WO2017129125A1 - 甾体类衍生物fxr激动剂 - Google Patents

甾体类衍生物fxr激动剂 Download PDF

Info

Publication number
WO2017129125A1
WO2017129125A1 PCT/CN2017/072567 CN2017072567W WO2017129125A1 WO 2017129125 A1 WO2017129125 A1 WO 2017129125A1 CN 2017072567 W CN2017072567 W CN 2017072567W WO 2017129125 A1 WO2017129125 A1 WO 2017129125A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
alkyl
acceptable salt
ring
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.)
Ceased
Application number
PCT/CN2017/072567
Other languages
English (en)
French (fr)
Inventor
贺海鹰
肖华玲
李鹏
杜春艳
罗志
陈曙辉
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.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
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
Priority to EP17743740.7A priority Critical patent/EP3409684B1/en
Priority to KR1020187024701A priority patent/KR102788843B1/ko
Priority to BR112018015474-1A priority patent/BR112018015474B1/pt
Priority to MYPI2018702594A priority patent/MY196292A/en
Priority to SG11201806348PA priority patent/SG11201806348PA/en
Priority to US16/072,839 priority patent/US10875888B2/en
Priority to AU2017213032A priority patent/AU2017213032B2/en
Priority to PH1/2018/550120A priority patent/PH12018550120B1/en
Priority to CN201780007715.1A priority patent/CN109071593B/zh
Priority to NZ745250A priority patent/NZ745250B2/en
Priority to JP2018539427A priority patent/JP6924765B2/ja
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Medshine Discovery Inc filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to MX2018009175A priority patent/MX391812B/es
Priority to CA3012396A priority patent/CA3012396C/en
Priority to EA201891690A priority patent/EA038580B9/ru
Publication of WO2017129125A1 publication Critical patent/WO2017129125A1/zh
Priority to IL260795A priority patent/IL260795B/en
Anticipated expiration legal-status Critical
Priority to ZA2018/05231A priority patent/ZA201805231B/en
Priority to US17/069,691 priority patent/US11667667B2/en
Priority to AU2021202018A priority patent/AU2021202018B2/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals

Definitions

  • the present invention relates to a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, and to its use in the preparation of a medicament for treating an FXR-related disease.
  • Farnesyl X receptor is an orphan nuclear receptor originally identified from rat liver cDNA libraries (BM. Forman, et al., Cell 81:687-693 (1995)), which is associated with insect molting. Hormone receptors are closely related. FXR is a member of the family of ligand-activated transcription factor nuclear receptors including steroids, retinoids, and thyroid hormone receptors (DJ. Mangelsdorf, et al., Cell 83:841-850 (1995)). Northern and in situ analysis revealed extensive expression of FXR in the liver, intestine, kidney, and adrenal gland (BM. Formanet al., Cell 81:687-693 (1995) and W. Seolet al., Mol.
  • FXR Farnesyl X receptor
  • FXR forms a heterodimer with the 9-cis retinoic acid receptor (RXR) to bind to DNA.
  • RXR 9-cis retinoic acid receptor
  • the FXR/RXR heterodimer preferentially binds to a component consisting of a binuclear receptor half site of the consensus AG(G/T)TCA, which forms an inverted repeat and is separated by a single nucleoside (IR-1 motif) ( BM. Forman, et al., Cell 81: 687-693 (1995)).
  • IR-1 motif single nucleoside
  • the cholic acid as the FXR ligand includes chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and taurine and glycine conjugates of these cholic acids.
  • WO-2005082925 discloses the use of INT747 in the preparation of a medicament for the treatment of FXR.
  • Ring A is selected from the group consisting of a 5- to 12-membered aryl group, a 5- to 12-membered heteroaryl group having 1 to 2 hetero atoms, a 5- to 6-membered non-aromatic heterocyclic group having 1 to 2 hetero atoms, or a 5- to 6-membered ring.
  • Alkyl said ring A is optionally substituted by 1, 2 or 3 R a or optionally 1, 2 or 3 oxo, said hetero atom being selected from N, O or S;
  • L is selected from C 1-8 alkyl, C 1-8 heteroalkyl or C 2-8 alkenyl, said L being optionally substituted by 1, 2 or 3 R b or optionally occurring 1, 2 or 3 Oxygen generation
  • R 1 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, 5- to 6-membered aryl, 4 to 6-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic ring.
  • the base is optionally substituted with 1, 2 or 3 R c or optionally 1, 2 or 3 oxo;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 3 O, CH 3 S, NH (CH 3 ) or N(CH 3 ) 2 .
  • the above ring A is selected from the group consisting of phenyl, pyridyl, pyridine-2(1H)-keto, pyrimidinyl, pyrazole Base, imidazolyl, oxazolyl, thiazolyl, thienyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, isoxazolyl, isothiazolyl, bicyclo[1.1.1]pentanyl, Benzooxazolyl, benzo[d]isoxazolyl, oxazolyl, indolyl, quinolyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo[2,3-B]pyridine a group, a mesoindolyl group, a benzothiazolyl group or a benzothienyl
  • the above ring A is selected from the group consisting of Said ring A is optionally substituted with 1, 2 or 3 R a.
  • the above ring A is selected from the group consisting of
  • the above L is selected from the group consisting of The L is optionally substituted by 1, 2 or 3 R b .
  • the above L is selected from the group consisting of
  • the above L is selected from the group consisting of
  • R 1 is selected from the group consisting of H, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl, pyridine , pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or thienyl, said C 1-3 alkyl, C 3-6 ring Alkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or thienyl are optionally 1, 2 or 3 R c is substituted, and R c is as defined above.
  • R 1 is selected from the group consisting of H, Me,
  • a preferred mode of the compound of the formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of the following formula (II) or a pharmaceutically acceptable salt thereof:
  • L 2 is selected from C 1-6 alkyl, C 1-6 heteroalkyl or C 2-6 alkenyl
  • Ring B is selected from a benzene ring, or a 5- to 6-membered heteroaryl ring containing 1 to 2 heteroatoms selected from N, O or S;
  • the ring B is optionally substituted with 1, 2 or 3 R 2 or optionally 1 oxo;
  • R 1 is selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, 5- to 6-membered aryl, 4 to 6-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic ring.
