is flutterred naphthalenedisulfonic acid Acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, para-anilinesulfonic acid, 2- acetyloxy phenyl Formic acid and isethionic acid etc.；Or sodium salt, sylvite, calcium salt, aluminium salt or ammonium salt that compound of Formula I and inorganic base are formed；Or Methylamine salt, ethylamine salt or the ethanolamine salt that compound of Formula I and organic base are formed.
The compound of the present invention further include compound of Formula I enantiomter (such as R- isomers or S- isomers) or Diastereoisomer or its racemic modification or mesomer.
Preparation method
Compound of Formula I of the invention can be prepared according to following scheme.
It is as follows to prepare 3 scheme of general formula intermediate
Wherein, R2, p define it is identical as the definition in general formula I above-mentioned；
Step a: 1 is dissolved in organic solvent, and oxidant is added dropwise at 0 DEG C, is stirred to react at 0 DEG C, and ether mentions after having reacted Organic layer is taken, then extracts combining water layer with sodium hydroxide solution, water layer is acidified to PH < 1 with sulfuric acid.Then extracted by ether is organic Layer, saturated common salt washing is dry, is spin-dried for obtaining intermediate 2.The organic solvent is acetone, tetrahydrofuran, ether, dimethyl Formamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride or its mixing Object；The oxidant is selected from PCC, PDC, Dai Si-Martin oxidant, Swern oxidant, H2O2, potassium permanganate and manganese dioxide In；
Step b: intermediate 2 is dissolved in organic solvent, and N, N'- carbonyl dimidazoles, nitrogen protection room temperature reaction one is added After hour, potassium ethyl malonate salt and magnesium chloride is added, overnight, hydrochloric acid after having reacted, ethyl acetate mentions for room temperature reaction Organic layer is taken, then organic layer is washed with saturated common salt, and it is dry, it is spin-dried for, crosses pillar and obtain intermediate 3.The organic solvent is Acetone, tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, Or mixtures thereof ethyl acetate, methylene chloride；
It is as follows to prepare 9 scheme of general formula intermediate
Wherein, R1、R2It is identical as the definition in general formula I above-mentioned with defining for p；
Step c: hydroxylamine hydrochloride is dissolved in the water, and sodium hydroxide is added dropwise under 0 DEG C of stirring.4 are added organic solvent dissolution After instill above-mentioned mixed solution, then heat to 90 DEG C and be stirred overnight.It is cooled to room temperature, is concentrated in vacuo to a large amount of solid after having reacted Body is precipitated, and filters to obtain solid, dry, intermediate 5；The organic solvent is tetrahydrofuran, ether, dimethylformamide, second two Or mixtures thereof diethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride.
Step d: organic solvent dissolution is added in intermediate 5, and chlorosuccinimide is dissolved in organic solvent at 40 DEG C and is dripped Enter in above-mentioned 5 solution, after reacted at 40 DEG C, be cooled to room temperature after having reacted, be added a large amount of water, ethyl acetate (EA) extraction, Organic layer is washed with water three times, saturated common salt water washing organic layer, anhydrous Na2SO4It is dry, it is spin-dried for organic layer, obtains intermediate 6；Institute Stating organic solvent is tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, second Or mixtures thereof alcohol, methanol, ethyl acetate, methylene chloride；
Step e: by intermediate 3 be added alkali in, after being stirred at room temperature, be cooled to 10 DEG C, under be slowly added dropwise intermediate 6 reaction Intermediate 7 is obtained after complete；The organic solvent is tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol two Ether, dioxane, ethyl alcohol, methanol or ethyl acetate, methylene chloride；The alkali is sodium acetate, NaOH, KOH, sodium ethoxide, first Sodium alkoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylamine.
Step f: intermediate 7 is dissolved in organic solvent, and under 0 DEG C of nitrogen protection, diisobutyl aluminium hydride 1M/ first is added dropwise Reaction is stirred at room temperature in benzene, after having reacted, methanol is added dropwise at 0 DEG C and a small amount of water quenching is gone out and stirred 10 minutes, takes out by diatomite Filter, organic solvent washing filter out sediment, filter vacuum concentration, dry intermediate 8；The organic solvent be tetrahydrofuran, Ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, dichloro Or mixtures thereof methane；
Step g: intermediate 8 is dissolved in organic solvent, and triphenyl phosphorus is added, and is cooled to 0 DEG C, and carbon tetrabromide is added, after It is reacting at room temperature, after having reacted, reaction solution is being concentrated in vacuo to obtain orange, silicagel column is crossed, is spin-dried for obtaining intermediate 9.It is described Organic solvent be tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, Or mixtures thereof methanol, ethyl acetate, methylene chloride；
It is as follows to prepare 12 scheme of general formula intermediate
Wherein, m, R4And R5Define it is identical as the definition in general formula I above-mentioned；
Step h: it by trimethyl iodine bisulfide solubilization in organic solvent, is added with stirring compound 10 and continues to stir, then Add potassium tert-butoxide；Obtain epoxide 2.The organic solvent can be dimethyl sulfoxide, tetrahydrofuran, ether, dimethyl methyl Amide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride or its mixing Object.
Step i: intermediate 11 is dissolved in organic solvent, is cooled to -10 DEG C~-40 DEG C, and the fluorine of 1-10 equivalent is added Change pyridinium hydroxide solution, the reaction was continued disappears to raw material, isolates and purifies to obtain intermediate 12；The organic solvent can for tetrahydrofuran, Ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, dichloro Or mixtures thereof methane.
It is as follows to synthesize general formula I scheme:
Wherein,R1、R2、R3、R4, the definition of n, m and p it is identical as the definition in aforementioned formula I；X is halogen or nitre Base；
Step j: intermediate 12 is dissolved in organic solvent, at 0 DEG C, addition compound 18- crown ether -6 (12.8g, 48.6mmol) and highly basic, reaction 30 minutes move to room temperature, are added dropwise intermediate 9 (being dissolved in organic solvent), reaction is stirred at room temperature, Intermediate 13 is isolated and purified to obtain after having reacted；The organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol two Or mixtures thereof methyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride；The highly basic is NaOH, KOH, potassium tert-butoxide, sodium ethoxide or sodium methoxide；
Step k: intermediate 13 is dissolved in organic solvent, and the organic molten of trifluoracetic acid (TFA) or hydrochloric acid (HCl) is added Boc protecting group is sloughed in agent, obtains intermediate 14；The organic solvent can be tetrahydrofuran, ether, dimethylformamide, ethylene glycol Or mixtures thereof dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride.
Step l: under nitrogen protection, intermediate 14,15 being dissolved in organic solvent, and cesium carbonate, three (dibenzylidenes are added Acetone) two palladium catalysts and 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl ligand after having reacted, isolates and purifies to obtain and produces eventually Object I；The organic solvent be toluene, tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, Or mixtures thereof dioxane, ethyl alcohol, methanol, ethyl acetate, methylene chloride；
Or step m: under nitrogen protection, intermediate 14,15 being dissolved in organic solvent, and N, N- diisopropyl second is added Amine after having reacted, isolates and purifies to obtain final product I；The organic solvent be toluene, tetrahydrofuran, ether, dimethylformamide, Glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethyl alcohol, methanol, ethyl acetate, N-methyl pyrrolidones, methylene chloride Or mixtures thereof.
Or the method for synthesis general formula I is as follows:
Wherein, R1、R2、R3、R4, the definition of n, m and p and the same；X is halogen or nitro；
Step j: in organic solvent, in the presence of 18- crown ether -6 and alkali, intermediate 12 and intermediate 9 are reacted, shape At intermediate 13；
Step k: in organic solvent, intermediate 13 is subjected to deprotection reaction, forms intermediate 14；
Step l: under nitrogen protection, in organic solvent, in the presence of alkali, palladium catalyst and ligand, intermediate 14 It is reacted with intermediate 15, forms intermediate compound I '；Or
Step m: under nitrogen protection, in organic solvent, in the presence of a base, intermediate 14 and intermediate 15 react, shape At intermediate compound I '；With
Step e: in organic solvent, intermediate compound I ' and HNR5R6、HNR5(CH2)y1CO2R6Or HNR5(CH2)y2SO3R6Into Row reaction, forms final product I；
Wherein,Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member virtue Ring group, substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to the hydrogen atom on group by 1,2,3 or 4 Substituent group selected from the group below replaces :-X4-CO2R5；Wherein, X4、R5It is as defined above
Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member aromatic ring yl, Substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from by 1,2,3 or 4 The substituent group of the following group replaces :-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6；Wherein, X4、 R5、R6, y1, y2 it is as defined above.
Pharmaceutical composition and method of administration
The compounds of this invention has excellent FXR agonism, can be used for preparing the disease for treating or preventing FXR mediation The pharmaceutical composition of disease.
The present invention provides a kind of pharmaceutical compositions, are selected from change shown in above-mentioned logical formula (I) containing therapeutically effective amount Object or its enantiomer or diastereomer or one of its pharmaceutical salt or their mixture or a variety of are closed, And optionally, one or more pharmaceutical carriers, excipient, adjuvant, auxiliary material and/or diluent.The auxiliary material is, for example, Odorant agent, flavouring agent, sweetener etc..
Pharmaceutical composition provided by the present invention preferably comprises the active ingredient that weight ratio is 1-99%, preferred ratio It is that compound of Formula I accounts for 65wt%~99wt% of total weight as active constituent, rest part is pharmaceutically acceptable load Body, dilution or solution or salting liquid.
Compound provided by the present invention and pharmaceutical composition can be diversified forms, as tablet, capsule, pulvis, syrup, Solution shape, suspension and aerosol etc., and can reside in the carrier or dilution of suitable solid or liquid and be suitable for In disinfector for injecting or instiling.
The various dosage forms of pharmaceutical composition of the invention can be prepared according to the customary preparation methods of pharmaceutical field.Its preparation is matched It include 0.05-200mg the compounds of this invention in the unit dosage of side, it is preferable that include in the unit dosage of pharmaceutical formulation 0.1mg-100mg the compounds of this invention.
The compounds of this invention and pharmaceutical composition can to mammal clinical use, including humans and animals, can by mouth, The administration route of nose, skin, lung or gastrointestinal tract etc..It is most preferably oral.Most preferably daily dose is 0.01-200mg/kg body Weight, disposably takes or 0.01-100mg/kg weight part vic.Which kind of ineffective instructions of taking, personal optimal dose are answered Depending on specific treatment.It is to gradually increase dosage until finding most suitable dose since low dose under normal conditions Amount.
The present invention also provides a kind of farnesoid X receptor (FXR) agonists, and it includes be selected from shown in above-mentioned general formula I to change Object or its enantiomer or diastereomer or one of its pharmaceutical salt or their mixture or a variety of are closed, And optionally one or more pharmaceutical carriers, excipient, adjuvant, auxiliary material and/or diluent.
The compounds of this invention and composition for treat and prevent liver system relevant to farnesoid X receptor (FXR) and Blood lipid disorder, the disease include, but are not limited to nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, fatty liver, primary The diseases such as bile acid cirrhosis, hyperlipemia.
Therefore, the present invention also provides above-mentioned general formula I compound represented or its enantiomer or diastereomer, Or its pharmaceutical salt or their mixture are used to treat liver relevant to farnesoid X receptor (FXR) in preparation System and blood lipid disorder, such as nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, fatty liver, primary biliary acid liver are hard Purposes in the drug of the diseases such as change, hyperlipemia.
The present invention also provides a kind for the treatment of liver system relevant to farnesoid X receptor (FXR) and blood lipid disorders, such as The side of the diseases such as nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, fatty liver, primary biliary acid cirrhosis, hyperlipemia Method comprising to need patient's application of the treatment selected from above-mentioned general formula I compound represented or its enantiomter or non-right Reflect isomers or one of its pharmaceutical salt or their mixture or a variety of.
Main advantages of the present invention are:
The compounds of this invention has excellent FXR agonism, and intracellular release is good and very safe.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
1 4- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzoic acid preparation (FL1)
The synthesis of 1.1 2,6- dichloro-benzaldehyde oximes
Hydroxylamine hydrochloride (67.6g, 0.943mol) is dissolved in 100mL water, sodium hydroxide 3N is added dropwise under 0 DEG C of stirring (314mL, 9.43mol.2,6- dichlorobenzaldehydes (150g, 0.857mol) instill above-mentioned mixing after ethyl alcohol (300mL) dissolution is added Solution then heats to 90 DEG C and is stirred overnight.It is monitored and is reacted with thin-layer chromatography (TLC), is cooled to room temperature after having reacted, vacuum is dense It is reduced to 10% solution, a large amount of solids are precipitated, and filter to obtain solid, and it is dry, 162 grams of white solid are obtained, yield 98%.ESI-MS m/ z:190(M+1)。
The 1.2 chloro- oximes of 2,6- dichloro-benzaldehyde
DMF (N, N- diformamide, 200mL) dissolution is added in 2,6- dichloro-benzaldehyde oximes (100g, 0.526mol), by chlorine Being dissolved in 100mL DMF for succimide (70.3g, 0.526mol), that above-mentioned 2,6- dichloro-benzaldehyde oxime is instilled at 40 DEG C is molten In liquid, after reacted 1 hour at 40 DEG C, with thin-layer chromatography (TLC) monitor react, be cooled to room temperature after react, be added largely Water, ethyl acetate (EA) extraction, wash organic layer three times with water 200mL, and saturated salt solution 200mL washs organic layer, anhydrous Na2SO4It is dry, it is spin-dried for organic layer, obtains crude product, hexane 100ml grinding is added, filters, it is dry, 88.6 grams of solid are obtained, is 2,6- The chloro- oxime of dichloro-benzaldehyde.ESI-MS m/z:224(M+1)
1.3 5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazole -4- methyl formate
3- cyclopropyl -3- oxo-propionic acid methyl ester (31.7g, 0.223mol) addition triethylamine (45.1g, 62mL, 0.446mol) dissolve, be stirred at room temperature, after 30 minutes, be cooled to 10 DEG C, under the chloro- oxime of 2,6- dichloro-benzaldehyde is slowly added dropwise Temperature is no more than 24 DEG C during (50.0g, 0.223mol are dissolved in 300mL ethyl alcohol) is added dropwise, and after dripping off, is stirred overnight at room temperature, and uses Thin-layer chromatography (TLC) monitoring reaction, after having reacted plus water 200mL, ethyl acetate (EA) 500mL are extracted, aqueous layer with ethyl acetate 200mL is extracted three times, merges organic layer, and saturated salt solution 200mL washs organic layer, anhydrous Na2SO4It is dry, it is concentrated in vacuo to 10% solution, a large amount of solids are precipitated, and filter to obtain crude product, and hexane 100ml grinding is added, filters, dry, obtain white solid 45.0 Gram, yield 65%.ESI-MS m/z:312(M+)。
1.4 [5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazole -4- base]-methanol
5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazole -4- methyl formate (20.0g, 64.1mmol) is dissolved in tetrahydro In furans (100mL), under 0 DEG C of nitrogen protection, it is added dropwise diisobutyl aluminium hydride 1M/ toluene (160.0mL, 160.8mmol), room Temperature stirring 2 hours.It is monitored and is reacted with thin-layer chromatography (TLC), after having reacted, methanol (10mL) and a small amount of water quenching are added dropwise at 0 DEG C It goes out and stirs 10 minutes, ethyl acetate (500mL) is added afterwards.Sediment, filtrate are filtered out through suction filtered through kieselguhr, ethyl acetate washing Vacuum concentration, 15.2 grams of white solid dry, yield 83%, ESI-MS m/z:285 (M+)。
1.5 4- bromomethyl -5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazoles
[5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazole -4- base]-methanol (15.0g, 52.8mmol) is dissolved in dichloro In methane 100mL, be added triphenyl phosphorus (20.8g, 79.2mmol), be cooled to 0 DEG C, be added carbon tetrabromide (26.3g, 79.2mmol), it in room temperature reaction 2h after, is monitored and is reacted with thin-layer chromatography (TLC), after having reacted, reaction solution is concentrated in vacuo Orange, petroleum ether (PE): ethyl acetate (EA)=5:1 crosses column, is spin-dried for obtaining 16.3 grams of white solid product, yield 89%, ESI-MS m/z:346 (M+).
The synthesis of 1.6 6- tertbutyloxycarbonyl -1- oxa- -6- azaspiro [2.5] octanes
130mL dimethyl sulfoxide (DMSO) is added into 250mL eggplant-shape bottle, agitating and heating weighs NaH solid 5g and is added to In DMSO solution, continue stirring 12 hours, stops heating, be cooled to room temperature.Trimethylsulfoxonium Iodide 25g is added, is stirred at room temperature 24 hours.The 25g N- t-butoxycarbonylpiperidin ketone being previously dissolved in DMSO is added in reaction solution, is further continued for being stirred to react 12 Hour, it is monitored and is reacted with thin-layer chromatography (TLC).Reaction terminates that 100-200mL water is added, and ethyl acetate (EA) 100mL extracts 3 Secondary, saturated salt solution 30mL washs organic layer three times, is spin-dried for organic layer, obtains colourless liquid 28g, is 6- tertbutyloxycarbonyl -1- oxygen Miscellaneous -6- azaspiro [2.5] octane.