  • the ring B is selected from the group consisting of a benzene ring and a 5-membered heteroaryl ring containing 1 to 2 atoms selected from N, O or S atoms. Or containing 1 to 2 6-membered heteroaryl rings selected from N atoms, said ring B being optionally substituted by 1, 2 or 3 R 2 or optionally 1 oxo, said R 2 being as defined above .
  • the ring B is selected from the group consisting of a benzene ring, a pyrazole, an imidazole, an oxazole, an isoxazole, a thiazole, an isothiazole, a pyridine, Pyridazine, pyrimidine or pyrazine, said ring B being optionally substituted by 1, 2 or 3 R 2 or optionally 1 oxo, said R 2 being as defined above.
  • the position of the R 2 substitution or oxo is on the ring B relative to the ortho position ( ⁇ position) of L 2 .
  • the R 1 is selected from the group consisting of H, C 1-3 alkyl, C 3-6 cycloalkyl, phenyl, Pyridyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or thienyl, said C 1-3 alkyl, C 3-6 A cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or thienyl group is optionally 1, 2 or Three R c substitutions, the R c being as defined above.
  • the R 1 is selected from the group consisting of H, Me,
  • the structural fragment L 1 -R 1 is selected from the group consisting of -OH, -NHSO 2 CH 3 , -NHSO 2 C(CH 3 ) 3 , -NHCH 2 CH 2 SO 2 OH, -NHCH 2 COOH, -NHSO 2 CH(CH 3 ) 2 , -NHCH 3 , -OCH 3 or
  • the compound of formula (II) or a pharmaceutically acceptable salt thereof, structural fragment Selected from The L 2 and R 2 are as defined above.
  • the present invention also provides a compound of the formula (III) or a pharmaceutically acceptable salt thereof:
  • Ring A is a 5- to 12-membered aryl group optionally substituted by 1, 2 or 3 R, a 5- to 12-membered heteroaryl group, or a 5- to 6-membered non-aromatic heterocyclic group, and a 5- to 6-membered cycloalkyl group;
  • L is a C 1-6 alkyl group, a C 1-6 heteroalkyl group, a C 2-6 alkenyl group optionally substituted by 1, 2 or 3 R;
  • R is F, Cl, Br, I, OH, CN, NO 2 , NH 2 or R is selected from C 1-3 alkylamino, N, N-di optionally substituted by 1, 2 or 3 R' (C 1-3 alkyl)amino, C 1-3 alkyl, C 1-3 alkyloxy, C 1-3 alkylthio;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 3 O, CH 3 S, NH (CH 3 ), N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above R is selected from the group consisting of F, Cl, Br, I, Me, CF 3 , CHF 2 , CH 2 F, Et, OMe, NH(CH 3 ), N(CH 3 ) 2 .
  • the above ring A is phenyl, pyridyl or pyridine-2 optionally substituted by 1, 2 or 3 R ( 1H)-keto, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, Pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, isoxazolyl, isothiazolyl, bicyclo[1.1.1]pentanyl, benzoxazolyl, benzo[d]isoxazolyl , carbazolyl, fluorenyl, quinolyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo[2,3-B]pyridyl, indolizinyl, benzothiazolyl, benzothiophene base,.
  • the above ring A is selected from the group consisting of optionally substituted by 1, 2 or 3 R.
  • the above ring A is selected from the group consisting of
  • the above L is selected from the group consisting of optionally substituted by 1, 2 or 3 R.
  • the above L is selected from the group consisting of
  • the above L is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for preparing various diseases related to the treatment of farnesoid X receptor, cholestasis liver disease, fibrotic disease, high cholesterol disease, high glycerin
  • the use of drugs for triester diseases and cardiovascular diseases are also provided.
  • the present invention also provides the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), cholestasis liver disease, chronic liver disease, hepatitis C infection, alcoholic liver disease, liver fibrosis, primary sclerosing cholangitis (PSC), gallstones, bile duct atresia, lower urinary tract symptoms and benign prostatic hyperplasia (BPH), ureteral calculi, obesity, type 2 diabetes, atherosclerosis, atherosclerosis, hypercholesterolemia, and drugs for liver damage caused by hyperlipidemia.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • PBC primary biliary cirrhosis
  • cholestasis liver disease chronic liver disease
  • hepatitis C infection alcoholic liver disease
  • the compounds of the invention are FXR agonists.
  • the compounds of the present invention are useful as a method of preventing or treating a disorder of dyslipidemia or a disorder associated with dyslipidemia, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present invention.
  • the compounds of the invention are useful for lowering total cholesterol levels, lowering LDL cholesterol levels, lowering VLDL cholesterol levels, increasing HDL cholesterol levels, and/or lowering triglyceride levels.
  • Lowering triglyceride levels as described herein refers to lowering triglycerides in a subject in need of treatment to below the initial triglyceride levels of the prophylactic or therapeutic subject prior to administration of the compound of the present application.
  • the compounds of the invention may reduce triglyceride production in the liver or reduce triglyceride secretion in the liver by reducing fat absorption.
  • the compounds of the invention also reduce serum triglycerides and hepatic triglycerides.
  • the compounds of the invention may be used to prevent or treat cardiovascular diseases associated with hypertriglyceridemia and/or hypercholesterolemia in a subject, such as a mammal, particularly a human, such as, but not limited to, atherosclerosis, Atherosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke or hypertension.
  • the compounds of the present invention can be used for preventing or treating liver/biliary diseases of a subject (e.g., a mammal, particularly a human), for example, but not limited to, cholestatic liver disease, high cholesterol disease, high triglyceride disease or fibrotic disease, specifically but not limited to non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), Primary sclerosing cholangitis (PSC), gallstones, nonalcoholic cirrhosis, bile duct atresia, cholestatic liver disease, chronic liver disease, hepatitis infection (type B or C), alcoholic liver disease or liver fibrosis.