The synthesis of 1.7 (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol
28g 6- tertbutyloxycarbonyl -1- oxa- -6- azaspiro [2.5] octane is dissolved in 100mL methylene chloride (DCM), It is cooling, 70% hydrogen fluoride pyridine solution 120mL is added, then react one 12 hours, reaction terminates, and 100mL water, DCM is added 100mL is extracted three times, and petroleum ether (PE): ethyl acetate (EA)=4:1 crosses column, is spin-dried for obtaining 21 grams of substantially colorless product liquid, is (the fluoro- 1-Boc substituted piperidine -4- base of 4-) methanol.
1.8 4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine resources -1- The synthesis of carboxylic acid tert-butyl ester
(the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol (10.0g, 42.8mmol) is dissolved in tetrahydrofuran 50mL In, at 0 DEG C, 18- crown ether -6 (12.8g, 48.6mmol) and potassium tert-butoxide (5.5g, 48.6mmol) is added, reacts 30 minutes, Room temperature is moved to, 4- bromomethyl -5- cyclopropyl -3- (2,6- Dichloro-phenyl)-isoxazole is added dropwise, and (9.9g, 28.6mmol are dissolved in 50mL tetrahydrofuran), reaction 14h is stirred at room temperature.It is monitored and is reacted with thin-layer chromatography (TLC), add water 200mL, second after having reacted Acetoacetic ester (EA, 3x 200mL) extraction merges organic layer, and saturated salt solution 200mL washs organic layer, and anhydrous Na 2SO4 is dry, Vacuum concentration, petroleum ether (PE): ethyl acetate (EA)=4:1 crosses column, is spin-dried for obtaining 10.1 grams of oily liquids, yield 71%, ESI- MS m/z:500(M+)。
1.9 5- cyclopropyl -3- (2,6- dichlorophenyl) -4- (((4- fluorine resources -4- base) methoxy) methyl) isoxazole
Under ice bath and nitrogen protection, 4- is added to 250mL eggplant-shape bottle, and (((5- cyclopropyl -3- (2,6- dichlorophenyl) is different Oxazole -4- base) methoxy) methyl) -4- fluorine resources -1- carboxylic acid tert-butyl ester (10.0g, 20.0mmol are dissolved in methylene chloride 50mL), Then 50mL trifluoroacetic acid (being added dropwise about 20 minutes) is added dropwise, reaction 1.5 hours is stirred at room temperature.It is supervised with thin-layer chromatography (TLC) Reaction is surveyed, vacuum is spin-dried for solution after having reacted, and adds 300mL ethyl acetate and 2N NaOH (2x 200mL), saturated salt solution 200mL washs organic layer, anhydrous Na2SO4It is dry, it is concentrated in vacuo to obtain 7.2 grams of oily liquids, yield 90%, ESI-MS m/z:400 (M+)。
1.10 4- (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine piperazine Pyridine -1- base) ethyl benzoate
Under nitrogen protection, 5- cyclopropyl -3- (2,6- dichlorophenyl) -4- (((4- fluorine piperazine is added to two neck bottle of 250mL Pyridine -4- base) methoxy) methyl) isoxazole (2.0g, 5.01mmol), the iodo- ethyl benzoate of 4- (1.26g, 4.55mmol), carbonic acid Caesium (2.97g, 9.11mmol), tris(dibenzylideneacetone) dipalladium (208.5mg, 0.228mmol) and 2- dicyclohexyl phosphorus -2,4, 6- tri isopropyl biphenyl (217.1mg, 0.455mmol), it is rear that the dissolution of 100mL toluene is added, 16h is stirred at 120 DEG C.Use thin layer (TLC) monitoring reaction is analysed, after having reacted, suction filtered through kieselguhr is cooled to room temperature, water (100mL) and ethyl acetate is added in filtrate (3x 100mL).Saturated salt solution 200mL washs organic layer, and anhydrous Na 2SO4 is dry, vacuum concentration, petroleum ether (PE): acetic acid Ethyl ester (EA)=4:1 to 1:1 crosses column, is spin-dried for obtaining 1.55 grams of solid as 4- (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) Isoxazole -4- base) methoxy) methyl) -4- fluorine resources -1- base) ethyl benzoate, yield 62%, ESI-MS m/z:548 (M+)。
The synthesis of 1.11 final product FL1
Under nitrogen protection, 4- (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) different evil is added to two neck bottle of 250mL Azoles -4- base) methoxy) methyl) -4- fluorine resources -1- base) ethyl benzoate (1.55g, 2.82mmol), rear addition 30mL methanol, 30mL tetrahydrofuran and 10mL Isosorbide-5-Nitrae-dioxane dissolution, are then added 2N KOH (30mL, 61.0mmol).It is stirred at 70 DEG C Overnight.It is monitored and is reacted with thin-layer chromatography (TLC), vacuum is spin-dried for solution after having reacted, and 100mL water and methyl tertiary butyl ether(MTBE) is added 50mL.Water layer is adjusted to pH 5 with 2N HCl, and methylene chloride CH2Cl2 (3x 100mL) extraction, saturated salt solution is then added 200mL washs organic layer, and anhydrous Na 2SO4 is dry, and the crude product of vacuum concentration recrystallizes to obtain white solid with MeOH/CH3CN 956.0mg, yield 62%,1H NMR(400MHz,DMSO-d6) δ 12.28 (s, 1H), 7.77 (d, J=8.9Hz, 2H), 7.70- 7.50 (m, 3H), 6.96 (d, J=9.0Hz, 2H), 4.32 (s, 2H), 3.61 (d, J=13.2Hz, 2H), 3.40 (s, 2H), 3.04 (t, J=10.9Hz, 2H), 2.37-2.30 (m, 1H), 1.71-1.38 (m, 4H), 1.22-1.02 (m, 4H)；ESI-MS m/z:520(M+)。
2 4- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzoic acid preparation (FL2)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2-, remaining required raw material, reagent and preparation method are the same as real Example 1 is applied, product FL2 is obtained.1H NMR(400MHz,DMSO-d6) δ 12.28 (s, 1H), 7.77 (d, J=8.9Hz, 2H), 7.62 (td, J=8.3,6.2Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.41 (t, J=8.7Hz, 1H), 6.95 (d, J=9.0Hz, 2H), 4.35 (s, 2H), 3.61 (d, J=13.2Hz, 2H), 3.39 (s, 2H), 3.03 (t, J=10.8Hz, 2H), 2.37-2.30 (m,1H),1.70-1.35(m,4H),1.19-1.04(m,4H).LRMS(EI)m/z 504(M+)。
3 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- ethyl -1H- indole -3-carboxylic acid preparation (FL3)
Change the iodo- ethyl benzoate of 4- into the bromo- 1- ethyl -1H- indole -3-carboxylic acid methyl esters of 6-, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains product FL3.1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.89(s,1H), 7.82 (d, J=8.7Hz, 1H), 7.64 (d, J=7.5Hz, 2H), 7.57 (dd, J=9.1,6.9Hz, 1H), 7.01-6.91 (m, 2H), 4.35 (s, 2H), 4.21 (q, J=7.0Hz, 2H), 3.50-3.36 (m, 4H), 2.90 (t, J=12.3Hz, 2H), 2.44- 2.30 (m, 1H), 1.78-1.47 (m, 4H), 1.37 (t, J=7.2Hz, 3H), 1.20-1.06 (m, 4H)；LRMS(EI)m/ z587(M+)。
4 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzo [b] thiophene -2-carboxylic acid preparation (FL4)
The iodo- ethyl benzoate of 4- is substituted for the bromo- benzo of 6- [b] thiophene-2-carboxylic acid methyl esters, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains product FL4.1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),7.91(s,1H), 7.78 (d, J=9.0Hz, 1H), 7.64-7.58 (m, 1H), 7.50 (d, J=8.1Hz, 1H), 7.43-7.38 (m, 2H), 7.17 (dd, J=9.0,2.1Hz, 1H), 4.35 (s, 2H), 3.56 (d, J=13.1Hz, 2H), 3.39 (s, 2H), 3.10-2.93 (m, 2H),2.36-2.30(m,1H),1.68-1.37(m,4H),1.18-1.02(m,4H)；LRMS(EI)m/z 576(M+)。
5 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -2- naphthoic acid (FL5)
The iodo- ethyl benzoate of 4- is substituted for the bromo- 2- 2-methyl naphthoate of 6-, remaining required raw material, reagent and preparation method With embodiment 1, product FL5 is obtained.1H NMR(400MHz,DMSO-d6) δ 12.73 (s, 1H), 8.40 (s, 1H), 7.91 (d, J= 9.1Hz, 1H), 7.84 (dd, J=8.6,1.5Hz, 1H), 7.74 (d, J=8.5Hz, 1H), 7.65-7.60 (m, 2H), 7.56 (dd, J=9.3,6.6Hz, 1H), 7.43 (dd, J=9.1,1.9Hz, 1H), 7.22 (d, J=1.7Hz, 1H), 4.33 (s, 2H), 3.65 (d, J=13.0Hz, 2H), 3.39 (d, J=20.2Hz, 2H), 3.05 (t, J=10.7Hz, 2H), 2.36-2.31 (m, 1H),1.75-1.43(m,4H),1.20-0.97(m,4H)；LRMS(EI)m/z 570(M+).
6 6- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) naphthoic acid preparation (FL6)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for the bromo- 2- naphthalene of 6- Methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain product FL6.1H NMR(400MHz,DMSO-d6) δ 12.74 (s, 1H), 8.41 (s, 1H), 7.92 (d, J=9.2Hz, 1H), 7.85 (dd, J=8.6,1.7Hz, 1H), 7.75 (d, J =8.7Hz, 1H), 7.62 (td, J=8.3,6.2Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.48-7.37 (m, 2H), 7.23 (d, J=2.0Hz, 1H), 4.37 (s, 2H), 3.66 (d, J=13.0Hz, 2H), 3.39 (d, J=20.4Hz, 2H), 3.05 (t, J =10.5Hz, 2H), 2.37-2.32 (m, 1H), 1.78-1.42 (m, 4H), 1.19-1.00 (m, 4H)；LRMS(EI)m/z 554 (M+)。
7 5- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) pyridine carboxylic acid preparation (FL7)
The iodo- ethyl benzoate of 4- is substituted for 5- bromopyridine -2- carboxylate methyl ester, remaining required raw material, reagent and preparation side Method obtains product FL7 with embodiment 1.1H NMR(400MHz,DMSO-d6)δ8.13-7.81(m,2H),7.80-7.40(m,4H), 4.33(s,2H),3.69-3.25(m,4H),3.20-2.85(m,2H),2.42-2.24(m,1H),1.76-1.37(m,4H), 1.19-0.93(m,4H)；LRMS(EI)m/z 521(M+)。
8 5- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) pyridine carboxylic acid preparation (FL8)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for 5- bromopyridine- 2- carboxylate methyl ester, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain product FL8.1H NMR(400MHz,DMSO- d6)δ8.09-7.90(m,2H),7.73-7.62(m,2H),7.56-7.26(m,2H),4.36(s,2H),3.64-3.34(m, 4H),3.15-2.90(m,2H),2.41-2.20(m,1H),1.75-1.37(m,4H),1.18-0.95(m,4H)；LRMS(EI) m/z 505(M+)。
9 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- Methyl-1H-indole -3- methyl formate preparation (FL9)
Change the iodo- ethyl benzoate of 4- into the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains product FL9.1H NMR(400MHz,CDCl3) δ 8.01 (d, J=8.7Hz, 1H), 7.67 (s, 1H), 7.40 (d, J=7.8Hz, 2H), 7.34-7.30 (m, 1H), 7.26 (s, 1H), 7.02 (d, J=8.4Hz, 1H), 6.79 (s, 1H), 4.39 (s, 3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.43-3.37 (m, 4H), 3.05 (t, J=10.6Hz, 2H), 2.22-2.14(m,1H),1.91-1.71(m,4H),1.32-1.19(m,4H),1.16-1.11(m,4H)；LRMS(EI)m/z 587(M+)。
10 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- Methyl-1H-indole -3- formic acid preparation (FL10)
Change the iodo- ethyl benzoate of 4- into the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining required raw material, reagent And the preparation method is the same as that of Example 1, obtains product FL10.1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.89-7.76(m, 2H), 7.72-7.49 (m, 3H), 6.96 (d, J=8.5Hz, 2H), 4.35 (s, 2H), 3.78 (s, 3H), 3.43-3.38 (m, 4H), 2.90 (t, J=13.0Hz, 2H), 2.40-2.33 (m, 1H), 1.79-1.54 (m, 4H), 1.21-1.06 (m, 4H)；LRMS (EI)m/z 573(M+)。
11 6- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1- Methyl-1H-indole -3- formic acid preparation (FL11)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- changes the bromo- 1- first of 6- into Base -1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL11.1H NMR(400MHz,DMSO-d6) δ 11.79 (s, 1H), 7.88-7.76 (m, 2H), 7.66-7.60 (m, 1H), 7.52 (d, J= 8.1Hz,1H),7.47-7.36(m,1H),7.00-6.88(m,2H),4.38(s,2H),3.78(s,3H),3.44-3.35(m, 4H), 2.90 (t, J=11.4Hz, 2H), 2.39-2.32 (m, 1H), 1.75-1.38 (m, 4H), 1.21-1.04 (m, 4H)；LRMS (EI)m/z 557(M+)。
12 6- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1- ethyl -1H- indole -3-carboxylic acid preparation (FL12)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- changes the bromo- 1- second of 6- into Base -1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL12.1H NMR(400MHz,DMSO-d6) δ 11.82 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=8.7Hz, 1H), 7.67-7.58 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.42 (t, J=8.7Hz, 1H), 7.02-6.86 (m, 2H), 4.38 (s, 2H), 4.21 (q, J=7.2Hz, 2H), 3.45-3.35 (m, 3H), 2.89 (t, J=10.9Hz, 2H), 2.89 (t, J=10.9Hz, 2H), 2.39-2.33 (m, 1H), 1.72-1.47 (m, 4H), 1.37 (t, J=7.2Hz, 2H), 1.20-1.07 (m, 4H)；LRMS(EI) m/z 571(M+)。
13 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzo [d] thiazole -6- methyl formate preparation (FL13)
5- cyclopropyl -3- (2,6- dichlorophenyl) -4- (((4- fluorine resources -4- base) methoxy) first is added in 100mL eggplant type bottle Base) isoxazole (2.0g, 5.01mmol), simultaneously [d] thiazole -6- methyl formate (1.09g, 4.01mmol), N, N- bis- are different for 2- bromobenzene Propylethylamine (776.8mg, 6.01mmol), it is rear that the dissolution of 50mL N-methyl pyrrolidones is added, it is stirred overnight at 60 DEG C.Use thin layer (TLC) monitoring reaction is chromatographed, after having reacted, water (100mL) and ethyl acetate (3x 100mL) is added.Saturated salt solution 200mL Organic layer is washed, anhydrous Na 2SO4 is dry, and vacuum concentration, petroleum ether (PE): ethyl acetate (EA)=5:1 to 1:1 crosses column, is spin-dried for Obtaining 2.04 grams of solid is 2- (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzo [d] thiazole -6- methyl formate, yield 69%,1H NMR(500MHz,CDCl3) δ 8.41 (d, J= 2.9Hz, 1H), 7.91 (dd, J=15.0,2.9Hz, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.57 (d, J= 15.0Hz, 1H), 7.45 (dd, J=14.9,1.0Hz, 2H), 4.80 (s, 2H), 4.41 (dt, J=24.8,11.4Hz, 2H), 3.96 (dt, J=24.8,11.4Hz, 2H), 3.90 (s, 3H), 3.76 (d, J=50.4Hz, 2H), 2.73 (p, J=20.2Hz, 1H), 1.96 (ddt, J=50.4,24.9,11.4Hz, 2H), 1.66 (ddt, J=50.3,24.9,11.4Hz, 2H), 1.45- 0.88(m,4H)；ESI-MS m/z:591(M+1).
14 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzo [d] thiazole -6- formic acid preparation (FL14)
Under nitrogen protection, 2- (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) different evil is added to two neck bottle of 250mL Azoles -4- base) methoxy) methyl) -4- fluorine resources -1- base) benzo [d] thiazole -6- methyl formate (FL13,2.05g, 3.56mmol), 30mL methanol, 30mL tetrahydrofuran and 10mL Isosorbide-5-Nitrae-dioxane dissolution are added afterwards, be then added 2N KOH (30mL, 61.0mmol).It is stirred overnight at 70 DEG C.It is monitored and is reacted with thin-layer chromatography (TLC), vacuum is spin-dried for solution after having reacted, and is added 100mL water and methyl tertiary butyl ether(MTBE) 50mL.Water layer is adjusted to pH 5 with 2N HCl, and methylene chloride CH2Cl2 (3x is then added It 100mL) extracts, saturated salt solution 200mL washs organic layer, and anhydrous Na 2SO4 is dry, and the crude product of vacuum concentration uses MeOH/ CH3CN recrystallizes to obtain white solid 1.4g, yield 70%.1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),8.38(d,J =1.7Hz, 1H), 7.86 (dd, J=8.4,1.8Hz, 1H), 7.66-7.52 (m, 3H), 7.48 (d, J=8.5Hz, 1H), 4.34 (s, 2H), 3.87 (d, J=12.7Hz, 2H), 3.41 (d, J=19.8Hz, 2H), 3.32-3.29 (m, 2H), 2.38-2.31 (m, 1H),1.79-1.44(m,4H),1.20-1.03(m,4H)；LRMS(EI)m/z 577(M+)。
15 6- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1- ethyl -1H- indole -3-carboxylic acid methyl esters preparation (FL15)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- changes the bromo- 1- second of 6- into Base -1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL15.1H NMR(400MHz,CDCl3) δ 8.02 (d, J=8.0Hz, 1H), 7.74 (s, 1H), 7.41-7.36m, 1H), 7.31 (d, J= 8.0Hz, 1H), 7.11 (t, J=8.4Hz, 1H), 7.01 (d, J=6.8Hz, 1H), 6.82 (s, 1H), 4.42 (s, 2H), 4.14 (q, J=7.3Hz, 2H), 3.89 (s, 3H), 3.38 (d, J=19.1Hz, 4H), 3.05 (t, J=12.9Hz, 2H), 2.20- 2.13 (m, 1H), 1.92-1.65 (m, 4H), 1.50 (t, J=7.3Hz, 3H), 1.30-1.22 (m, 2H), 1.16-1.11 (m, 2H)；LRMS(EI)m/z 585(M+)。
16 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- (2- ethoxy) -1H- indole -3-carboxylic acid preparation (FL16)
The iodo- ethyl benzoate of 4- is substituted for the bromo- 1- of 6- (2- ((trimethyl silicon substrate) oxygen) ethyl) -1H- indoles -3- first Acid, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL16.1H NMR(400MHz,DMSO-d6)δ 8.17-7.96(m,3H),7.69-7.69(m,3H),7.59-7.55(m,1H),4.37(s,2H),4.30(s,2H),3.79- 3.70(m,4H),3.50(s,4H),2.41-2.35(m,1H),2.08-1.80(m,4H),1.20-1.06(m,4H)；LRMS (EI)m/z 603(M+)。
17 5- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) pyridine carboxylic acid methyl esters preparation (FL17)
The iodo- ethyl benzoate of 4- is substituted for 5- bromopyridine -2- carboxylate methyl ester, remaining required raw material, reagent and preparation side Method obtains target product FL17 with embodiment 1.1H NMR(400MHz,CDCl3) δ 8.35 (d, J=2.9Hz, 1H), 8.01 (d, J= 8.8Hz, 1H), 7.40 (d, J=1.9Hz, 1H), 7.38 (s, 1H), 7.33 (dd, J=9.3,6.6Hz, 1H), 7.17 (dd, J= 8.9,2.9Hz, 1H), 4.37 (s, 2H), 3.97 (s, 3H), 3.67 (d, J=13.1Hz, 2H), 3.36 (d, J=17.9Hz, 2H), 3.22 (td, J=12.8,2.6Hz, 2H), 2.17-2.10 (m, 1H), 1.83 (t, J=11.6Hz, 2H), 1.75-1.50 (m,2H),1.33-1.26(m,2H),1.16-1.11(m,2H)；LRMS(EI)m/z 535(M+)。
18 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -2- 2-methyl naphthoate preparation (FL18)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for the bromo- 2- naphthalene of 6- Methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL18.1H NMR(400MHz, CDCl3) δ 8.48 (s, 1H), 7.99 (d, J=7.7Hz, 1H), 7.82 (d, J=8.1Hz, 1H), 7.68 (d, J=5.3Hz, 1H), 7.37 (td, J=8.2,5.9Hz, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 7.09 (t, J=8.4Hz, 2H), 4.41 (s, 2H), 3.96 (s, 3H), 3.63 (d, J=12.6Hz, 2H), 3.37 (d, J=19.1Hz, 2H), 3.20 (s, 2H), 2.20- 2.10(m,1H),1.95-1.80(m,2H),1.57(s,2H),1.31-1.24(m,2H),1.15-1.10(m,2H)；LRMS (EI)m/z 568(M+)。
19 2- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) benzo [d] thiazole -6- formic acid preparation (FL19)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2-, remaining required raw material, reagent and preparation method are the same as real Example 14 is applied, target product FL19 is obtained.1H NMR(400MHz,DMSO-d6) δ 12.69 (s, 1H), 8.38 (d, J=1.7Hz, 1H), 7.86 (dd, J=8.5,1.8Hz, 1H), 7.61 (td, J=8.3,6.2Hz, 1H), 7.49 (t, J=8.0Hz, 2H), 7.44- 7.36 (m, 1H), 4.36 (s, 2H), 3.86 (d, J=12.7Hz, 2H), 3.53-3.17 (m, 4H), 2.37-2.30 (m, 1H), 1.88-1.43(m,4H),1.20-1.04(m,4H)；LRMS(EI)m/z 561(M+)。
20 3- of embodiment ((4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1H- indazole -6- formic acid preparation (FL20)
The iodo- ethyl benzoate of 4- is substituted for the bromo- 1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- methyl formate, Remaining required raw material, reagent and the preparation method is the same as that of Example 1, obtain target product FL20.1H NMR(400MHz,DMSO-d6)δ 13.00 (s, 1H), 12.31 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=8.6Hz, 1H), 7.65-7.60 (m, 2H), 7.56- 7.52 (m, 2H), 4.35 (s, 2H), 3.58 (d, J=12.7Hz, 2H), 3.40 (d, J=20.4Hz, 2H), 3.09-2.96 (m, 2H),2.39-2.33(m,1H),1.80-1.57(m,4H),1.20-1.06(m,4H)；LRMS(EI)m/z 560(M+)。
21 3- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1H- indazole -6- formic acid preparation (FL21)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for the bromo- 1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 1, Obtain target product FL21.1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),12.34(s,1H),7.95(s,1H),7.82 (d, J=8.6Hz, 1H), 7.63-7.57 (m, 1H), 7.54 (dd, J=8.6,1.3Hz, 1H), 7.50 (d, J=8.6Hz, 1H), 7.44-7.36 (m, 1H), 4.38 (s, 2H), 3.61-3.54 (m, 2H), 3.39 (d, J=20.6Hz, 2H), 3.08-2.99 (m, 2H),2.39-2.32(m,1H),1.78-1.56(m,4H),1.21-1.07(m,4H)；LRMS(EI)m/z 544(M+)。
22 3- of embodiment ((4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1H- indazole -5- formic acid preparation (FL22)
The iodo- ethyl benzoate of 4- is substituted for the bromo- 1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole -5- methyl formate, Remaining required raw material, reagent and the preparation method is the same as that of Example 1, obtain target product FL22.1H NMR(400MHz,DMSO-d6)δ 12.71 (s, 1H), 12.36 (s, 1H), 8.35 (s, 1H), 7.86 (dd, J=8.8,1.2Hz, 1H), 7.65-7.60 (m, 2H), 7.55 (dd, J=9.2,6.8Hz, 1H), 7.41 (d, J=8.8Hz, 1H), 4.35 (s, 2H), 3.59 (d, J=15.5Hz, 2H), 3.41 (d, J=20.1Hz, 2H), 3.17-2.88 (m, 2H), 2.39-2.33 (m, 1H), 1.82-1.54 (m, 4H), 1.21- 1.00(m,4H)；LRMS(EI)m/z 560(M+)。
23 3- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -1H- indazole -5- formic acid preparation (FL23)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for the bromo- 1- of 3- (tetrahydro -2H- pyrans -2- base) -1H- indazole -6- methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 1, Obtain target product FL23.1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),12.36(s,1H),8.34(s,1H),7.86 (dd, J=8.8,1.3Hz, 1H), 7.61 (td, J=8.3,6.2Hz, 1H), 7.51 (d, J=8.1Hz, 1H), 7.43-7.43 (m, 2H), 4.38 (s, 2H), 3.59 (d, J=14.2Hz, 2H), 3.40 (d, J=20.3Hz, 2H), 3.16-3.03 (m, 2H), 2.39-2.32(m,1H),1.88-1.49(m,4H),1.20-0.98(m,4H)；LRMS(EI)m/z 544(M+)。
Embodiment 24 5- cyclopropyl -3- (2,6- dichlorophenyl) -4- (((the fluoro- 1- of 4- (4- (trifluoromethyl) phenyl) piperazine Pyridine -4- base) methoxy) methyl) and isoxazole preparation (FL24)
The iodo- ethyl benzoate of 4- is substituted for 1- bromo- 4- (trifluoromethyl) benzene, remaining required raw material, reagent and preparation side Method obtains target product FL24 with embodiment 1.1H NMR(400MHz,CD3OD)δ7.63-7.59(m,2H),7.58-7.52(m, 1H), 7.49 (d, J=8.8Hz, 2H), 7.04 (d, J=8.8Hz, 2H), 4.32 (s, 2H), 3.58 (d, J=13.1Hz, 2H), 3.39(s,2H),3.10-2.94(m,2H),2.37-2.30(m,1H),1.73-1.36(m,4H),1.22-1.00(m,4H)； LRMS(EI)m/z 544(M+)。
25 3- of embodiment (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl -4- (((the fluoro- 1- of 4- (4- (trifluoromethyl) phenyl) piperazine Pyridine -4- base) methoxy) methyl) and isoxazole preparation (FL25)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for the bromo- 4- of 1- (trifluoromethyl) benzene, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL25.1H NMR (400MHz,DMSO-d6) δ 7.62 (td, J=8.3,6.2Hz, 1H), 7.51-7.48 (m, 3H), 7.46-7.37 (m, 1H), 7.05 (d, J=8.8Hz, 2H), 4.35 (s, 2H), 3.86-3.50 (m, 2H), 3.36 (d, J=20.2Hz, 2H), 3.10-2.89 (m,2H),2.37-2.30(m,1H),1.67-1.38(m,4H),1.21-1.06(m,4H)；LRMS(EI)m/z 527(M+)。
26 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- difluorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- Methyl-1H-indole -3- formic acid preparation (FL26)
2,6- dichlorobenzaldehyde is substituted for 2,6- difluorobenzaldehyde and the iodo- ethyl benzoate of 4- changes the bromo- 1- methyl-of 6- into 1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL26.1H NMR (400MHz,DMSO-d6) δ 11.76 (s, 1H), 7.84 (s, 1H), 7.81 (d, J=9.5Hz, 1H), 7.74-7.59 (m, 1H), 7.40-7.21(m,2H),7.01-6.92(m,2H),4.41(s,2H),3.77(s,3H),3.42-3.36(m,4H),3.03- 2.77(m,2H),2.38-2.31(m,1H),1.82-1.42(m,4H),1.19-1.03(m,4H)；LRMS(EI)m/z 540(M+).
27 6- of embodiment (4- (((5- cyclopropyl -3- (2,6- difluorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -1- ethyl -1H- indole -3-carboxylic acid preparation (FL27)
2,6- dichlorobenzaldehyde is substituted for 2,6- difluorobenzaldehyde and the iodo- ethyl benzoate of 4- changes the bromo- 1- ethyl-of 6- into 1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL27.1H NMR (400MHz,DMSO-d6) δ 11.81 (s, 1H), 7.89 (s, 1H), 7.81 (d, J=8.7Hz, 1H), 7.69-7.58 (m, 1H), 7.33-7.28 (m, 2H), 6.98 (d, J=1.5Hz, 1H), 6.96-6.92 (m, 1H), 4.41 (s, 2H), 4.20 (q, J= 7.2Hz,2H),3.39-3.36(m,4H),3.06-2.77(m,2H),2.38-2.31(m,1H),1.75-1.50(m,4H), 1.36 (t, J=7.2Hz, 3H), 1.18-1.03 (m, 4H)；LRMS(EI)m/z 554(M+).
28 2- of embodiment (3- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) benzo [d] thiazole -6- formic acid preparation (FL28)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- of 4- Base) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, Reagent and the preparation method is the same as that of Example 13,14, obtains target product FL28.1H NMR(400MHz,DMSO-d6)δ12.66(s,1H), 8.40 (s, 1H), 7.87 (d, J=8.4Hz, 1H), 7.65 (dd, J=14.4,7.8Hz, 1H), 7.59-7.43 (m, 3H), 4.39 (s, 2H), 4.31 (s, 2H), 3.51 (d, J=30.0Hz, 2H), 2.42-2.35 (m, 1H), 2.06-1.84 (m, 8H), 1.33- 1.04(m,4H)；LRMS(EI)m/z 587(M+).
29 2- of embodiment (3- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL29)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2-, 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate is replaced At the bromo- 4- fluorobenzene of 2-, simultaneously [d] thiazole -6- methyl formate and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol are substituted for Tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and preparation side Method obtains target product FL29 with embodiment 13,14.1H NMR(400MHz,DMSO-d6) δ 13.02 (s, 1H), 8.27 (d, J= 1.5Hz 1H), 7.68-7.61 (m, 2H), 7.56 (d, J=8.1Hz, 1H), 7.51-7.43 (m, 1H), 4.39 (s, 2H), 4.34 (s, 2H), 3.51 (d, J=29.8Hz, 2H), 2.42-2.35 (m, 1H), 2.02-1.91 (m, 8H), 1.20-1.07 (m, 4H)； LRMS(EI)m/z 605(M+)。
30 2- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL30)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate is replaced At the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain mesh Mark product FL30.1H NMR(400MHz,DMSO-d6) δ 12.97 (s, 1H), 8.21 (d, J=1.5Hz, 1H), 7.64 (d, J= 1.1Hz, 1H), 7.62 (s, 1H), 7.59 (dd, J=11.5,1.5Hz, 1H), 7.54 (dd, J=9.0,7.2Hz, 1H), 4.34 (s,2H),3.79-3.37(m,6H),2.40-2.33(m,1H),1.82-1.69(m,2H),1.54-1.37(m,2H),1.21- 1.06(m,4H)；LRMS(EI)m/z 579(M+).
31 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL31)
By 2- bromobenzene, simultaneously [d] thiazole -6- methyl formate is substituted for the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate, Raw material, reagent needed for remaining and the preparation method is the same as that of Example 14, obtains target product FL31.1H NMR(400MHz,DMSO-d6)δ 12.94 (s, 1H), 8.25 (d, J=1.5Hz, 1H), 7.63 (d, J=1.9Hz, 1H), 7.61-7.59 (m, 2H), 7.55 (dd, J =9.3,6.6Hz, 1H), 4.33 (s, 2H), 3.88 (d, J=11.6Hz, 2H), 3.46-3.28 (m, 4H), 2.38-2.31 (m, 1H),1.84-1.50(m,4H),1.19-1.06(m,4H)；LRMS(EI)m/z 595(M+).
32 2- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- methyl formate preparation (FL32)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate is replaced At the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain mesh Mark product FL32.1H NMR(400MHz,CDCl3) δ 8.08 (d, J=0.8Hz, 1H), 7.70 (dd, J=11.3,0.7Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.32 (dd, J=8.7,7.4Hz, 1H), 4.36 (s, 2H), 3.91 (s, 3H), 3.71- 3.43(m,6H),2.17-2.11(m,1H),1.84-1.68(m,2H),1.70-1.57(m,2H),1.31-1.25(m,2H), 1.17-1.12(m,2H)；LRMS(EI)m/z 593(M+).
33 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid (FL33)
By 2- bromobenzene simultaneously [d] thiazole -6- methyl formate be substituted for the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain target product FL33.1H NMR(400MHz,DMSO-d6) δ 12.96 (s, 1H), 8.27 (d, J=1.5Hz, 1H), 7.70 (d, J=1.2Hz, 1H), 7.68 (s,1H),7.64-7.58(m,2H),4.36(s,4H),3.56-3.29(m,4H),2.46-2.32(m,1H),2.05-1.83 (m,6H),1.21-1.05(m,4H)；LRMS(EI)m/z 621(M+).
34 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) benzo [d] thiazole -6- formic acid preparation (FL34)
(the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- Azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and the preparation method is the same as that of Example 14.1H NMR (400MHz,DMSO-d6) δ 8.40 (d, J=1.7Hz, 1H), 7.87 (dd, J=8.5,1.8Hz, 1H), 7.69 (d, J= 1.3Hz, 1H), 7.67 (s, 1H), 7.60 (dd, J=9.1,7.1Hz, 1H), 7.53 (d, J=8.5Hz, 1H), 4.35 (s, 2H), 4.30 (s, 2H), 3.51 (d, J=30.2Hz, 2H), 2.42-2.31 (m, 1H), 2.01-1.87 (m, 6H), 1.47-1.40 (m, 2H),1.21-1.07(m,4H)；LRMS(EI)m/z 603(M+).