  • a subject e.g., a mammal, particularly a human
  • cholestatic liver disease e.g., high cholesterol disease, high triglyceride disease or fibrotic disease
  • NASH non-alcoholic steatohepatitis
  • PBC primary bil
  • the compounds of the invention may be used to prevent or treat obesity in a subject, such as a mammal, particularly a human.
  • the compounds of the present invention are useful for preventing or treating diabetes in a subject (e.g., a mammal, particularly a human), or a disease associated with insulin resistance, glucose intolerance.
  • the compounds of the present invention are useful for preventing or treating lower urinary tract symptoms (near areas) and benign prostatic hyperplasia (BPH) or ureteral stones in a subject (e.g., a mammal, particularly a human).
  • a subject e.g., a mammal, particularly a human.
  • Another aspect of the invention provides a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of formula I, formula II or formula III, for use in the manufacture of a medicament for the prophylaxis or treatment of a disease that benefits from FXR agonism, FXR-stimulated diseases, including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near areas) and benign prostatic hyperplasia (BPH) or ureteral stones.
  • FXR agonism FXR-stimulated diseases
  • cardiovascular disease including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near areas) and benign prostatic hyperplasia (BPH) or ureteral stones.
  • BPH benign prostatic hyperplasia
  • Another aspect of the invention provides a method for preventing or treating a disease that benefits from FXR agonism comprising administering to a patient a therapeutically effective amount of a pharmaceutically acceptable salt of Formula I, Formula II or Formula III, or a pharmaceutical composition thereof
  • the disease benefiting from FXR stimuli including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near area) and benign prostatic hyperplasia (BPH) or ureteral calculi.
  • the cardiovascular disease includes cardiovascular diseases associated with high triglyceride blood and/or hypercholesterolemia.
  • the cardiovascular disease further includes atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke or hypertension.
  • the liver/biliary system diseases include cholestatic liver diseases, high cholesterol diseases, high triglyceride diseases, or fibrotic diseases.
  • the liver/biliary system diseases further include nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, nonalcoholic cirrhosis, Bile duct atresia, cholestatic liver disease, chronic liver disease, hepatitis infection (type B or C), alcoholic liver disease or liver fibrosis.
  • NASH nonalcoholic steatohepatitis
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • gallstones nonalcoholic cirrhosis
  • Bile duct atresia cholestatic liver disease
  • chronic liver disease chronic liver disease
  • hepatitis infection type B or C
  • alcoholic liver disease or liver fibrosis alcoholic liver disease or liver fibrosis.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • the ring after oxo may remain aromatic and may lose aromaticity, and it is understood that the group after oxo generation is stable.
  • the benzene ring is oxo, it can be selected from
  • pyridine is oxo, it can be selected from
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g.
  • the ring B is substituted by 1, 2 or 3 R 2 or 1 oxo generation” means ring B Substituted by 1, 2 or 3 R 2 or 1 oxo, or ring B is not substituted by R 2 or oxo is not produced. It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn herein is that the moiety has an integer number of carbon atoms in a given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-3 alkyl means that the group may be selected from C 1 , C 2 and C 3 alkyl
  • C 3-10 cycloalkyl means that the group may be selected from C 3 , C 4 ,
  • 5- to 6-membered cycloalkyl means that the group may be selected from a 5-membered and 6-membered heterocycloalkyl group.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • substitution or oxo are independent of each other, including only the substitution anaerobic, only oxo unsubstituted or substituted or oxo.
  • ring A is optionally substituted with 1, 2 or 3 R a or 1 , 2 or 3 oxo, 1) has no substituent on ring A and no oxo, 2) is only on ring A 1, 2 or 3 R a substitutions, 3) only 1, 2 or 3 oxo groups occur on ring A, 4) ring A has both R a substitution and oxo.
  • a portion of the segment structure may be joined to other structures at the left end and at the same time to other structures at the right end.
  • a dotted line or a solid line indicates a connection key, it will be understood by those skilled in the art by reading the present application, which indicates the connection state of the segment structure with other structures in a directional manner.
  • ring A is selected from The left-handed dotted line indicates that the N atom is bonded to the L group of the compound of the formula (I), and the right-handed dotted line indicates that the C atom is bonded to the carbonyl moiety of the compound of the formula (I); for example, if the ring A is selected from The left-handed dotted line indicates that the C atom is bonded to the L group of the compound of the formula (I), and the right-handed dotted line indicates that the N atom is bonded to the carbonyl moiety of the compound of the formula (I).
  • the left-handed dashed line or solid line refers to the left-hand, left-, or left-down direction from the segment structure itself; the right-ward dotted line or solid line refers to the segment structure itself, to the upper right, right, or bottom right direction. Extend.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino means -NH 2 group.
  • nitro refers to a -NO 2 group.
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • alkyl sulfonyl refers to -SO 2 - group.
  • alkylthio refers to -S-alkyl.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C1-6 alkyl refers to an alkyl group containing from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety i.e., alkyl
  • an alkoxy group an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group
  • alkyl i.e., alkyl
  • heteroalkyl refers to an alkyl structure containing a hetero atom. Unless otherwise indicated, the heteroalkyl group is typically an alkyl group containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group having at least one double bond consisting of a carbon atom and a hydrogen atom.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkenyl refers to a straight-chain alkenyl group.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like.
  • non-aromatic heterocyclic group refers to a non-aromatic ring which is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and which may exist as a monocyclic, bicyclic or spiro ring.
  • the heterocyclic ring is typically a 3 to 6 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • heterocyclic groups include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl. , pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a relatively acidic functional group is contained in the compound of the present invention
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • the pharmaceutically acceptable salt may, for example, be a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like.
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • Optically active (R)- and (S)-isomers as well as D and L isoforms can be prepared by chiral synthesis or chiral reagents or other conventional techniques. Structure. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Example Compound 2-16 The operation of Example Compound 2-16 was carried out as in Example 1, as follows:
  • Triethylamine (153.0 mg, 1.5 mmol) and ethyl chloroformate (167.0 mg, 1.5 mmol) were added to a solution of Example 1A (500.0 mg, 1 mmol) in THF (5 mL). The reaction was carried out for 2 hours at a temperature of Celsius. The system was cooled to 0 ° C. A solution of sodium borohydride (210.0 mg, 5.6 mmol) in methanol (5 mL) was slowly added to the reaction mixture. The reaction was carried out at 0 ° C for 15 minutes and at 25 ° C for 15 minutes. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • Example 2A (250.0 mg, 70%).