35 2- of embodiment (3- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -4- fluorobenzene simultaneously [d] thiazole -6- methyl formate preparation (FL35)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate replaces Change the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate and the replacement of (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol into At tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and preparation Method obtains target product FL35 with embodiment 14.1H NMR(400MHz,CDCl3) δ 8.31 (d, J=1.6Hz, 1H), 8.01 (dd, J=8.5,1.5Hz, 1H), 7.60-7.50 (m, 2H), 7.43-7.38 (m, 2H), 4.47 (s, 2H), 4.44 (s, 2H), 3.92 (s, 3H), 3.51 (d, J=28.0Hz, 2H), 2.33-2.05 (m, 5H), 1.65-1.49 (m, 4H), 1.28-1.19 (m, 2H),1.15-1.08(m,2H)；LRMS(EI)m/z 650(M+).
36 2- of embodiment (3- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL36)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate replaces Change the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate and the replacement of (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol into At tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and preparation Method obtains target product FL36 with embodiment 14.1H NMR(400MHz,DMSO-d6) δ 13.00 (s, 1H), 8.27 (d, J= 1.5Hz, 1H), 7.73-7.69 (m, 1H), 7.67 (dd, J=6.5,1.7Hz, 1H), 7.64 (dd, J=4.1,1.6Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.58-7.55 (m, 1H), 4.44 (s, 2H), 4.35 (s, 2H), 3.54 (d, J=29.6Hz, 2H), 2.41-2.34 (m, 1H), 2.05-1.85 (m, 6H), 1.51 (q, J=6.5Hz, 2H), 1.21-1.05 (m, 4H)；LRMS (EI)m/z636(M+).
37 2- of embodiment (3- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) benzo [d] thiazole -6- formic acid preparation (FL37)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine-of 4- 4- yl) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, and it is former needed for remaining Material, reagent and the preparation method is the same as that of Example 14, obtain target product FL37.1H NMR(500MHz,CDCl3) δ 8.58 (d, J= 3.1Hz, 1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 8.07 (dd, J=14.9,3.0Hz, 1H), 7.68 (d, J= 15.0Hz, 1H), 7.57-7.29 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 4.80 (s, 2H), 4.77 (ddd, J= 12.9,7.4,4.2Hz, 2H), 4.11 (d, J=50.6Hz, 2H), 2.72 (p, J=20.1Hz, 1H), 2.36 (ddd, J= 50.6,24.9,6.4Hz, 2H), 2.11 (ddd, J=50.4,24.9,6.4Hz, 2H), 2.01-1.76 (m, 4H), 1.34-1.11 (m,2H),1.11-0.89(m,2H).LRMS(EI)m/z 618(M+).
38 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - 4- fluorine resources -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL38)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine-of 4- 4- yl) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, and it is former needed for remaining Material, reagent and the preparation method is the same as that of Example 14, obtain target product FL38.1H NMR(500MHz,CDCl3) δ 8.00 (d, J=8.0, 2H), 7.53 (d, J=8.4,2H), 7.17 (s, 1H), 6.86 (s, 1H), 3.96 (s, 3H), 3.91 (s, 6H), 3.74 (s, 2H), 3.32-3.41(m,3H),2.85-2.92(m,2H),2.52-2.71(m,1H),2.28-2.48(m,1H),2.19-2.30(m, 1H),2.07-2.14(m,4H),1.70-1.82(m,4H)；LRMS(EI)m/z 610(M+).
39 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - 4- fluorine resources -1- base) benzo [d] thiazole -6- formic acid preparation (FL39)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, remaining required raw material, reagent and preparation method With embodiment 14, target product FL39. is obtained1H NMR(500MHz,CDCl3) δ 8.58 (d, J=3.1Hz, 1H), 8.43 (dd, J= 14.3,3.7Hz, 1H), 8.07 (dd, J=15.0,2.9Hz, 1H), 7.68 (d, J=15.0Hz, 1H), 7.55-7.32 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 4.80 (s, 2H), 4.52 (dt, J=24.9,11.0Hz, 2H), 4.24 (dt, J =24.9,11.0Hz, 2H), 3.77 (d, J=50.4Hz, 2H), 2.89 (p, J=20.2Hz, 1H), 2.05 (ddt, J=50.4, 24.9,11.0Hz, 2H), 1.74 (ddt, J=50.4,24.7,11.0Hz, 2H), 1.23 (m, 2H), 1.11-0.87 (m, 2H) .LRMS(EI)m/z 592(M+).
40 6- of embodiment (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) -1- Methyl-1H-indole -3- methyl formate preparation (FL40)
(the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- Azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change the bromo- 1- Methyl-1H-indole -3- formic acid first of 6- into Ester, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL40.1H NMR(500MHz,CDCl3)δ 9.00 (s, 1H), 8.10 (d, J=7.5Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.46 (d, J=7.4Hz, 2H), 6.62 (dd, J=7.5,1.4Hz, 1H), 6.48 (d, J=1.4Hz, 1H), 4.80 (s, 2H), 4.24-4.15 (m, 2H), 3.93 (d, J =25.3Hz, 2H), 3.82 (d, J=80.0Hz, 6H), 2.71 (p, J=10.2Hz, 1H), 2.22-1.96 (m, 4H), 1.79 (ddd, J=25.3,12.5,3.2Hz, 2H), 1.54 (tdd, J=5.8,3.8,1.9Hz, 2H), 1.35-1.13 (m, 2H), 1.10-0.90(m,2H).LRMS(EI)m/z 613(M+).
41 6- of embodiment (3- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -1- Methyl-1H-indole -3- methyl formate preparation (FL41)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine-of 4- 4- yl) methanol is substituted for the fluoro- 3- of tert-butyl 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- benzene first of 4- Acetoacetic ester changes the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining required raw material, reagent and the same embodiment of preparation method into 1, obtain target product FL14.1H NMR(500MHz,CDCl3) δ 9.00 (s, 1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 8.10 (d, J=15.0Hz, 1H), 7.65-7.35 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.62 (dd, J= 15.0,2.9Hz, 1H), 6.48 (d, J=2.9Hz, 1H), 4.80 (s, 2H), 4.12 (tt, J=8.6,6.4Hz, 2H), 4.00 (d, J=50.4Hz, 2H), 3.82 (d, J=80.0Hz, 6H), 2.80 (dd, J=40.3,20.2Hz, 1H), 2.11 (m, 4H), 1.86-1.39(m,4H),1.36-0.78(m,4H).LRMS(EI)m/z 628(M+).
42 6- of embodiment (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) -1- Methyl-1H-indole -3- formic acid preparation (FL42)
(the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- Azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change the bromo- 1- Methyl-1H-indole -3- formic acid first of 6- into Ester, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL42.1H NMR(500MHz,CDCl3)δ 9.26 (s, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.60-7.28 (m, 3H), 6.72 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.26 (tt, J=8.5,6.4Hz, 2H), 3.96 (d, J= 50.4Hz, 2H), 3.74 (s, 3H), 3.03 (p, J=20.2Hz, 1H), 2.34 (ddd, J=50.4,24.8,6.4Hz, 2H), 2.22-1.84(m,4H),1.81-1.40(m,2H),1.37-0.82(m,4H).LRMS(EI)m/z 599(M+).
43 6- of embodiment (3- (((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -1- Methyl-1H-indole -3- formic acid preparation (FL43)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine-of 4- 4- yl) methanol is substituted for the fluoro- 3- of tert-butyl 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- benzene first of 4- Acetoacetic ester changes the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining required raw material, reagent and the same embodiment of preparation method into 1, obtain target product FL43.1H NMR(500MHz,CDCl3) δ 9.26 (s, 1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 7.78-7.29 (m, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.68 (d, J=2.9Hz, 1H), 6.12 (dd, J= 15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.25 (tt, J=8.6,6.4Hz, 2H), 4.03 (d, J=50.4Hz, 2H), 3.74 (s,3H),3.13-2.77(m,1H),2.52-1.96(m,6H),1.81(s,1H),1.41-0.73(m,4H).LRMS(EI)m/z 614(M+).
44 6- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxy) methyl) -4- fluorine resources -1- base) -1- Methyl-1H-indole -3- formic acid preparation (FL44)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate and The iodo- ethyl benzoate of 4- changes the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining required raw material, reagent and preparation method into With embodiment 1,1H NMR(500MHz,CDCl3)δ9.26(s,1H),7.89-7.58(m,1H),7.52-7.21(m,3H),6.79 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 3.76 (t, J=25.2Hz, 5H), 3.64-3.40 (m, 3H), 3.39-3.18 (m, 2H), 2.94 (dd, J=24.8,14.6Hz, 1H), 2.35-2.02 (m, 2H), 1.98-1.50(m,3H),0.80(m,2H).LRMS(EI)m/z 623(M+).
45 2- of embodiment (4- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxy) methyl) -4- fluorine resources -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL45)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate and Simultaneously [d] thiazole -6- methyl formate is substituted for the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate to 2- bromobenzene, remaining required raw material, Reagent and the preparation method is the same as that of Example 14, obtains target product FL45.1H NMR(500MHz,CDCl3) δ 8.35 (d, J=2.9Hz, 1H), 7.96 (dd, J=15.9,2.9Hz, 1H), 7.64 (dd, J=16.2,13.7Hz, 1H), 7.46 (dd, J=14.8, 1.1Hz, 2H), 4.80 (s, 2H), 4.37 (dt, J=24.9,10.9Hz, 2H), 4.03 (dt, J=24.9,10.9Hz, 2H), 3.63 (d, J=50.4Hz, 2H), 3.23 (dd, J=24.7,17.0Hz, 1H), 2.94 (dd, J=24.8,17.0Hz, 1H), 2.09 (ddt, J=50.4,24.7,10.9Hz, 2H), 1.90-1.37 (m, 3H), 1.33-0.54 (m, 2H) .LRMS (EI) m/z 645(M+).
46 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- difluorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) benzo [d] thiazole -6- formic acid preparation (FL46)
2,6- dichlorobenzaldehyde is substituted for 2,6- difluorobenzaldehyde, remaining required raw material, reagent and preparation method are the same as real Example 14 is applied, target product FL46 is obtained.1H NMR(400MHz,DMSO-d6) δ 13.02 (s, 1H), 8.25 (d, J=1.3Hz, 1H), 7.63 (ddd, J=11.6,7.7,1.5Hz, 2H), 7.30 (t, J=8.1Hz, 2H), 4.40 (s, 2H), 3.88 (d, J= 10.3Hz, 2H), 3.62-3.26 (m, 6H), 2.34 (ddd, J=13.4,8.3,5.3Hz, 1H), 1.87-1.31 (m, 4H), 1.36-0.86(m,4H).LRMS(EI)m/z 544(M+).
47 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- difluorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL47)
2,6- dichlorobenzaldehyde is substituted for 2,6- difluorobenzaldehyde and 2- bromobenzene, and simultaneously [d] thiazole -6- methyl formate is replaced At the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain mesh Mark product DC69, yield 80%.1H NMR(500MHz,CDCl3) δ 8.32 (d, J=2.9Hz, 1H), 7.64 (dd, J=16.0, 3.0Hz, 1H), 7.53-7.19 (m, 1H), 7.21-6.83 (m, 2H), 4.78 (s, 2H), 4.56 (dt, J=24.9,11.4Hz, 2H), 4.00-3.78 (m, 4H), 2.91 (p, J=20.1Hz, 1H), 2.12-1.68 (m, 4H), 1.41-0.71 (m, 4H)； LRMS(EI)m/z 562(M+).
48 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid (FL48)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo Simultaneously [d] thiazole -6- methyl formate is substituted for the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- first for [3.2.1] octyl- 8- carboxylate and 2- bromobenzene Sour methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain target product FL48.1H NMR(500MHz, CDCl3) δ 9.00-8.07 (m, 1H), 8.05 (dd, J=14.9,3.0Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.47 (d, J =7.4Hz, 2H), 4.82 (s, 2H), 4.66 (tt, J=8.5,6.4Hz, 2H), 4.27 (d, J=50.4Hz, 1H), 3.29- 2.91(m,2H),2.60-1.90(m,4H),1.89-1.31(m,5H),1.26-0.66(m,2H)；LRMS(EI)m/z 671(M+).
49 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) and benzo [d] thiazole -6- formic acid preparation (FL49)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and preparation method obtain target product FL49 with embodiment 32.1H NMR(500MHz,CDCl3) δ 9.01-8.08 (m, 1H), 8.07 (dd, J=14.9,3.0Hz, 1H), 7.90-7.53 (m, 2H), 7.46 (dd, J=14.9,1.0Hz, 2H), 4.80 (s, 2H), 4.64 (tt, J=8.5,6.4Hz, 2H), 4.25 (d, J= 50.4Hz,1H),3.29-2.90(m,2H),2.60-1.93(m,4H),1.89-1.32(m,5H),1.26-0.67(m,2H)； LRMS(EI)m/z653(M+).
50 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -1- Methyl-1H-indole -3- formic acid (FL50)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change the bromo- 1- Methyl-1H-indole -3- methyl formate of 6-, remaining institute into It needs raw material, reagent and the preparation method is the same as that of Example 1, obtain target product FL50.1H NMR(500MHz,CDCl3)δ9.26(s,1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.49-7.32 (m, 3H), 6.73 (d, J=2.9Hz, 1H), 6.12 (dd, J= 15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.56-4.24 (m, 2H), 4.19 (dd, J=72.1,28.4Hz, 2H), 3.98- 3.77 (m, 2H), 3.74 (s, 3H), 3.52 (dd, J=24.8,16.4Hz, 1H), 3.19-2.48 (m, 3H), 2.02-1.24 (m, 3H),1.27-0.29(m,4H).LRMS(EI)m/z 649(M+).
51 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) -4- fluorine resources -1- base) and -1- ethyl -1H- indole -3-carboxylic acid preparation (FL51)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate and The iodo- ethyl benzoate of 4- changes the bromo- 1- ethyl -1H- indole -3-carboxylic acid methyl esters of 6-, remaining required raw material, reagent and preparation method into With embodiment 1, target product FL51 is obtained.1H NMR (500MHz, CDCl3) δ 9.26 (s, 1H), 7.64 (dd, J=16.1, 13.7Hz, 1H), 7.56-7.23 (m, 3H), 6.79 (d, J=3.1Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.24 (q, J=12.6Hz, 2H), 3.77 (d, J=50.4Hz, 2H), 3.52 (dt, J=24.9,12.9Hz, 2H), 3.23 (ddd, J=25.0,13.5,6.6Hz, 3H), 2.85 (dd, J=24.8,15.2Hz, 1H), 2.32-2.00 (m, 2H), 1.94-1.48 (m, 3H), 1.06 (t, J=12.6Hz, 3H), 1.24-0.39 (m, 2H)；LRMS(EI)m/z 637(M+).
52 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) and -1- ethyl -1H- indole -3-carboxylic acid preparation (FL52)
By 3- cyclopropyl -3- oxo-propionic acid methyl ester change into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change the bromo- 1- ethyl -1H- indole -3-carboxylic acid methyl esters of 6-, remaining institute into It needs raw material, reagent and the preparation method is the same as that of Example 1, obtain target product FL52.1H NMR(500MHz,CDCl3)δ9.26(s,1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.57-7.33 (m, 3H), 6.71 (d, J=3.1Hz, 1H), 6.12 (dd, J= 15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.47-4.08 (m, 6H), 4.07-3.75 (m, 2H), 3.46 (dd, J=24.8, 12.4Hz,1H),3.16-2.78(m,3H),2.15-1.47(m,3H),1.40-0.16(m,7H)；LRMS(EI)m/z 663(M+).
53 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole -4- Base) methoxyl methyl) -4- fluorine resources -1- base) and benzo [d] thiazole -6- formic acid preparation (FL53)
Change 3- cyclopropyl -3- oxo-propionic acid methyl ester into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate, Remaining required raw material, reagent and the preparation method is the same as that of Example 14, obtain target product FL53.1H NMR(500MHz,CDCl3)δ8.58 (d, J=1.6Hz, 1H), 8.07 (dd, J=7.5,1.4Hz, 1H), 7.83-7.57 (m, 2H), 7.46 (d, J=7.4Hz, 2H), 4.80 (s, 2H), 4.50 (dt, J=12.3,5.5Hz, 2H), 4.19 (dt, J=12.4,5.5Hz, 2H), 3.88 (dd, J= 12.4,7.6Hz, 1H), 3.81 (d, J=25.3Hz, 2H), 2.84 (dd, J=12.4,7.6Hz, 1H), 2.02 (ddt, J= 25.2,12.3,5.4Hz, 2H), 1.74 (ddt, J=25.1,12.4,5.5Hz, 2H), 1.69-1.51 (m, 1H), 1.42-1.20 (m,1H),0.78-0.64(m,1H).LRMS(EI)m/z 627(M+).
54 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- (2,2- difluorocyclopropyl) isoxazole -4- base) methoxy Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL54)
3- cyclopropyl -3- oxo-propionic acid methyl ester is changed into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate to change At 3-, (2,2- difluorocyclopropyl -3- oxopropanoic acid, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol are substituted for tertiary fourth Simultaneously [d] thiazole -6- methyl formate replaces for the fluoro- 3- of base 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and 2- bromobenzene Change the bromo- 4- fluorobenzene of 2- simultaneously [d] thiazole -6- methyl formate into, remaining required raw material, reagent and the preparation method is the same as that of Example 14 obtain Target product FL54.1H NMR(500MHz,CDCl3) δ 8.35 (d, J=3.1Hz, 1H), 7.74 (dd, J=15.9,3.1Hz, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.46 (dd, J=14.9,1.0Hz, 2H), 4.77-4.71 (m, 2H), 4.70 (s, 2H), 4.31 (d, J=50.6Hz, 2H), 3.33 (tt, J=41.8,23.1Hz, 1H), 2.84 (ddd, J=50.4,24.8, 6.7Hz, 2H), 2.17-1.95 (m, 2H), 1.83 (ddd, J=50.5,24.8,6.7Hz, 2H), 1.71-1.48 (m, 2H), 1.39-0.98(m,2H)；LRMS(EI)m/z 657(M+).
55 22- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- (2,2- difluorocyclopropyl) isoxazole -4- base) methoxy Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) benzo [d] thiazole -6- formic acid preparation (FL55)
3- cyclopropyl -3- oxo-propionic acid methyl ester is changed into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate to change At 3-, (2,2- difluorocyclopropyl -3- oxopropanoic acid and (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol are substituted for uncle Butyl 3- fluoro- 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate, remaining required raw material, reagent and preparation method With embodiment 14, target product FL55 is obtained.1H NMR(500MHz,CDCl3) δ 8.58 (d, J=3.1Hz, 1H), 8.07 (dd, J= 14.9,3.0Hz, 1H), 7.83-7.53 (m, 2H), 7.46 (dd, J=14.9,1.0Hz, 2H), 4.89-4.59 (m, 4H), 4.29 (d, J=50.4Hz, 2H), 3.26 (tt, J=41.8,23.1Hz, 1H), 2.76 (ddd, J=50.5,24.8,6.8Hz, 2H), 2.18-1.97 (m, 2H), 1.84 (ddd, J=50.4,24.8,6.7Hz, 2H), 1.66-1.42 (m, 2H), 1.37-0.99 (m, 2H).LRMS(EI)m/z 639(M+)。
56 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- (2,2- difluorocyclopropyl) isoxazole -4- base) methoxy Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -1- Methyl-1H-indole -3- formic acid preparation (FL56)
3- cyclopropyl -3- oxo-propionic acid methyl ester is changed into methyl 4- (2,2- difluoro cyclopropane) -3- oxobutyrate to change At 3-, (2,2- difluorocyclopropyl -3- oxopropanoic acid, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol are substituted for tertiary fourth The fluoro- 3- of base 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change the bromo- 1- first of 6- into Base -1H- indole -3-carboxylic acid methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 obtain target product FL56.1H NMR(500MHz,CDCl3) δ 9.26 (s, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.56-7.26 (m, 3H), 6.62 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.76 (s, 2H), 4.26 (s, 2H), 3.81 (d, J= 50.4Hz, 2H), 3.74 (s, 3H), 2.88 (tt, J=41.9,23.0Hz, 1H), 2.34-2.02 (m, 6H), 1.72-0.90 (m, 4H)；LRMS(EI)m/z635(M+)。
57 2- of embodiment (3- (((5- (2,2- difluorocyclopropyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- Base) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL57)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, remaining required raw material, reagent and preparation method With embodiment 54, target product FL57 is obtained.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J=14.4,3.7Hz, 1H), 8.35 (d, J=3.1Hz, 1H), 7.74 (dd, J=16.0,3.0Hz, 1H), 7.43 (ddd, J=18.1,14.0,3.3Hz, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 4.81 (s, 2H), 4.73 (ddd, J=8.4,6.5,2.0Hz, 2H), 4.19 (d, J= 50.4Hz, 2H), 3.01 (tt, J=41.8,22.9Hz, 1H), 2.52-1.65 (m, 8H), 1.55-0.76 (m, 2H)；LRMS (EI)m/z672(M+).
58 2- of embodiment (3- (((5- ((2,2- difluorocyclopropyl) methyl) -3- (2- (trifluoromethoxy) phenyl) different evil Azoles -4- base) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -1- Methyl-1H-indole -3- formic acid preparation (FL58)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, remaining required raw material, reagent and preparation method With embodiment 50, target product FL58 is obtained.1H NMR(500MHz,CDCl3) δ 9.25 (s, 1H), 8.42 (dd, J=14.2, 3.7Hz, 1H), 7.59-7.32 (m, 3H), 7.11 (dd, J=14.2,3.7Hz, 1H), 6.69 (d, J=3.0Hz, 1H), 6.11 (dd, J=15.0,2.9Hz, 1H), 4.79 (s, 2H), 4.55-4.10 (m, 4H), 3.73 (s, 3H), 3.34 (dd, J=24.7, 16.3Hz, 1H), 2.64 (dd, J=24.7,16.3Hz, 1H), 2.50-2.08 (m, 6H), 1.77-1.24 (m, 3H), 1.12- 0.83(m,2H)；LRMS(EI)m/z 664(M+).
59 2- of embodiment (3- (((5- ((2,2- difluorocyclopropyl) methyl) -3- (2- (trifluoromethoxy) phenyl) different evil Azoles -4- base) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid system Standby (FL59)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, remaining required raw material, reagent and preparation method With embodiment 48, target product FL59 is obtained.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J=14.4,3.7Hz, 1H), 8.35 (d, J=3.1Hz, 1H), 7.94 (dd, J=16.0,3.0Hz, 1H), 7.59-7.30 (m, 2H), 7.12 (dd, J=14.2, 3.7Hz, 1H), 4.80 (s, 2H), 4.67-4.56 (m, 2H), 4.41 (d, J=50.4Hz, 2H), 3.21 (dd, J=24.7, 14.3Hz, 1H), 2.98 (dd, J=24.9,14.2Hz, 1H), 2.45 (ddd, J=50.5,24.8,6.7Hz, 2H), 2.08- 1.84(m,2H),1.85-1.46(m,5H),1.15-0.51(m,2H).LRMS(EI)m/z 686(M+).
60 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) oxygen) methyl) - 4- fluorine resources -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL60)
Preparation method obtains target product FL60 with embodiment 38.1H NMR(500MHz,CDCl3) δ 8.00 (d, J=8.0, 2H), 7.53 (d, J=8.4,2H), 7.17 (s, 1H), 6.86 (s, 1H), 3.96 (s, 3H), 3.91 (s, 6H), 3.32-3.41 (m,3H),2.85-2.92(m,2H),2.52-2.71(m,1H),2.28-2.48(m,1H),2.19-2.30(m,1H),2.07- 2.14(m,4H),1.70-1.82(m,4H)；LRMS(EI)m/z 610(M+).；LRMS(EI)m/z 596(M+).
61 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) oxygen) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL61)
Target product FL61 is made with embodiment 36 in preparation method.1H NMR(CDCl3, 500MHz) and 8.27 (d, J= 1.5Hz, 1H), 7.73-7.69 (m, 1H), 7.67 (dd, J=6.5,1.7Hz, 1H), 7.64 (dd, J=4.1,1.6Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.58-7.55 (m, 1H), 4.35 (s, 2H), 3.54 (d, J=29.6Hz, 2H), 2.41-2.34 (m, 1H), 2.05-1.85 (m, 6H), 1.51 (q, J=6.5Hz, 2H), 1.21-1.05 (m, 4H)；LRMS(EI)m/z 636(M +).LRMS(EI)m/z 622(M+).
62 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) oxygen) methyl) -4- fluorine piperazine Pyridine -1- base) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL62)
Target product FL62 is made with embodiment 31 in preparation method.1H NMR(CDCl3, 500MHz) and 8.25 (d, J= 1.5Hz, 1H), 7.63 (d, J=1.9Hz, 1H), 7.61-7.59 (m, 2H), 7.55 (dd, J=9.3,6.6Hz, 1H), 3.88 (d, J=11.6Hz, 2H), 3.46-3.28 (m, 4H), 2.38-2.31 (m, 1H), 1.84-1.50 (m, 4H), 1.19-1.06 (m, 4H)；LRMS(EI)m/z581(M+).
(4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) oxygen) methyl) -3- is fluoro- by 63 2- of embodiment 8- azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL63)
Target product FL63 is made with embodiment 33 in preparation method.1H NMR(CDCl3, 500MHz) and 8.27 (d, J= 1.5Hz, 1H), 7.70 (d, J=1.2Hz, 1H), 7.68 (s, 1H), 7.64-7.58 (m, 2H), 4.36 (s, 2H), 3.56-3.29 (m,4H),2.46-2.32(m,1H),2.05-1.83(m,6H),1.21-1.05(m,4H)；LRMS(EI)m/z 607(M+).
(4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) oxygen) methyl) -3- is fluoro- by 64 2- of embodiment 8- azabicyclo [3.2.1] octyl- 8- yl) -1- Methyl-1H-indole -3- formic acid preparation (FL64)
Target product FL64 is made with embodiment 42 in preparation method.1H NMR(CDCl3,500MHz)δ9.00(s,1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 8.10 (d, J=15.0Hz, 1H), 7.65-7.35 (m, 2H), 7.12 (dd, J= 14.2,3.7Hz, 1H), 6.62 (dd, J=15.0,2.9Hz, 1H), 6.48 (d, J=2.9Hz, 1H), 4.12 (tt, J=8.6, 6.4Hz, 2H), 4.00 (d, J=50.4Hz, 2H), 3.82 (d, J=80.0Hz, 6H), 2.80 (dd, J=40.3,20.2Hz, 1H),2.11(m,4H),1.86-1.39(m,4H),1.36-0.78(m,4H).LRMS(EI)m/z 585(M+).
65 2- of embodiment (4- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) oxygen) methyl) -4- fluorine piperazine Pyridine -1- base) -1- Methyl-1H-indole -3- formic acid preparation (FL65)
The preparation method is the same as that of Example 10, and target product FL65 is made.1H NMR(CDCl3,500MHz)δ9.18(s,1H), 7.58 (dd, J=16.1,13.6Hz, 1H), 7.48-7.25 (m, 3H), 7.01 (d, J=2.9Hz, 1H), 6.07 (dd, J= 14.8,2.9Hz, 1H), 4.47 (d, J=50.2Hz, 2H), 3.71 (s, 3H), 3.34 (ddt, J=117.5,24.7,13.1Hz, 4H), 2.75 (p, J=20.1Hz, 1H), 2.18-1.61 (m, 4H), 559 (M of 1.19-0.76 (m, 4H) .LRMS (EI) m/z+).
66 7- of embodiment (3- (((5- ((2,2- difluorocyclopropyl) methyl) -3- (2- (trifluoromethoxy) phenyl) different evil Azoles -4- base) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) imidazo [1,2-a] Nicotinicum Acidum system Standby (FL66)
Change the bromo- 1- Methyl-1H-indole -3- methyl formate of 6- into 7- bromine imidazo [1,2-a] Nicotinicum Acidum methyl esters, Target product FL66 is made with embodiment 58 in remaining required raw material, reagent and preparation method.1H NMR(500MHz,CDCl3)δ 8.43 (dd, J=14.4,3.7Hz, 1H), 8.33 (d, J=15.0Hz, 1H), 7.66 (s, 1H), 7.56-7.30 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.65 (d, J=3.1Hz, 1H), 6.56 (dd, J=14.9,3.0Hz, 1H), 4.80 (s, 2H), 4.29-4.16 (m, 3H), 4.13 (s, 1H), 3.57 (dd, J=24.8,14.7Hz, 1H), 2.80-2.39 (m, 3H), 2.12-1.83(m,4H),1.79-1.36(m,3H),1.14-0.60(m,2H)；LRMS(EI)m/z 651(M+).
67 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) first Base) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) imidazo [1,2-a] Nicotinicum Acidum preparation (FL67)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine-of 4- 4- yl) methanol is substituted for the fluoro- 3- of tert-butyl 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- benzene first of 4- Acetoacetic ester changes 7- bromine imidazo [1,2-a] Nicotinicum Acidum methyl esters into, remaining required raw material, reagent and preparation method are the same as implementation Target product FL67 is made in example 1.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J=7.5,1.6Hz, 1H), 8.33 (d, J= 7.5Hz, 1H), 7.66 (s, 1H), 7.43 (dtd, J=30.9,7.4,1.5Hz, 1H), 7.12 (dd, J=7.4,1.5Hz, 1H), 6.70 (d, J=1.4Hz, 1H), 6.57 (dd, J=7.5,1.6Hz, 1H), 4.80 (s, 1H), 4.35-4.05 (m, 1H), 3.94 (d, J=25.1Hz, 1H), 3.15 (ddd, J=25.3,12.4,3.3Hz, 1H), 2.56 (p, J=10.2Hz, 1H), 2.21- 1.95(m,2H),1.90-1.51(m,4H),1.40-1.13(m,2H),1.13-0.84(m,2H).LRMS(EI)m/z 601(M+).
68 2- of embodiment (4- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) first Base) -4- fluorine resources -1- base) imidazo [1,2-a] Nicotinicum Acidum preparation (FL68)
2,6- dichlorobenzaldehyde is substituted for 2- (trifluoromethyl) benzaldehyde and the iodo- ethyl benzoate of 4- changes 7- bromine imidazoles into And target product is made in [1,2-a] Nicotinicum Acidum methyl esters, remaining required raw material, reagent and the same embodiment of preparation method FL68。1H NMR(500MHz,CDCl3) δ 8.39 (dd, J=14.2,3.7Hz, 1H), 8.29 (d, J=14.8Hz, 1H), 7.62 (s, 1H), 7.52-7.30 (m, 2H), 7.09 (dd, J=14.2,3.7Hz, 1H), 6.75-6.50 (m, 2H), 4.78 (s, 2H), 3.79 (d, J=50.2Hz, 2H), 3.43 (dt, J=25.0,12.9Hz, 2H), 3.12 (dt, J=24.8,12.9Hz, 2H), 2.86-2.55 (m, 1H), 2.09 (ddt, J=50.5,25.1,12.9Hz, 2H), 1.71 (ddt, J=50.6,24.8, 13.0Hz,2H),1.41-0.82(m,4H).LRMS(EI)m/z 575(M+).
69 6- of embodiment (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine Piperidin-1-yl) imidazo [1,2-a] Nicotinicum Acidum preparation (FL69)
Change the iodo- ethyl benzoate of 4- into 7- bromine imidazo [1,2-a] Nicotinicum Acidum methyl esters, remaining required raw material, examination Target product FL69 is made in agent and the preparation method is the same as that of Example 1.1H NMR(500MHz,CDCl3) δ 8.33 (d, J=15.0Hz, 1H), 7.98-7.55 (m, 2H), 7.46 (dd, J=14.9,1.0Hz, 2H), 6.93 (d, J=3.1Hz, 1H), 6.80 (dd, J= 14.9,3.0Hz, 1H), 4.80 (s, 2H), 3.83 (d, J=50.6Hz, 2H), 3.65-3.34 (m, 3H), 3.14 (dt, J= 24.9,13.2Hz,2H),2.26-1.57(m,4H),1.45-0.73(m,4H).LRMS(EI)m/z 560(M+).
70 6- of embodiment (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) imidazo [1,2-a] Nicotinicum Acidum preparation (FL70)
(the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- base of 4-) methanol is substituted for tert-butyl 3- fluoro- 3- (methylol) -8- Azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- ethyl benzoate of 4- change 7- bromine imidazo [1,2-a] Nicotinicum Acidum first into Target product FL70 is made in ester, remaining required raw material, reagent and the preparation method is the same as that of Example 1.1H NMR(500MHz,CDCl3)δ 8.33 (d, J=15.0Hz, 1H), 7.74-7.53 (m, 2H), 7.46 (dd, J=14.9,1.0Hz, 2H), 6.66 (d, J= 3.0Hz, 1H), 6.58 (dd, J=14.9,3.0Hz, 1H), 4.80 (s, 2H), 4.46 (d, J=50.4Hz, 2H), 4.34-4.15 (m, 2H), 3.04 (p, J=20.0Hz, 1H), 2.72 (ddd, J=50.4,24.8,6.7Hz, 2H), 2.51-2.05 (m, 4H), 1.84-1.49(m,2H),1.45-0.58(m,4H).LRMS(EI)m/z 586(M+).
71 2- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -4- Fluorine resources -1- base) imidazo [1,2-a] Nicotinicum Acidum preparation (FL71)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2- and the iodo- ethyl benzoate of 4- is substituted for 7- bromine imidazoles And target product is made in [1,2-a] Nicotinicum Acidum methyl esters, remaining required raw material, reagent and the preparation method is the same as that of Example 1 FL71。1H NMR(500MHz,CDCl3) δ 8.33 (d, J=14.9Hz, 1H), 7.66 (s, 1H), 7.51-7.11 (m, 3H), 7.00-6.71 (m, 2H), 4.80 (s, 2H), 3.87 (d, J=50.4Hz, 2H), 3.30 (dtd, J=37.6,25.0,12.9Hz, 4H), 2.86 (p, J=20.0Hz, 1H), 2.32-1.51 (m, 4H), 544 (M of 1.46-0.80 (m, 4H) .LRMS (EI) m/z+).