  • 1 H NMR (400MHz, CHLOROFORM- d) ⁇ 8.15 (s, 1H), 8.04 (s, 1H), 5.19 (br.s., 1H), 4.77-4.66 (m, 1H), 3.66-3.57 (m , 2H), 2.06-1.77 (m, 7H), 1.45-1.06 (m, 21H), 0.97-0.88 (m, 9H), 0.66 (s, 3H).
  • Example 2A 280.0 mg, 605 ⁇ mol
  • triphenylphosphine 476.0 mg, 1.8 mmol
  • imidazole 124.0 mg, 1.8 mmol
  • Iodine 461.0 mg, 1.8 mmol
  • Example 2B 250.0 mg, 70%).
  • Example 2A To a solution of Example 2A (500.0 mg, 1.1 mmol), copper acetate (99.0 mg, 0.6 mmol) and lead acetate (2.4 g, 11.0 mmol) in toluene (5 ml), pyridine (980.0 mg, 12.4 mmol) The reaction system was reacted at 110 ° C for 12 hours.
  • Example 3A (100.0 mg, 0.2 mmol), sodium carbonate (74.0 mg, 0.7 mmol) and tetrabutylammonium bromide (66.0 mg, 0.2 mmol) of N,N-dimethylformamide 2 ml) of the solution was added with palladium acetate (5.0 mg, 23.0 ⁇ mol) and methyl 2-iodobenzoate (60.8 mg, 0.2 mmol), and the reaction was carried out at 85 ° C for 12 hours.
  • Example 3C 90.0 mg, 90.0%).
  • 1 H NMR 400MHz, CHLOROFORM- d
  • ⁇ 8.18-8.11 m, 1H
  • 8.06-8.00 m, 1H
  • 7.85-7.81 m, 2H
  • 7.35-7.31 m, 2H
  • 5.18 Br.s.,1H
  • 4.76-4.51 m,1H
  • 2.77-2.64 m,1H
  • Example 5B (1.0 g, 2.4 mmol) was dissolved in 1,4-dioxane (20.0 mL), 1,4-dihydropyran (2.0 g, 23.9 mmol, 2.2 mL) and p-toluene The sulfonic acid (90.9 mg, 478.0 ⁇ mol) was stirred at thirty degrees Celsius for thirty-six hours. The solvent was evaporated, and water (5 ml) was evaporated.
  • Example 5C (170.0 mg, 296.8 micromoles, dissolved in anhydrous ethanol) Stir for half an hour at zero degrees Celsius. Then diethyl oxalate (65.0 mg, 445.1 ⁇ mol, 60.8 ⁇ l, dissolved in 1 ml of absolute ethanol) was added dropwise. The reaction was stirred at 0 ° C for half an hour and then warmed to 25 ° C and stirring was continued for thirty-five. hour. Ethyl alcohol (6 ml) was added to the reaction mixture, and the solvent was evaporated, evaporated, ethyl ether (40 ml).
  • Example 5D (90.0 mg, 131.0 ⁇ mol) was dissolved in ethanol (3.0 ml), hydroxylamine hydrochloride (27.3 mg, 393.0 ⁇ mol) was added, and the reaction mixture was stirred at 80 ° C for five hours. The solvent was evaporated, and water (5 ml) was evaporated. The organic layer was washed with water (10 ml) dried over anhydrous sodium sulfate. The crude product was obtained without purification to give Example 5E (86.0 mg, crude, yellow oil).
  • Example 6A To a solution of Example 6A (800 mg, 1.4 mmol) in methanol (10 mL), 10% sodium hydroxide (methanol to water 1:1) (600 mg, 15 mmol, 6 ml) The reaction system was reacted at 70 ° C for 2 hours. The solvent was evaporated to dryness. EtOAc (EtOAc m.
  • Example 22 To a solution of Example 22 (100.0 mg, 194.7 ⁇ mol), DCC (60.3 mg, 292 ⁇ mol) and DMAP (23.8 mg, 194.7. 389.3 micromolar). The reaction system was reacted at 25 ° C for 12 hours. Water (5 ml) was added to the mixture. EtOAc (EtOAc m. The residue was purified by preparative EtOAc EtOAc EtOAc.
  • Example 12A 25 mg, 43.9%.
  • Example 14A (41 g, 100% yield) was obtained without purification and was used directly in the next step.
  • Example 14A The solution of Example 14A (41 g, 95.1 mmol) was dissolved in anhydrous tetrahydrofuran (300 ml), and the mixture was warmed to 50 ° under nitrogen atmosphere, and a solution of methylmagnesium bromide (800 ml, 1 M) in tetrahydrofuran was slowly added dropwise. After the completion of the dropwise addition, the reaction solution was cooled to room temperature and stirred overnight. After the reaction was completed, cyclohexane (25 ml) was added and filtered, and the residue was dissolved in a mixture of 3N aqueous hydrochloric acid (800 ml) and dichloromethane (200 ml). In the solution, stirring was continued for 30 minutes.
  • Example 14B (51 g, 100% yield) was obtained without purification and was used directly in the next step.
  • Example 14B Acetic anhydride (9.9 ml, 105.1 mmol), pyridine (1.6 ml, 19.8 mmol) and 4-dimethylaminopyridine (0.8 g, 6.6 mmol) were added to Example 14B (51 g, 95.1 mmol)
  • anhydrous tetrahydrofuran 300 ml
  • the reaction mixture was stirred at room temperature overnight.
  • the aqueous phase was extracted with dichloromethane (3 ⁇ 150 ml) Wash with water (100 ml), dry over anhydrous sodium
  • Example 14C 55 g, 100% yield was obtained without purification and was used directly in the next step.
  • Example 16D To a solution of Example 16D (100.0 mg, 245.9 ⁇ mol) and 5-aminopyridine-3-carboxylic acid (50.0 mg, 295 ⁇ mol) in DMF (5 mL), 1,3-dicyclohexylcarbodiimide ( 101.5 mg, 492 micromoles) and 4-dimethylaminopyridine (1.5 mg, 12.3 micromoles). The reaction system was reacted at 30 ° C for 16 hours. A solution of lithium hydroxide (10.3 mg, 246 micromoles) in water (2.0 mL) was added to the system. The reaction system was reacted at 30 ° C for 2 hours.
  • Reference Example 1F (10.0 g, 23.9 mmol) was dissolved in tetrahydrofuran (60.0 mL), and perchloric acid (240.0 mg, 2.4 mmol, 144.6 ⁇ l) (about 10 drops) was added at 30 ° C for half an hour.
  • Formic acid (40.3 g, 874.7 mmol, 33.0 ml) was added dropwise, and the reaction mixture was stirred at 50 ° C for eleven and five hours. The solvent was concentrated, and water (35.0 ml) was evaporated.
  • Example 16B (3.5 g, 8.5 mmol) was dissolved in methanol (100.0 ml), aqueous potassium hydroxide (70.0 g, 1.3 mol, dissolved in water, 100.0 ml) was added, and the reaction mixture was stirred at 100 ° C for twelve hours. Part of the solvent was removed by concentration and extracted with dichloromethane (30 mL ⁇ 3). The aqueous phase was acidified with EtOAc (EtOAc)EtOAc.
  • Example 16C (3.2 g, 7.9 mmol, 93.5% yield, yellow oil) was obtained without purification.
  • Example 16C a solution of sodium hydroxide (949.2 mg, 23.7 mmol, 10.00 ml of water) was added to Example 16C (3.2 g, 7.9 mmol), and the reaction mixture was heated to 80 ° C, and sodium borohydride (1.8 g, 47.5 mmol), the reaction solution was stirred at one hundred degrees Celsius for twelve hours.
  • Triethylamine 49.8 mg, 491.9 mmol, 68.2 ⁇ L
  • N,O-dimethylhydroxylamine hydrochloride were added to a solution of EtOAc (2 mL, EtOAc) Salt (24.0 mg, 245.9 micromolar).
  • EtOAc 2 mL, EtOAc
  • O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate 98.7 mg, 307.4 ⁇ mol
  • the reaction mixture was poured into cold water (30 ml), EtOAc (EtOAc m. 90 mg, 91.4% yield, white solid).
  • Protein glutathione-S-transferase-labeled FXR human protein (Invitrogen)
  • Coactivator biotinylated steroid receptor coactivator (Anaspec)
  • Detection reagent homogeneous proximity luminescence amplification test (alphascreen) detection kit (PerkinElmer)
  • test compound was prepared as a 40 ⁇ M DMSO solution, and then the compound was diluted 3-fold to 10 concentration points.
  • the reference compound was prepared as a 400 ⁇ M DMSO solution, followed by dilution at 1.5 fold to 10 concentration points.
  • the diluted DMSO solution was added to the wells of a 384-well plate at a volume of 150 nL per well.
  • the wells of the 384-well plate were added in a volume of 15 ⁇ L per well. Incubate for 1 hour at room temperature.
  • the receptor pellet mixture in the homogeneous proximity luminescence amplification assay (alphascreen) assay kit was diluted 125-fold and added to the wells of a 384-well plate at a volume of 7.5 ⁇ L per well. The experiment process is protected from light. Incubate for 1 hour at room temperature.
  • the donor pellet mixture in the homogeneous proximity luminescence amplification assay (alphascreen) assay kit was diluted 125-fold and added to the wells of a 384-well plate at a volume of 7.5 ⁇ L per well. The experiment process is protected from light. Incubate for 1 hour at room temperature.
  • Analytical data Data were analyzed using Prism 5.0 to calculate the EC50 value of the activation of the compound. The highest signal value of the compound is then compared to the highest signal value of the reference compound to determine the percent activation efficacy of the compound (Efficacy).
  • Cell culture medium 10% serum and Penicillin/Streptomycin (1 ⁇ ) were added to DMEM medium.
  • test compound was prepared as a 100 ⁇ M DMSO solution, and then the compound was diluted 3-fold to 10 concentration points.
  • the reference compound was prepared as a 100 ⁇ M DMSO solution, followed by dilution at 1.3 fold to 10 concentration points.
  • the diluted DMSO solution was added to the wells of a 384-well plate at a volume of 200 nL per well.
  • FXR HEK 293T DA cells were resuspended, resuspended in medium, diluted to a density of 5 ⁇ 10 5 /mL, and added to the wells of a 384-well plate at a volume of 40 ul per well.
  • the 384 microplate was incubated for 16 hours at 37 ° C under 5% CO 2 .
  • the mixed solution B C 1mM LiveBLAzer 6 ⁇ L of TM -FRET B / G (CCF4- AM) and the substrate with 60 ⁇ L 934 ⁇ L of volume per well was added 8 ⁇ L micropores 384 well plate.
  • Analytical data Data were analyzed using Prism 5.0 to calculate the EC50 value of the activation of the compound. The highest signal value of the test compound is then compared to the highest signal value of the reference compound (chenodeoxycholic acid, CDCA) to determine the percent activation efficacy of the compound (Efficacy).
  • CDCA chenodeoxycholic acid
  • mice Twelve C57BL/6J male mice were randomly divided into two groups, 6 in each group.
  • the first group was intravenous group.
  • the solvent is 10% HPbCD aqueous solution, when the drug solubility is not ideal, the help solvent will be added
  • the second group is oral group, irrigation
  • the stomach was administered at 10 mg/kg and 10 mL/kg (the vehicle was a 0.5% HPMC aqueous solution).
  • Plasma (K 2 -EDTA is anticoagulated) samples were taken at 0.083, 0.25, 0.5, 1, 2, 4, 6 , 8 and 24 hours after intravenous administration; 0.25, 0.5, 1, 2, 4 after oral administration Plasma samples were taken at 6, 8 and 24 hours.