72 2- of embodiment (4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) methoxy) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl)-imidazo [1,2-a] Nicotinicum Acidum preparation (FL72)
2,6- dichlorobenzaldehyde is substituted for the chloro- 6- fluorobenzaldehyde of 2-, (the fluoro- 1- tertbutyloxycarbonyl substituted piperidine -4- of 4- Base) methanol is substituted for the fluoro- 3- of tert-butyl 3- (methylol) -8- azabicyclo [3.2.1] octyl- 8- carboxylate and the iodo- benzoic acid of 4- Ethyl ester is substituted for 7- bromine imidazo [1,2-a] Nicotinicum Acidum methyl esters, remaining required raw material, reagent and preparation method are the same as implementation Target product FL72 is made in example.1H NMR(500MHz,CDCl3) δ 8.33 (d, J=7.5Hz, 1H), 7.66 (s, 1H), 7.50- 7.11 (m, 3H), 6.78-6.51 (m, 2H), 4.80 (s, 2H), 4.42 (d, J=25.1Hz, 2H), 4.26-3.97 (m, 2H), 2.66 (p, J=10.1Hz, 1H), 2.55-2.04 (m, 6H), 570 (M of 1.40-0.81 (m, 6H) .LRMS (EI) m/z+).
(4- (((3- (the chloro- 6- fluorophenyl of 2-) -5- cyclopropyl isoxazole -4- base) oxygen) methyl) -3- is fluoro- by 73 2- of embodiment 8- azabicyclo [3.2.1] octyl- 8- yl)-imidazo [1,2-a] Nicotinicum Acidum preparation (FL73)
Target product FL73 is made with embodiment 72 in preparation method.1H NMR(500MHz,CDCl3) δ 8.33 (d, J= 15.0Hz, 1H), 7.66 (s, 1H), 7.46-7.14 (m, 3H), 6.86-6.49 (m, 2H), 5.23 (d, J=50.4Hz, 2H), 4.39-4.05(m,2H),2.94-2.14(m,7H),1.86-0.73(m,6H).LRMS(EI)m/z 556(M+).
74 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - 4- fluorine resources -1- base) -1- Methyl-1H-indole -3- amide) methyl acetate preparation (FL74)
By 2- (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine piperazine Pyridine -1- base) -3 formic acid (0.06mmo1) of -1- Methyl-1H-indole, glycine methyl ester (0.06mmo1), 2- (7- azo benzo three Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (0.065mmo1), N, N- diisopropylethylamine (0.05mI) addition two In chloromethanes (2mL), reaction stirring 2h.With thin-layer chromatography (TLC) monitor react, react afterwards vacuum be spin-dried for solution, then plus Enter saturated sodium bicarbonate, ethyl acetate extraction, organic layer anhydrous Na2SO4It is dry, petroleum ether (PE): ethyl acetate (EA)=(0- 100%) column is crossed, FL74 is obtained.1H NMR(500MHz,CDCl3) δ 8.37 (s, 1H), 7.64 (dd, J=16.2,13.7Hz, 1H), 7.52-7.35 (m, 3H), 7.04 (s, 1H), 6.83 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,2.9Hz, 1H), 4.80 (s, 2H), 3.87 (s, 2H), 3.78 (d, J=36.3Hz, 4H), 3.67 (d, J=40.8Hz, 4H), 3.34 (ddt, J= 111.0,24.9,12.5Hz, 4H), 2.87 (dd, J=40.2,20.1Hz, 1H), 1.86 (ddtd, J=62.8,37.3,24.8, 12.5Hz,4H),1.42-0.74(m,4H).LRMS(EI)m/z 644(M+).
75 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - 4- fluorine resources -1- base) -1- Methyl-1H-indole -3- amide) acetic acid preparation (FL75)
Under nitrogen protection, to two neck bottle of 250mL addition 2-, (((((5- cyclopropyl -3- (2,6- dichlorophenyl) is different by 3- by 6- Oxazole -4- base) methoxy) methyl) -4- fluorine resources -1- base) -1- Methyl-1H-indole -3- amide) methyl acetate (0.05mmol), 2mL methanol and 2mL Isosorbide-5-Nitrae-dioxane dissolution are added afterwards, 4N LiOH (4mL) then is added.It is stirred overnight at 70 DEG C.With thin The reaction of analysis (TLC) monitoring layer by layer, vacuum is spin-dried for solution after having reacted, and water and methyl tertiary butyl ether(MTBE) is added.Water layer 2N HCl tune To pH 5, methylene chloride CH2Cl2 extraction is then added, saturated common salt water washing organic layer, anhydrous Na 2SO4 is dry, and vacuum is dense The crude product of contracting, methylene chloride (PE): methanol (EA) crosses column, obtains FL75.1H NMR(500MHz,CDCl3)δ8.30(s,1H), 7.77 (s, 1H), 7.58 (dd, J=16.1,13.6Hz, 1H), 7.53-7.32 (m, 3H), 7.09 (d, J=3.1Hz, 1H), 6.07 (dd, J=14.9,3.0Hz, 1H), 4.76 (s, 2H), 3.73 (d, J=20.1Hz, 4H), 3.61 (d, J=39.4Hz, 3H), 3.34 (dt, J=24.6,11.3Hz, 2H), 3.12 (dt, J=24.7,11.2Hz, 2H), 2.89 (p, J=19.9Hz, 1H),2.09-1.58(m,4H),1.40-0.80(m,4H).LRMS(EI)m/z 630(M+).
76 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -1- Methyl-1H-indole -3- amide) and acetic acid preparation (FL76)
Target product FL76 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.2,3.7Hz, 1H), 8.37 (s, 1H), 7.57-7.35 (m, 3H), 7.12 (dd, J=14.3,3.8Hz, 1H), 6.59 (d, J =2.9Hz, 1H), 6.53 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.25 (tt, J=8.6, 6.4Hz, 2H), 3.98 (d, J=50.4Hz, 2H), 3.74 (s, 3H), 3.60 (s, 2H), 3.04 (p, J=20.1Hz, 1H), 2.39 (ddd, J=50.4,24.7,6.4Hz, 2H), 2.26-1.93 (m, 4H), 1.75-1.39 (m, 2H), 1.33-0.68 (m, 4H).LRMS(EI)m/z 671(M+).
(((((5- ((2,2- difluorocyclopropyl) methyl) -3- (2- (trifluoromethoxy) phenyl) is different by 3- by 6- by 77 2- of embodiment Oxazole -4- base) methoxy) methyl) -3- fluorine azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- amide) acetic acid Preparation (FL77)
Target product FL77 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.48-7.33 (m, 2H), 7.30-7.06 (m, 2H), 5.33 (s, 1H), 4.80 (s, 2H), 4.51-4.14 (m, 2H), 4.04 (d, J=50.6Hz, 2H), 3.84 (s, 2H), 3.12 (ddd, J= 169.2,24.8,13.8Hz, 2H), 2.24 (ddd, J=50.4,24.7,6.6Hz, 2H), 1.99-1.20 (m, 7H), 1.24- 0.30(m,2H).LRMS(EI)m/z 743(M+).
78 2- of embodiment (6- (3- (((5- (2,2- difluorocyclopropyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole - 4- yl) methoxy) methyl) -3- fluorine azabicyclo [3.2.1] octyl- 8- yl) -1- Methyl-1H-indole -3- amide) and acetic acid preparation (FL78)
Target product FL78 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.37 (s, 1H), 7.74 (s, 1H), 7.53-7.29 (m, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.73 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.88 (s, 2H), 4.47-4.27 (m, 2H), 4.21 (d, J=50.4Hz, 2H), 3.99-3.80 (m, 2H), 3.74 (s, 3H), 3.60 (s, 2H), 3.14-2.66 (m, 3H), 707 (M of 1.63 (ddd, J=50.4,24.8,13.3Hz, 2H), 1.41-0.94 (m, 4H) .LRMS (EI) m/z+).
79 2- of embodiment (6- (3- (((5- (2,2- difluorocyclopropyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole - 4- yl) methoxy) methyl) -3- fluorine azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and acetic acid preparation (FL79)
Target product FL79 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.46 (dddd, J=33.1,29.1,15.5,3.2Hz, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.14 (s, 1H), 4.73 (s, 2H), 4.66 (tt, J=8.6,6.4Hz, 2H), 4.14 (d, J =50.4Hz, 2H), 3.84 (s, 2H), 3.08 (tt, J=41.8,23.0Hz, 1H), 2.46 (ddd, J=50.4,24.9, 6.4Hz,2H),2.30-1.67(m,6H),1.41-0.90(m,2H).LRMS(EI)m/z 729(M+).
Embodiment 80 1H NMR (500MHz, CDCl3) LRMS (EI) m/z (M+) .2- (6- (3- (((5- ((2,2- difluoro Cyclopropyl) methyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) methyl) -3- fluorine azabicyclo [3.2.1] Octyl- 8- yl) -1- Methyl-1H-indole -3- amide) acetic acid preparation (FL80)
Target product FL80 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.3,3.7Hz, 1H), 8.37 (s, 1H), 7.61-7.35 (m, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.62 (d, J =3.1Hz, 1H), 6.30 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.31 (tt, J=8.6, 6.4Hz, 2H), 4.08 (d, J=50.4Hz, 2H), 3.93 (dd, J=24.7,15.8Hz, 1H), 3.74 (s, 3H), 3.60 (s, 2H),2.61-2.32(m,3H),2.28-2.02(m,4H),1.86-1.44(m,3H),1.17-0.67(m,2H).LRMS(EI) m/z 721(M+).
81 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and acetic acid preparation (FL81)
Target product FL81 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.54 (dd, J=16.0,3.0Hz, 1H), 7.51-7.32 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.21 (s, 1H), 4.80 (s, 2H), 4.55 (tt, J=8.6,6.4Hz, 2H), 4.01 (d, J=50.4Hz, 2H), 3.84 (s, 2H), 2.76 (p, J=20.1Hz, 1H), 2.25 (ddd, J=50.4,24.9,6.4Hz, 2H),2.04-1.47(m,6H),1.42-0.48(m,4H).LRMS(EI)m/z 693(M+).
82 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -1- Methyl-1H-indole -3- amide) acetic acid preparation (FL82)
Target product FL82 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3)δ8.36(s,1H), 7.63 (dd, J=16.1,13.6Hz, 1H), 7.52-7.35 (m, 3H), 6.58 (d, J=3.1Hz, 1H), 6.29-6.01 (m, 2H), 4.79 (s, 2H), 4.18 (tt, J=8.6,6.4Hz, 2H), 3.93 (d, J=50.4Hz, 2H), 3.73 (s, 3H), 3.59 (s, 2H), 2.71 (p, J=20.2Hz, 1H), 2.34-1.90 (m, 4H), 1.82 (ddd, J=50.4,24.9,6.4Hz, 2H), 1.66-1.38(m,2H),1.28-0.99(m,4H).LRMS(EI)m/z 656(M+).
83 2- of embodiment (2- (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole - 4- yl) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) acetic acid It prepares (FL83)
Target product FL83 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.15 (d, J= 2.9Hz, 1H), 7.63 (dd, J=16.1,13.7Hz, 1H), 7.51 (dd, J=16.0,3.0Hz, 1H), 7.44 (dd, J= 14.8,1.1Hz, 2H), 6.12 (s, 1H), 4.79 (s, 2H), 4.76-4.60 (m, 2H), 4.46 (d, J=50.2Hz, 2H), 3.83 (s, 2H), 3.06 (ddd, J=80.4,24.8,14.2Hz, 2H), 2.72 (ddd, J=50.4,24.8,6.7Hz, 2H), 2.21-1.42(m,7H),1.07-0.47(m,2H).LRMS(EI)m/z 728(M+).
84 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) acetic acid preparation (FL84)
Target product FL84 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.15 (d, J= 2.9Hz, 1H), 7.63 (dd, J=16.1,13.7Hz, 1H), 7.52 (dd, J=15.9,2.9Hz, 1H), 7.44 (dd, J= 14.9,1.0Hz, 2H), 6.20 (s, 1H), 4.79 (s, 2H), 4.64 (tt, J=8.4,6.4Hz, 2H), 4.08 (d, J= 50.4Hz, 2H), 3.83 (s, 2H), 2.73 (dd, J=40.3,20.1Hz, 1H), 2.16-1.49 (m, 8H), 1.54-0.62 (m, 4H).LRMS(EI)m/z 678(M+).
85 2- of embodiment (2- (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole - 4- yl) oxygen) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and acetic acid system Standby (FL85)
Target product FL85 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.17 (d, J= 2.9Hz, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.54 (dd, J=16.0,3.0Hz, 1H), 7.46 (dd, J= 14.9,1.0Hz, 2H), 6.20 (s, 1H), 4.94 (d, J=50.4Hz, 2H), 4.58 (tt, J=8.6,6.4Hz, 2H), 3.84 (s, 2H), 3.33 (ddd, J=92.3,24.7,15.6Hz, 2H), 2.32 (ddd, J=50.6,24.9,6.4Hz, 2H), 1.90 (ddd, J=50.4,24.7,6.3Hz, 2H), 1.79-1.47 (m, 5H), 714 (M of 1.14-0.64 (m, 2H) .LRMS (EI) m/z+).
86 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) oxygen) methyl) -3- Fluoro- 8- azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- amide) acetic acid preparation (FL86)
Target product FL86 is made with embodiment 75 in preparation method.1H NMR(500MHz,CDCl3) δ 8.17 (d, J= 2.9Hz, 1H), 7.73 (s, 1H), 7.60 (ddd, J=19.0,16.0,8.3Hz, 2H), 7.46 (dd, J=14.9,1.0Hz, 2H), 5.24 (d, J=50.4Hz, 2H), 4.98-4.62 (m, 2H), 3.84 (s, 2H), 2.74 (p, J=20.2Hz, 1H), 2.42 (ddd, J=50.4,24.8,6.7Hz, 2H), 2.24-1.83 (m, 4H), 1.79-1.51 (m, 2H), 1.45-0.64 (m, 4H) .LRMS(EI)m/z 634(M+).
87 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -1- Methyl-1H-indole -3- amide) ethanesulfonic acid preparation (FL87)
By 2- (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) -4- fluorine piperazine Pyridine -1- base) -1- Methyl-1H-indole -3 formic acid (0.1mmol) be dissolved in tetrahydrofuran (1.0mL), be added N- methyl Ma Lin (0.7mmol) is stirred at room temperature to acid dissolution.The chloro- 4,6- dimethoxy -1,3,5- triazine (0.15mmol) of 2- is added 50 DEG C reaction has precipitating generate for 20 minutes.Stir evenly lower addition tarine (0.40mmol is dissolved in DMA 4mL).Then 80 DEG C are sealed in react 2 hours.It is cooled to room temperature after having reacted, water, ethyl acetate extraction is added.Organic layer anhydrous Na2SO4It is dry It is dry, it is spin-dried for, crosses column, obtain pure FL87.1H NMR(500MHz,CDCl3) δ 8.37 (s, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.52-7.38 (m, 3H), 7.19 (d, J=2.9Hz, 1H), 6.87 (s, 1H), 6.68 (s, 1H), 6.12 (dd, J= 15.0,3.1Hz, 1H), 4.80 (s, 2H), 3.71 (t, J=25.2Hz, 5H), 3.59-3.05 (m, 8H), 2.73 (p, J= 20.1Hz,1H),2.49-1.84(m,4H),1.48-0.65(m,4H).LRMS(EI)m/z 680(M+).
88 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - 4- fluorine resources -1- base) -1- Methyl-1H-indole -3- amide) ethanesulfonic acid preparation (FL88)
Target product FL88 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3)δ8.37(s,1H), 7.61 (s, 1H), 7.54-7.39 (m, 3H), 6.68 (s, 1H), 6.58 (d, J=2.9Hz, 1H), 6.51 (s, 1H), 6.12 (dd, J=14.9,3.0Hz, 1H), 4.80 (s, 2H), 4.18 (tt, J=8.6,6.4Hz, 2H), 3.93 (d, J=50.4Hz, 2H), 3.74 (s, 3H), 3.56-3.11 (m, 4H), 2.92-2.54 (m, 1H), 2.37-1.92 (m, 4H), 1.79 (ddd, J=50.4, 24.7,6.4Hz,2H),1.67-1.41(m,2H),1.38-0.77(m,4H).LRMS(EI)m/z 706(M+).
89 2- of embodiment (2- (3- (((3- (2,6- dichlorophenyl) -5- ((2,2- difluorocyclopropyl) methyl) isoxazole - 4- yl) methoxy) methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) ethanesulfonic acid Preparation (FL89)
Target product FL89 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.17 (d, J= 2.9Hz, 1H), 7.71-7.58 (m, 1H), 7.52 (dd, J=15.9,2.9Hz, 1H), 7.47 (d, J=0.6Hz, 1H), 7.44 (d, J=1.4Hz, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 4.80 (s, 2H), 4.79-4.70 (m, 2H), 4.15 (d, J= 50.4Hz, 2H), 3.68 (td, J=16.6,1.5Hz, 2H), 3.33 (td, J=16.8,1.5Hz, 2H), 3.19 (dd, J= 24.7,16.1Hz,1H),3.04-2.70(m,3H),2.21-1.03(m,8H),0.85-0.66(m,1H).LRMS(EI)m/ z778(M+).
90 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4- base) methoxy) methyl) - Fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of 3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) ethanesulfonic acid preparation (FL90)
, target product FL90 is made in remaining required raw material, reagent and the same embodiment of preparation method.1H NMR(500MHz, CDCl3) δ 8.37 (s, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.52-7.38 (m, 3H), 7.19 (d, J=2.9Hz, 1H), 6.87 (s, 1H), 6.68 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 3.71 (t, J= 25.2Hz, 5H), 3.59-3.05 (m, 8H), 2.73 (p, J=20.1Hz, 1H), 2.49-1.84 (m, 2H), 1.48-0.65 (m, 4H).LRMS(EI)m/z 728(M+).
91 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -1- Methyl-1H-indole -3- amide) and ethanesulfonic acid preparation (FL91)
Target product FL91 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.37 (s, 1H), 7.55-7.25 (m, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.66 (s, 1H), 6.60 (d, J=2.9Hz, 1H), 6.54 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 4.14 (tt, J=8.6,6.4Hz, 2H), 3.97 (d, J=50.4Hz, 2H), 3.74 (s, 3H), 3.54-3.19 (m, 4H), 2.68 (p, J =20.1Hz, 1H), 2.48-1.71 (m, 6H), 721 (M of 1.68-0.41 (m, 6H) .LRMS (EI) m/z+).
92 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) Methyl) -4- fluorine resources -1- base) -1- Methyl-1H-indole -3- amide) and ethanesulfonic acid preparation (FL92)
Target product FL92 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.37 (s, 1H), 7.54-7.27 (m, 3H), 7.20 (d, J=3.1Hz, 1H), 7.12 (dd, J= 14.2,3.7Hz, 1H), 6.70 (s, 1H), 6.52 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 3.76 (t, J=25.2Hz, 5H), 3.64-3.04 (m, 8H), 2.78 (p, J=20.1Hz, 1H), 2.14-1.68 (m, 4H), 1.48-0.77(m,4H).LRMS(EI)m/z 695(M+).
93 2- of embodiment (6- (3- (((5- (2,2- difluorocyclopropyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole - 4- yl) methoxy) methyl) -3- fluorine azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and ethanesulfonic acid system Standby (FL93)
Target product FL93 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.54 (dd, J=16.0,3.0Hz, 1H), 7.51-7.35 (m, 2H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.57 (d, J=72.5Hz, 2H), 4.80 (s, 2H), 4.79-4.73 (m, 2H), 4.27 (d, J=50.4Hz, 2H), 3.72-2.89 (m, 6H), 2.52 (ddd, J=50.5,24.8,6.6Hz, 2H), 2.23- 1.41(m,7H),1.32-0.40(m,2H).LRMS(EI)m/z(M+).
94 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) methoxy) Methyl) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and ethanesulfonic acid preparation (FL94)
Target product FL94 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3)δ8.37(s,1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.52-7.38 (m, 3H), 7.19 (d, J=2.9Hz, 1H), 6.87 (s, 1H), 6.68 (s, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.80 (s, 2H), 3.71 (t, J=25.2Hz, 5H), 3.59- 3.05 (m, 8H), 2.73 (p, J=20.1Hz, 1H), 2.49-1.84 (m, 2H), 1.48-0.65 (m, 4H) .LRMS (EI) m/ z743(M+).
95 2- of embodiment (6- (3- (((5- (2,2- difluorocyclopropyl) -3- (2- (trifluoromethoxy) phenyl) isoxazole - 4- yl)) methyl) -3- fluorine azabicyclo [3.2.1] octyl- 8- yl) -4- fluorobenzene simultaneously [d] thiazole -6- amide) ethanesulfonic acid preparation (FL95)
Target product FL95 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.46 (dddd, J=29.1,18.4,15.6,3.3Hz, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.67 (s, 1H), 6.39 (s, 1H), 4.75-4.47 (m, 4H), 3.89-3.57 (m, 3H), 3.33 (td, J=16.8,1.5Hz, 2H), 2.82 (dd, J=24.8,16.6Hz, 1H), 2.52-1.51 (m, 9H), 1.19- 0.59(m,2H).LRMS(EI)m/z 779(M+).
96 2- of embodiment (6- (3- (((5- cyclopropyl -3- (2- (trifluoromethoxy) phenyl) isoxazole -4- base) oxygen) first Base) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- amide) and ethanesulfonic acid preparation (FL96)
Target product FL96 is made with embodiment 87 in preparation method.1H NMR(500MHz,CDCl3) δ 8.43 (dd, J= 14.4,3.7Hz, 1H), 8.17 (d, J=2.9Hz, 1H), 7.45 (dddd, J=33.1,29.1,15.5,3.2Hz, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.65 (s, 1H), 6.50 (s, 1H), 5.00-4.68 (m, 4H), 3.68 (td, J=16.3, 1.4Hz,4H),2.94-2.24(m,3H),2.16-1.44(m,6H),1.50-0.74(m,4H).LRMS(EI)m/z 729(M+).
97 6- of embodiment (4- (((3- (2,6- dichlorophenyl) -5- (2- (trifluoromethyl) cyclopropyl) isoxazole -4- base) Methoxy) methyl) -4- fluorine resources -1- base) and -1- Methyl-1H-indole -3- formic acid preparation (FL97)
The preparation method is the same as that of Example 1, and target product FL97 is made.1H NMR(500MHz,CDCl3)δ9.26(s,1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.47 (d, J=0.6Hz, 1H), 7.44 (dd, J=8.2,6.8Hz, 2H), 7.21 (d, J=2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.93 (s, 2H), 3.76 (s, 1H), 3.74 (s, 3H), 3.66 (s, 1H), 3.44 (dt, J=24.9,11.3Hz, 2H), 3.20 (dt, J=24.9,11.3Hz, 2H), 2.07 (ddt, J= 50.4,24.7,11.3Hz, 2H), 1.91-1.61 (m, 3H), 1.57-1.17 (m, 2H), 0.94 (ddd, J=24.3,21.7, 19.5Hz,1H).LRMS(EI)m/z 641(M+).
98 2- of embodiment (4- (((3- (2,6- dichlorophenyl) -5- (2- (trifluoromethyl) cyclopropyl) isoxazole -4- base) Methoxy) methyl) -4- fluorine resources -1- base) and -4- fluorobenzene simultaneously [d] thiazole -6- formic acid preparation (FL98)
The preparation method is the same as that of Example 13, and target product FL98 is made.1H NMR(500MHz,CDCl3) δ 8.35 (d, J= 3.1Hz, 1H), 7.90 (dd, J=15.9,2.9Hz, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.46 (dd, J= 14.9,1.0Hz, 2H), 4.72 (s, 2H), 4.61 (dt, J=24.9,11.4Hz, 2H), 4.05 (dt, J=24.7,11.4Hz, 2H), 3.79 (d, J=50.4Hz, 2H), 2.04 (ddt, J=50.5,24.9,11.4Hz, 2H), 1.90-1.32 (m, 4H), 1.18 (ddd, J=24.5,21.2,19.6Hz, 1H), 0.96 (ddd, J=24.6,21.7,19.9Hz, 1H) .LRMS (EI) m/z 663(M+).
99 2- of embodiment (3- (((3- (2,6- dichlorophenyl) -5- (2- (trifluoromethyl) cyclopropyl) isoxazole -4- base) Methoxy) methyl) -4- fluorine resources -1- base) fluoro- 8- azabicyclo [3.2.1] the octyl- 8- yl of -3-) -4- fluorobenzene simultaneously [d] thiazole -6- first The preparation (FL99) of acid
The preparation method is the same as that of Example 13, and target product FL98 is made.1H NMR(500MHz,CDCl3) δ 8.35 (d, J= 3.1Hz, 1H), 7.95 (dd, J=15.9,2.9Hz, 1H), 7.64 (dd, J=16.1,13.7Hz, 1H), 7.46 (dd, J= 14.9,1.0Hz, 2H), 4.91 (s, 2H), 4.72 (tt, J=8.4,6.4Hz, 2H), 4.21 (d, J=50.4Hz, 2H), 2.24 (ddd, J=50.4,24.7,6.4Hz, 2H), 2.09-1.54 (m, 7H), 1.55-1.35 (m, 1H), 1.24 (ddd, J=24.4, 21.2,19.7Hz, 1H), 0.90 (ddd, J=24.5,21.6,19.7Hz, 1H) .LRMS (EI) m/z, 689 (M+).
100 6- of embodiment (the fluoro- 3- of 3- (((3- (2- (trifluoromethoxy) phenyl) -5- (2- (trifluoromethyl) cyclopropyl) Isoxazole -4- base) methoxy) methyl) -8- azabicyclo [3.2.1] octyl- 8- yl) -1- Methyl-1H-indole -3- formic acid preparation (FL100)
The preparation method is the same as that of Example 1, and target product FL100 is made.1H NMR(500MHz,CDCl3)δ9.26(s,1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 7.82-7.25 (m, 3H), 7.12 (dd, J=14.2,3.7Hz, 1H), 6.64 (d, J =2.9Hz, 1H), 6.12 (dd, J=15.0,3.1Hz, 1H), 4.92 (s, 2H), 4.45 (s, 1H), 4.41-4.24 (m, 3H), 3.74 (s, 3H), 2.82 (ddd, J=50.4,24.8,6.7Hz, 2H), 2.05 (dddd, J=47.4,31.5,17.8,7.0Hz, 4H), 1.72 (td, J=21.4,17.9Hz, 1H), 1.59-1.15 (m, 4H), 0.89 (ddd, J=24.4,21.7,19.4Hz, 1H).LRMS(EI)m/z 682(M+).
The fluoro- 2- of 101 4- of embodiment (the fluoro- 3- of 3- (((3- (2- (trifluoromethoxy) phenyl) -5- (2- (trifluoro methoxy) ring Propyl) isoxazole -4- base) methoxy) methyl) -8- azabicyclo [3.2.1] octyl- 8- yl) and benzo [d] thiazole -6- formic acid preparation (FL101)
The preparation method is the same as that of Example 13, and target product FL101 is made.1H NMR(500MHz,CDCl3) δ 8.40 (dd, J= 14.2,3.7Hz, 1H), 8.32 (d, J=2.9Hz, 1H), 7.92 (dd, J=16.0,3.0Hz, 1H), 7.53-7.31 (m, 2H), 7.09 (dd, J=14.2,3.7Hz, 1H), 4.75 (s, 2H), 4.61 (tt, J=8.6,6.4Hz, 2H), 4.29 (d, J= 50.4Hz, 2H), 2.65 (ddd, J=50.4,24.7,6.4Hz, 2H), 2.37-1.91 (m, 4H), 1.88-1.34 (m, 4H), 1.32-0.80(m,2H)..LRMS(EI)m/z 704M+).
102 6- of embodiment (the fluoro- 4- of 4- (((3- (2- (trifluoromethoxy) phenyl) -5- (2- (trifluoromethyl) cyclopropyl) Isoxazole -4- base) methoxy) methyl) piperidin-1-yl) -1- Methyl-1H-indole -3- formic acid preparation (FL102)
The preparation method is the same as that of Example 1, and target product FL102 is made.1H NMR(500MHz,CDCl3)δ9.26(s,1H), 8.43 (dd, J=14.4,3.7Hz, 1H), 7.78-7.36 (m, 3H), 7.24-7.01 (m, 2H), 6.12 (dd, J=15.0, 3.1Hz, 1H), 4.91 (s, 2H), 3.74 (t, J=25.2Hz, 5H), 3.32 (ddt, J=105.9,24.7,11.3Hz, 4H), 2.22-1.56(m,5H),1.57-0.83(m,3H).LRMS(EI)m/z 656(M+).
Pharmacological activity test embodiment
Embodiment 1
Screening technique:
Number: 142
Title: FXR- luciferase model agonist screening
Instrument:
Micropore board detector: EnVisionTM (PerkinElmer)
Material:
Screen plate: ViewPlate-96 has 96 microwell plate of white of clear bottom
Detection kit: fluorescent worm fluorescent reporter gene detection kit (Britelite plus model)
Process:
By FXR expression plasmid and FXRE luciferase reporting plasmid cotransfection to 293T cell, in 96 hole flat bottom microtiter plates Middle culture cell and after ensuring plasmid expression, is added FXR agonist.By detecting luciferase fluorescence signal intensity, calculate simultaneously It quantitatively judges agonist and activates degree.Wherein when primary dcreening operation, untested compound and positive compound OCA take 10 μM to act on cell, Measurement untested compound is to the relative activity of positive compound respectively, relative activity be higher than the compound of positive compound 50% into Enter secondary screening, calculates its dose-dependence, i.e. EC50Value.
Sample treatment:
Sample is dissolved with DMSO, cryo-conservation, DMSO in final system concentration control do not influence to detect it is active Within the scope of.
Data processing and result explanation:
Primary dcreening operation selects under single concentration conditions, such as 20 μ g/ml, tests the activity of sample.For in certain condition Under show active sample, such as inhibiting rate % inhibits to be greater than 50, test agents amount dependence, i.e. IC50/EC50Value, Nonlinear Quasi is carried out to sample concentration by sample activity and is obtained, calculating software used is Graphpad Prism 4, fitting Used model is that sigmoidaldose-response (variable slope) will intend most of inhibitor screening models It closes curve bottom and top and is set as 0 and 100.Under normal circumstances, each sample is respectively provided with multiple holes (n >=2) in testing, is tying It is indicated in fruit with standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE).Generally In the case of, test has reported compound as reference every time.
By active testing, the multiple compounds of the present invention have excellent pharmacological activity.Compound FL3, FL10 etc. are multiple EC of the compound in cellular level50Lower than 10nM, it is better than positive compound OCA (shellfish cholic acid difficult to understand) and FL4-13, shows stronger Pharmacological activity.
FL4-13:
The Rat Liver Fibrosis Model experiment of 2. thioacetamide of embodiment (TAA) induction
In order to further evaluate the drug effect of compound, We conducted the Rat Liver Fibrosis Model experiments of TAA induction.
Modeling method are as follows: 150mg/kg TAA normal saline solution is injected intraperitoneally, weekly in the SD male rat of 6-8 week old Three times, after continuous injection 4 weeks, start to give compound FL4-14 (FL10), FL4-15 (FL11) (20mg/kg P.O qd), phase OCA and FL4-13 (LY-2562175) with dosage are used as positive control, and surrounding is administered, continues to give TAA during administration Modeling.The model is it is observed that liver coefficient increases, serum alkaline phosphatase (ALP) level increases, α-smooth muscle flesh in liver In filamentous actin (α-SMA), the up-regulation of Type I collagen albumen (1 mRNA of Col1 α) expression and pathological section (sirius red dyeing) The content of Liver Collagen increases.
The results showed that FL4-14 (FL10) can be substantially reduced ALP level (Fig. 1) in serum, lower in compound Col1 α 1mRNA expresses (Fig. 2).Compound FL4-14 (FL10) reduces the content of collagen in hepatic pathology section, shows with sun Property the comparable anti-hepatic fibrosis effect of OCA, but be better than control compound FL4-13 (LY-2562175) (Fig. 3).And FL4-14 pairs Rat blood serum inner cholesterol (TC), highly dense ester gp (HDL), low-density lipoprotein (LDL) content have no significant effect, and positive drug OCA can significantly increase the effect of TC, HDL, LDL content in rat blood serum, prompt FL4-14 (FL10) is possible can be to avoid clinic Upper OCA can cause LDL to increase and bring side effect, also superior to positive reference compound FL4-13 (Fig. 4).In addition, FL4-14 (FL10) group liver coefficient also avoids the effect (figure that positive drug OCA bring liver coefficient significantly increases without significant change 5)。
The test of 3. pharmacokinetics of embodiment
Initial pharmacokinetic test has been carried out to selected chemicals FL36 and control compound FL4-13.
1. material
1.1 animals and grouping
Male SD rat, 12.
1.2 drugs and reagent
FL4-13；FL36；DMSO (dimethyl sulfoxide)；EtOH；PEG300 (polyethylene glycol)；NaCl；HPMC (hydroxypropyl methyl Cellulose)
2. method
2.1 medication
2.2 pharmacokinetics in rats parameter such as following tables
Data are analyzed it can be seen that exposed amount (AUC) of the compound FL36 in blood plasma is remote high under same dosage In positive reference compound FL4-13, good pharmacokinetic property is showed.
4. Mouse Acute Toxicity preliminary test of embodiment
1. material
1.1 animals and grouping
Female C57 mouse, 6-8 week old, 6, SPF grades.
1.2 drugs and reagent
FL4-14(FL10)(MW:572.45)
DMSO, Tween80, MC
2. method
2.1 experimentation
Female ICR mice 6, after being deprived of food but not water 12 hours are taken, oral administration gavage gives tested material FL4-14 500mg/ Kg, administered volume 10mL/kg, solvent 10%DMSO+10%Tween80+80%0.5%MC.It is observed immediately after administration small The toxic reaction situation of mouse is observed continuously 7 days.