  • mice Six C57BL/6J male mice were grouped into the oral group.
  • the preparation contained 5 kinds of research and development drugs, and 2 mg/kg/compound was administered by intragastric administration (the solvent was 0.5% HPMC aqueous solution).
  • the five compounds were first dissolved in a solvent, respectively, and formed into a 1 mg/mL solution (clear solution or suspension) by sonication or cyclone, and then the five compound solutions were mixed in equal volumes (1:1:1:1:1, v). :v:v:v:v:v) in a glass bottle.
  • 3 animals were collected for plasma and liver tissue samples 0.5 hours after administration; the other 3 animals were collected corresponding samples 3 hours after administration.
  • Plasma and liver tissue samples were analyzed using a five-in-one LC-MS/MS analysis method developed in advance. Plasma concentrations and liver tissue homogenate concentrations were obtained and the ratio of liver tissue to plasma concentration was calculated using Excel.
  • ND means not detected.
  • Example 22 in the drug liver was higher in 0.5 hours and 3 hours than in the control compound, and the liver/blood concentration ratio was also high in 0.5 hours and 3 hours.
  • the concentration of Example 26 in the 0.5 hour drug liver was higher than that of the control compound, and the liver/blood concentration ratio was higher than the control compound at 0.5 hour and 3 hours.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Endocrinology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及式(Ⅰ)所示化合物、其互变异构体或其药学上可接受的盐，并涉及其在制备治疗FXR相关疾病药物中的应用。

Description

甾体类衍生物FXR激动剂 技术领域
本发明涉及式(Ⅰ)所示化合物、其互变异构体或其药学上可接受的盐，并涉及其在制备治疗FXR相关疾病药物中的应用。
背景技术
法尼酯X受体(FXR)是一种最初从大鼠肝cDNA文库中鉴定的孤儿核受体(BM.Forman，et al.，Cell 81：687-693(1995))，其与昆虫蜕皮激素受体密切相关。FXR是包括类固醇，类维生素A，和甲状腺激素受体的配基-激活转录因子核受体家族的成员(DJ.Mangelsdorf，et al.，Cell 83：841-850(1995))。Northern和原位分析显示FXR在肝，肠，肾，和肾上腺中大量表达(BM.Formanet al.，Cell 81：687-693(1995)和W。Seolet al.，Mol.Endocrinnol。9：72-85(1995))。FXR与9-顺式维生素A酸受体(RXR)形成异源二聚体与DNA结合。FXR/RXR异源二聚体优先与由共有AG(G/T)TCA的双核受体半位点组成的成分结合，其形成反向重复并被单一核苷分离(IR-1模体)(BM.Forman，et al.，Cell 81：687-693(1995))。然而，这些化合物无法激活小鼠和人类FXR，使得内源性FXR配基的自然性还不确定。一些自然发生的胆酸在生理浓度下结合并激活FXR(PCTWO 00/37077，2000年6月29日出版))。如此所述，作为FXR配基的胆酸包括鹅脱氧胆酸(CDCA)，脱氧胆酸(DCA)，石胆酸(LCA)，和这些胆酸的牛磺酸及氨基乙酸共轭物。
WO-2005082925公开了INT747在制备治疗FXR相关疾病中的应用。
Figure PCTCN2017072567-appb-000001
发明内容
本发明的目的在于提供式(Ⅰ)所示化合物或其药学上可接受的盐，
Figure PCTCN2017072567-appb-000002
其中，
环A选自5～12元芳基、含有1～2个杂原子的5～12元杂芳基、含有1～2个杂原子的5～6元非芳香杂环基或5～6元环烷基，所述环A任选被1、2或3个Ra取代或任选发生1、2或3个氧代，所述杂原子选自N、O或S；
L选自C1-8烷基、C1-8杂烷基或C2-8链烯基，所述L任选被1、2或3个Rb取代或任选发生1、2或3个氧代；
L1选自O、N(Rd)、N(Rd)S(＝O)2或N(Rd)S(＝O)；
R1选自H、C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基，所述C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基任选被1、2或3个Rc取代或任选发生1、2或3个氧代；
Ra、Rb、Rc和Rd各自独立地选自H、F、Cl、Br、I、OH、CN、NO2、NH2、COOH、S(＝O)2OH、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基或C1-3烷基硫基，所述C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基或C1-3烷基硫基任选被1、2或3个R’取代；
R’选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CH2F、CHF2、CF3、CH3O、CH3S、NH(CH3)或N(CH3)2。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述Ra、Rb、Rc和Rd各自独立地选自H、F、Cl、Br、I、COOH、S(＝O)2OH、Me、CF3、CHF2、CH2F、Et、OMe、NH(CH3)或N(CH3)2。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述环A选自苯基、吡啶基、吡啶-2(1H)-酮基、嘧啶基、吡唑基、咪唑基、噁唑基、噻唑基、噻吩基、吡咯烷基、哌啶基、吗啉基、哌嗪基、异噁唑基、异噻唑基、双环[1.1.1]戊烷基、苯并噁唑基、苯并[d]异噁唑基、吲唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、1H-吡咯并[2,3-B]吡啶基、中氮茚基、苯并噻唑基或苯并噻吩基，所述环A任选被1、2或3个Ra取代。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述环A选自
Figure PCTCN2017072567-appb-000003
Figure PCTCN2017072567-appb-000004
Figure PCTCN2017072567-appb-000005
Figure PCTCN2017072567-appb-000006
所述环A任选被1、2或3个Ra取代。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述环A选自