Observation table is as follows after 2.2 the weight of animals and administration
Conclusion: the preliminary anxious poison experiment mainly observation compound 500mg/kg dosage whether there is or not obvious toxic reaction or Death, the results showed that the compound of the application has good safety.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims (11)

1. a kind of with the fluorine-containing isoxazole class compound of structure shown in following general formula I or its enantiomter or diastereo-isomerism Body or its officinal salt or their mixture:
Wherein:
M is 0,1,2 or 3；
N is 0,1 or 2；
P is 0,1 or 2；
Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, replaces substituted or unsubstituted 6-20 member aromatic ring yl Or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from the group by 1,2,3 or 4 Substituent group replace: deuterium (D), tritium (T), halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alcoxyl Base ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitro, ammonia Base, amido (preferably C1-C6Amido), hydroxyl, carboxyl, C1-C6Ester group, C6-C10Aryl, C6-C10Aryloxy ,-X4-CO2R5、 C1-C6Alkyl hydroxy ,-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6, 3-12 circle heterocyclic ring base With 3-12 circle heterocyclic ring base oxygroup；Wherein, described q, r, s, y1 and y2 may respectively be 1,2,3 or 4；The aromatic heterocyclic, virtue Ring group or heterocycle contain 1~4 hetero atom in oxygen, sulphur and nitrogen each independently；X4For key, C1-C6 alkylidene, C1-2Alkylene, cyclopropyl or epoxy ethyl；
R1Be selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member aromatic ring yl, replace or not Substituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group selected from the group below is taken by 1,2,3 or 4 Replace for base: deuterium, tritium, halogen, C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitro, amino, amido (preferably C1-C6Amine Base), hydroxyl, methylol, carboxyl, C6-C10Aryl, C6-C10Aryloxy, 3-12 circle heterocyclic ring base and 3-12 circle heterocyclic ring base oxygroup； Wherein, described q, r and s may respectively be 1,2,3 or 4；Aromatic heterocyclic, aryl or the heterocycle contains 1 each independently ~4 hetero atoms in oxygen, sulphur and nitrogen；
R2It can be independently selected from the substituent group of 1,2,3 or 4 the following group: hydrogen, halogen, substituted or unsubstituted C1-C6Alkyl, substitution Or unsubstituted C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Ring Alkoxy, cyano, nitro, amino, amido (preferably C1-C6Amido), hydroxyl, methylol, carboxyl；Wherein, the substitution refers to Hydrogen atom on group is replaced by 1,2,3 or 4 substituent group selected from the group below: hydrogen, halogen, nitro, cyano, trifluoromethyl, three Fluoro ethyl, trifluoro propyl, trifluoromethoxy, trifluoro ethoxy, amino, amido (preferably C1-C6Amido), hydroxyl, methylol, Carboxyl, sulfydryl and sulfonyl；
R3And R4It is each independently selected from the following group: hydrogen, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1- C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3-C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitre Base, amino, amido (preferably C1-C6Amido), hydroxyl, methylol and carboxyl；Or R3And R4It links together and C is collectively formed1- C6Alkylidene；
R5And R6For from independently hydrogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring base.
2. fluorine-containing isoxazole class compound according to claim 1 or its enantiomer or diastereomer or its Officinal salt or their mixture, which is characterized in that
Ring is selected from the group: phenyl, pyridyl group, pyrimidine radicals, pyridazinyl, thiazolyl, benzothiazolyl, benzo [d] isothiazole Base, imidazo [1,2-a] pyridyl group, quinolyl, 1H- indyl, pyrrolo- [1,2-b] pyridazinyl, benzofuranyl, benzo [b] thiophenyl, 1H- indazolyl, benzo [d] isoxazolyl, thiazolinyl, 1H- pyrrolo- [3,2-c] pyridyl group, pyrazolo [1, 5-a] pyrimidine radicals, imidazoles [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyrrole radicals；Above-mentioned group is substituted or unsubstituted；Its In, the substitution refers to that the hydrogen atom on group is replaced by 1,2,3 or 4 substituent group selected from the group below: D, T, halogen, C1-C6Alkane Base, halogenated C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkoxy ,-O [(CH2)qO]rR5、-O(CH2)sC6-C10Aryl, C3- C8Cycloalkyloxy, halogenated C3-C8Cycloalkyloxy, cyano, nitro, amino, amido (preferably C1-C6Amido), hydroxyl, carboxyl, C1- C6Ester group, C6-C10Aryl, C6-C10Aryloxy ,-X4-CO2R5、C1-C6Alkyl hydroxy ,-X4-CONR5R6、-X4-CONR5 (CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6, 3-12 circle heterocyclic ring base and 3-12 circle heterocyclic ring base oxygroup；
Wherein, described q, r, s, y1 and y2 may respectively be 1,2,3 or 4；
Heteroaromatic, aryl or heterocycle contain 1~4 hetero atom in oxygen, sulphur and nitrogen each independently；
X4For key, C1-C6 alkylidene, C1-2Alkylene, cyclopropyl, epoxy ethyl；
R5And R6It is each independently hydrogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring base.
3. fluorine-containing isoxazole class compound according to claim 1 or its enantiomer or diastereomer or its Officinal salt or their mixture, which is characterized in thatIt is selected from the group:
Wherein,
R8It is selected from the group: hydrogen, halogen, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, C1-C6It is alkoxy carbonyl, halogenated C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl, C3-C8Naphthenic base, cyano, nitro, amino, hydroxyl, methylol, carboxyl, mercapto Base, sulfonyl, C6-C10Aryl and 3-12 circle heterocyclic ring base；
T is 0,1,2,3,4 or 5；
XlAnd X2It is each independently N, CH or CR8；
X3For O or S；
R9For-X4-CO2R5、C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Hydroxyl ,-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6；Y1 and y2 is each independently 1,2,3 or 4；X4For key, C1-C6 alkylidene, C1-2Alkene Alkyl, cyclopropyl or epoxy ethyl；
R5And R6It is each independently hydrogen, C1-6Alkyl, halogenated C1-C6Alkyl, C2-C6Alkenyl, methylol or 5-7 circle heterocyclic ring base；
R10For hydrogen, C1-C6Alkyl hydroxy, C1-C6Alkyl, halogenated C1-C6Alkyl, C1-C6Alkoxy, C1-C6Alkoxy carbonyl, halogen For C1-C6Alkoxy, C2-C6Alkenyl, C2-C6Alkynyl or C3-C8Naphthenic base.
4. fluorine-containing isoxazole class compound according to claim 1 or its enantiomer or diastereomer or its Officinal salt or their mixture, which is characterized in thatIt is selected from the group:Its In, R8、R9、R10It is as defined above with t.
5. fluorine-containing isoxazole class compound according to claim 1 or its enantiomer or diastereomer or its Officinal salt or their mixture, which is characterized in that R1Be selected from the group: phenyl, pyridyl group, pyridine 1-oxide base, cyclohexyl, Cyclopenta, cyclopropyl；Above-mentioned group is substituted or unsubstituted；Wherein, the substitution refers to the hydrogen atom on group by 1,2,3 Or 4 substituent groups selected from the group below replace: hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoroethyl, trifluoro propyl, fluoroform Oxygroup, trifluoro ethoxy, phenyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, C1-6Alkyl, Cl-6Naphthenic base, C1-6Alkane Oxygroup, Cl-6Cycloalkyloxy, cyclopropyl.
6. fluorine-containing isoxazole class compound according to claim 1 or its enantiomer or diastereomer or its Officinal salt or their mixture, which is characterized in that the compound is selected from the group:
7. a kind of pharmaceutical composition, which is characterized in that it includes the described in any one of claims 1-6 fluorine-containing of therapeutically effective amount Isoxazole class compound or its enantiomer or diastereomer or its officinal salt or their mixture and medicine Acceptable carrier on.
8. a kind of FXR agonist, which is characterized in that it includes fluorine-containing isoxazole class chemical combination described in any one of claims 1-6 Object or its enantiomer or diastereomer or its officinal salt or their mixture.
9. fluorine-containing isoxazole class compound described in any one of claims 1-6 or its enantiomer or diastereomer, Or the purposes of its officinal salt or their mixture, which is characterized in that be used to prepare prevention or treat the disease that FXR is mediated The drug of disease.
10. purposes as claimed in claim 9, which is characterized in that the disease is selected from the group: non-alcoholic fatty liver disease, non- Alcoholic fatty liver inflammation, fatty liver, liver fibrosis, primary biliary cirrhosis, hyperlipemia, dyslipidemia.
11. the preparation method of fluorine-containing isoxazole class compound as claimed in any one of claims 1 to 6, which is characterized in that
(a) the method includes the steps:
Wherein,R1、R2、R3、R4, n, m and p define it is identical as the definition in general formula I described in claim 1；X is halogen Element or nitro；
Step j: in organic solvent, in the presence of 18- crown ether -6 and alkali, intermediate 12 and intermediate 9 are reacted, in formation Mesosome 13；
Step k: in organic solvent, intermediate 13 is subjected to deprotection reaction, forms intermediate 14；
Step l: under nitrogen protection, in organic solvent, in the presence of alkali, palladium catalyst and ligand, intermediate 14 is in Mesosome 15 reacts, and forms final product I；Or
Step m: under nitrogen protection, in organic solvent, in the presence of a base, intermediate 14 and intermediate 15 react, and are formed eventually Product I；
Or
(b) the method includes the steps:
Wherein, R1、R2、R3、R4, n, m and p define it is identical as the definition in general formula I described in claim 1；X is halogen or nitre Base；
Step j: in organic solvent, in the presence of 18- crown ether -6 and alkali, intermediate 12 and intermediate 9 are reacted, in formation Mesosome 13；
Step k: in organic solvent, intermediate 13 is subjected to deprotection reaction, forms intermediate 14；
Step l: under nitrogen protection, in organic solvent, in the presence of alkali, palladium catalyst and ligand, intermediate 14 is in Mesosome 15 reacts, and forms intermediate compound I '；Or
Step m: under nitrogen protection, in organic solvent, in the presence of a base, intermediate 14 and intermediate 15 react, in formation Mesosome I '；With
Step e: in organic solvent, intermediate compound I ' and HNR5R6、HNR5(CH2)y1CO2R6Or HNR5(CH2)y2SO3R6It carries out anti- It answers, forms final product I；
Wherein,Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, substituted or unsubstituted 6-20 member aromatic ring yl, Substituted or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from by 1,2,3 or 4 The substituent group of the following group replaces :-X4-CO2R5；Wherein, X4、R5It is as defined above
Ring is selected from the group: substituted or unsubstituted 6-20 circle heterocyclic ring base, replaces substituted or unsubstituted 6-20 member aromatic ring yl Or unsubstituted 6-20 member aromatic heterocyclic；Wherein, the substitution refers to that the hydrogen atom on group is selected from the group by 1,2,3 or 4 Substituent group replace :-X4-CONR5R6、-X4-CONR5(CH2)y1CO2R6、-X4-CONR5(CH2)y2SO3R6；Wherein, X4、R5、R6、 Y1, y2 are as defined above.
CN201810431514.0A 2018-05-08 2018-05-08 Fluorine-containing isoxazole compound and preparation method, pharmaceutical composition and application thereof Active CN110452235B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201810431514.0A CN110452235B (en) 2018-05-08 2018-05-08 Fluorine-containing isoxazole compound and preparation method, pharmaceutical composition and application thereof
PCT/CN2019/086068 WO2019214656A1 (en) 2018-05-08 2019-05-08 Fluorine-containing isoxazole compound, preparation method therefor, and pharmaceutical composition and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810431514.0A CN110452235B (en) 2018-05-08 2018-05-08 Fluorine-containing isoxazole compound and preparation method, pharmaceutical composition and application thereof

Publications (2)

Publication Number Publication Date
CN110452235A true CN110452235A (en) 2019-11-15
CN110452235B CN110452235B (en) 2023-02-17

Family

ID=68467209

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810431514.0A Active CN110452235B (en) 2018-05-08 2018-05-08 Fluorine-containing isoxazole compound and preparation method, pharmaceutical composition and application thereof

Country Status (2)

Country Link
CN (1) CN110452235B (en)
WO (1) WO2019214656A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022057672A1 (en) * 2020-09-18 2022-03-24 凯思凯迪（上海）医药科技有限公司 Preparation of novel fxr small molecule agonist and use thereof
CN114315844A (en) * 2022-01-18 2022-04-12 中国科学院上海药物研究所 FXR (FXR) regulators and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513213A (en) * 2013-09-28 2015-04-15 山东亨利医药科技有限责任公司 Fxr agonist
US20160340309A1 (en) * 2015-05-22 2016-11-24 Genentech, Inc. Substituted benzamides and methods of use thereof
WO2017118294A1 (en) * 2016-01-06 2017-07-13 广州市恒诺康医药科技有限公司 Fxr receptor modulator, preparation method therefor, and uses thereof
WO2017128896A1 (en) * 2016-01-26 2017-08-03 江苏豪森药业集团有限公司 Fxr agonist and preparation method and use thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200906823A (en) * 2007-07-16 2009-02-16 Lilly Co Eli Compounds and methods for modulating FXR
US11091482B2 (en) * 2016-08-23 2021-08-17 Ardelyx, Inc. Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators
WO2018059314A1 (en) * 2016-09-28 2018-04-05 四川科伦博泰生物医药股份有限公司 Azabicycle derivatives and preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104513213A (en) * 2013-09-28 2015-04-15 山东亨利医药科技有限责任公司 Fxr agonist
US20160340309A1 (en) * 2015-05-22 2016-11-24 Genentech, Inc. Substituted benzamides and methods of use thereof
WO2017118294A1 (en) * 2016-01-06 2017-07-13 广州市恒诺康医药科技有限公司 Fxr receptor modulator, preparation method therefor, and uses thereof
WO2017128896A1 (en) * 2016-01-26 2017-08-03 江苏豪森药业集团有限公司 Fxr agonist and preparation method and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JUNYOU LI等: "Discovery and Optimization of Non-bile Acid FXR Agonists as Preclinical Candidates for the Treatment of Nonalcoholic Steatohepatitis", 《J. MED. CHEM.》 *
年四昀等: "法尼醇X受体激动剂的研究进展", 《中国药物化学杂志》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022057672A1 (en) * 2020-09-18 2022-03-24 凯思凯迪（上海）医药科技有限公司 Preparation of novel fxr small molecule agonist and use thereof
CN114315844A (en) * 2022-01-18 2022-04-12 中国科学院上海药物研究所 FXR (FXR) regulators and preparation method and application thereof

Also Published As

Publication number Publication date
CN110452235B (en) 2023-02-17
WO2019214656A1 (en) 2019-11-14

Similar Documents

Publication Publication Date Title
TWI427078B (en) Compositions and methods for modulating fxr
EP1615878B1 (en) Compounds, compositions and methods of treatment for heart failure
DE60221098T2 (en) CONDENSED HETEROCYCLIC DERIVATIVES
CA3093802A1 (en) Substituted imidazopyridines as inhibitors of plasma kallikrein and uses thereof
CN104837828B (en) It is used as the phenylethyl pyridine derivate of PDE4 inhibitor
CN108064223A (en) FXR (NR1H4) modulating compound of hydroxyl
TW200944520A (en) Spiro compounds as NPY Y5 receptor antagonists
CN107001320B (en) 1- alkyl -6- oxo -1,6- dihydropyridine -3- based compound and application thereof
KR20130124524A (en) Polycyclic lpa1 antagonist and uses thereof
EP3704106B1 (en) Alkene compounds as farnesoid x receptor modulators
CZ20031028A3 (en) Aza- and polyazanaphthalenyl carboxamides
CA2670404A1 (en) Heteromonocyclic compound and use thereof
JP7223016B2 (en) Alkene spirocyclic compounds as farnesoid X receptor modulators
MX2014011373A (en) Diacylglycerol acyltransferase 2 inhibitors.
TW201039823A (en) Azaspiranyl alkylcarbamate derivatives of 5-membered heterocycles, preparation thereof and therapeutic use thereof
JP2021526123A (en) Autotaxin inhibitors and their use
TW200838508A (en) Chemical compounds
TW201121941A (en) Adamantyl amide derivatives and uses of same
EP2976341A1 (en) Acyclic cyanoethylpyrazolo pyridones as janus kinase inhibitors
EP3704107A1 (en) Multicyclic compounds as farnesoid x receptor modulators
CN110452235A (en) Fluorine isoxazole class compound and preparation method thereof, pharmaceutical composition and purposes
CN106573901A (en) Fumarate analogs and uses thereof in the treatment of an autoimmune disease or an inflammatory disease
CN114981257A (en) Substituted pyrazolopiperidinecarboxylic acids
CN103140134A (en) Novel pyrrolidine derived beta 3 adrenergic receptor agonists
CN108699011A (en) NRF2 reactivity compounds and application thereof

Legal Events

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