Figure PCTCN2017072567-appb-000007
Figure PCTCN2017072567-appb-000008
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述L选自C1-4烷基、C1-4 烷氧基、C1-4烷硫基、C1-4烷氨基、C1-4烷基-C(＝O)NH-、C2-4烷烯基或C1-3烷基-O-C1-3烷基，所述L任选被1、2或3个Rb取代。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述L选自
Figure PCTCN2017072567-appb-000009
Figure PCTCN2017072567-appb-000010
所述L任选被1、2或3个Rb取代。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述L选自
Figure PCTCN2017072567-appb-000011
Figure PCTCN2017072567-appb-000012
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述L选自
Figure PCTCN2017072567-appb-000013
Figure PCTCN2017072567-appb-000014
本发明的一些方案中，上述L1选自O、NH、NHS(＝O)2和NHS(＝O)。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述R1选自H、C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基，所述C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基任选被1、2或3个Rc取代，所述Rc如前所定义。
本发明的一些方案中，式(Ⅰ)所示化合物或其药学上可接受的盐中，上述R1选自H、Me、
Figure PCTCN2017072567-appb-000015
作为式(Ⅰ)所示化合物或其药学上可接受的盐的优选方式，选自下述式(Ⅱ)所示化合物或其药学上可接受的盐：
Figure PCTCN2017072567-appb-000016
其中，
L2选自C1-6烷基、C1-6杂烷基或C2-6链烯基；
环B选自苯环，或含有1～2个杂原子的5～6元杂芳环，所述杂原子选自N、O或S；
所述环B任选被1、2或3个R2取代或任选发生1个氧代；所述R2选自F、Cl、Br、I、OH、CN、NO2、NH2、COOH、S(＝O)2OH、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基或C1-3烷基硫基；
L1选自O、NH、NHS(＝O)2或NHS(＝O)；
R1选自H、C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基，所述C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基任选被1、2或3个Rc取代或任选发生1、2或3个氧代，所述Rc选自F、Cl、Br、I、OH、CN、NO2、NH2、COOH或S(＝O)2OH。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，L2选自-(CH2)1～6-、-(CH2)0～4-X-(CH2)0～4-或-(CH2)0～4-Y-(CH2)0～4-，所述X选自NH、O或S，所述Y选自-CH＝CH-，条件是L2链长度选自1～6，优选自2～4。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，L2选自-CH2CH2-、-CH2CH2CH2-、-CH＝CH-、-CH2CH＝CH-、-CH＝CHCH2-、-CH2CH2O-、-CH2CH2CH2O-、-CH2CH2NH-、-CH2CH2CH2NH-、-CH2CH2S-或-CH2CH2CH2S-；优选自-CH2CH2-、-CH2CH2CH2-、-CH＝CH-、-CH2CH2O-、-CH2CH2CH2O-或-CH2CH2NH-。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，环B选自苯环、含有1～2个选自N、O或S原子的5元杂芳环或含有1～2个选自N原子的6元杂芳环，所述环B任选被1、2或3个R2取代或任选发生1个氧代，所述R2如前所定义。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，环B选自苯环、吡唑、咪唑、噁唑、异噁唑、噻唑、异噻唑、吡啶、哒嗪、嘧啶或吡嗪，所述环B任选被1、2或3个R2取代或任选发生1个氧代，所述R2如前所定义。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，所述环B任选被1个R2取代或任选发生1个氧代，所述R2选自F、Cl、Br、I、OH、CN、NO2、NH2、COOH或S(＝O)2OH，优 选F、Cl或Br。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，所述R2取代或氧代的位置处于环B上相对L2的邻位(α位)。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，所述R1选自H、C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基，所述C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基任选被1、2或3个Rc取代，所述Rc如前所定义。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，所述R1选自H、Me、
Figure PCTCN2017072567-appb-000017
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，结构片段L1-R1选自-OH、-NHSO2CH3、
Figure PCTCN2017072567-appb-000018
-NHSO2C(CH3)3、-NHCH2CH2SO2OH、-NHCH2COOH、
Figure PCTCN2017072567-appb-000019
-NHSO2CH(CH3)2、
Figure PCTCN2017072567-appb-000020
-NHCH3、-OCH3或
Figure PCTCN2017072567-appb-000021
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，结构片段
Figure PCTCN2017072567-appb-000022
选自
Figure PCTCN2017072567-appb-000023
Figure PCTCN2017072567-appb-000024
Figure PCTCN2017072567-appb-000025
Figure PCTCN2017072567-appb-000026
所述L2和R2如前所定义。
本发明的一些方案中，式(Ⅱ)所示化合物或其药学上可接受的盐中，结构片段
Figure PCTCN2017072567-appb-000027
选自
Figure PCTCN2017072567-appb-000028
Figure PCTCN2017072567-appb-000029
Figure PCTCN2017072567-appb-000030
Figure PCTCN2017072567-appb-000031
本发明还提供了式(Ⅲ)所示化合物或其药学上可接受的盐：
Figure PCTCN2017072567-appb-000032
其中，
环A为任选被1、2或3个R取代的5～12元芳基、5～12元杂芳基、或5～6元非芳香杂环基、5～6元环烷基；
L为任选被1、2或3个R取代的C1-6烷基、C1-6杂烷基、C2-6链烯基；
R为F、Cl、Br、I、OH、CN、NO2、NH2，或者R选自任选被1、2或3个R’取代的C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基、C1-3烷基硫基；
R’选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CH2F、CHF2、CF3、CH3O、CH3S、NH(CH3)、N(CH3)2；
所述“杂”代表杂原子或杂原子团，选自-C(＝O)NH-、N、-NH-,-C(＝NH)-、-S(＝O)2NH-、-S(＝O)NH-、-O-、-S-、N、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、和-NHC(＝O)NH-；
上述任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述R选自F、Cl、Br、I、Me、CF3、CHF2、CH2F、Et、OMe、NH(CH3)、N(CH3)2。
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述环A为任选被1、2或3个R取代的苯基、吡啶基、吡啶-2(1H)-酮基、嘧啶基、吡唑基、咪唑基、噁唑基、噻唑基、噻吩基、 吡咯烷基、哌啶基、吗啉基、哌嗪基、异噁唑基、异噻唑基、双环[1.1.1]戊烷基、苯并噁唑基、苯并[d]异噁唑基、吲唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、1H-吡咯并[2,3-B]吡啶基、中氮茚基、苯并噻唑基、苯并噻吩基、。
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述环A选自任选被1、2或3个R取代的
Figure PCTCN2017072567-appb-000033
Figure PCTCN2017072567-appb-000034
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述环A选自
Figure PCTCN2017072567-appb-000035
Figure PCTCN2017072567-appb-000036
Figure PCTCN2017072567-appb-000037
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述L选自任选被1、2或3个R取代的C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C1-4烷基-C(＝O)NH-、C2-4烷烯基。
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述L选自任选被1、2或3个R取代的
Figure PCTCN2017072567-appb-000038
Figure PCTCN2017072567-appb-000039
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述L选自
Figure PCTCN2017072567-appb-000040
Figure PCTCN2017072567-appb-000041
本发明的一些方案中，式(Ⅲ)所示化合物或其药学上可接受的盐中，上述L选自
Figure PCTCN2017072567-appb-000042
Figure PCTCN2017072567-appb-000043
本发明的化合物，其选自：
Figure PCTCN2017072567-appb-000044
Figure PCTCN2017072567-appb-000045
Figure PCTCN2017072567-appb-000046
Figure PCTCN2017072567-appb-000047
Figure PCTCN2017072567-appb-000048
Figure PCTCN2017072567-appb-000049
Figure PCTCN2017072567-appb-000050
本发明还提供了一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗法尼酯X受体相关各种病症、胆汁淤积性肝疾病、纤维变性疾病、高胆固醇疾病、高甘油三酯疾病及心血管疾病的药物中的应用。
本发明还提供了上述化合物或其药学上可接受的盐或上述药物组合物在制备治疗非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、胆汁淤积性肝病、慢性肝病、C型肝炎感染、酒精性肝病、肝纤维变性、原发性硬化性胆管炎(PSC)、胆结石、胆管闭锁、下尿路症状与良性前列腺增生(BPH)、输尿管结石、肥胖、二型糖尿病、动脉粥样硬化、动脉硬化症、高胆固醇血症和高血脂症导致的肝功能损害的药物中的应用。
本发明的化合物是FXR激动剂。本发明的化合物可用于预防或治疗血脂代谢紊乱或与血脂代谢紊乱相关的疾病的方法，该方法包括对需要该治疗的患者施用治疗有效量的本发明的化合物。
本发明的化合物可用于降低总胆固醇水平，降低LDL胆固醇水平，降低VLDL胆固醇水平、提高HDL胆固醇水平，和/或降低甘油三酯水平。本发明所述的降低甘油三酯水平是指将需要治疗的对象中的甘油三酯降低到低于该预防或治疗对象在服用本申请化合物之前的最初的甘油三酯水平。例如，本发明化合物可以通过减少脂肪吸收，减少肝的甘油三酯产生或者减少肝的甘油三酯分泌。本发明化合物还可以降低血清甘油三脂和肝甘油三脂。
本发明的化合物可以用于预防或治疗受治疗者(例如哺乳动物，特别是人)中与高甘油三酯血和/或高胆固醇血有关的心血管疾病，例如但不仅限于动脉粥样硬化、动脉硬化症、高胆固醇血症、高血脂症、血栓形成、冠状动脉病、中风或高血压疾病。
本发明的化合物可以用于预防或治疗受治疗者(例如哺乳动物，特别是人)的肝/胆系统疾病，例 如但不仅限于胆汁淤积性肝疾病、高胆固醇疾病、高甘油三酯疾病或纤维变性疾病，具体例如但不仅限于非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、胆结石、非酒精性肝硬化、胆管闭锁、胆汁淤积性肝病、慢性肝病、肝炎感染(B型或C型)、酒精性肝病或肝纤维变性。
本发明的化合物可以用于预防或治疗受治疗者(例如哺乳动物，特别是人)的肥胖症。
本发明的化合物可以用于预防或治疗受治疗者(例如哺乳动物，特别是人)的糖尿病，或胰岛素抗性、葡萄糖不耐受相关的疾病。
本发明的化合物可以用于预防或治疗受治疗者(例如哺乳动物，特别是人)的下尿路症状(附近地区)与良性前列腺增生(BPH)或输尿管结石。
本发明另一方面提供如式Ⅰ、式Ⅱ或式Ⅲ所示的化合物、其药学上可接受的盐或者上述药物组合物在制备预防或治疗受益于FXR激动的疾病的用途，所述受益于FXR激动的疾病，包括心血管疾病、肝/胆系统疾病、肥胖症、糖尿病、下尿路症状(附近地区)与良性前列腺增生(BPH)或输尿管结石。
本发明的另一方面提供用于预防或治疗受益于FXR激动的疾病的方法，包括给予患者治疗有效量的如式Ⅰ、式Ⅱ或式Ⅲ、其药学上可接受的盐或者上述药物组合物，所述受益于FXR激动的疾病，包括心血管疾病、肝/胆系统疾病、肥胖症、糖尿病、下尿路症状(附近地区)与良性前列腺增生(BPH)或输尿管结石。
所述心血管疾病包括与高甘油三酯血和/或高胆固醇血有关的心血管疾病。所述心血管疾病进一步包括动脉粥样硬化、动脉硬化症、高胆固醇血症、高血脂症、血栓形成、冠状动脉病、中风或高血压。所述肝/胆系统疾病包括胆汁淤积性肝疾病、高胆固醇疾病、高甘油三酯疾病或纤维变性疾病。所述肝/胆系统疾病进一步包括非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、胆结石、非酒精性肝硬化、胆管闭锁、胆汁淤积性肝病、慢性肝病、肝炎感染(B型或C型)、酒精性肝病或肝纤维变性。
定义与说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。
术语“氧代”指特定原子上的两个氢原子被＝O取代。当具有芳香性的环发生氧代时，氧代后的环可能保持芳香性也可能丧失芳香性，可以理解的是，发生氧代后的基团是稳定的。例如，当苯环发生氧 代时，可以选自
Figure PCTCN2017072567-appb-000051
当吡啶发生氧代时，可以选自
Figure PCTCN2017072567-appb-000052
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)；又例如，“任选地，所述环B被1、2或3个R2取代或发生1个氧代”指，环B被1、2或3个R2取代或发生1个氧代，或者环B不被R2取代或不发生氧代。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
本文中的数字范围，是指给定范围中的各个整数。例如“C1-3烷基”指该基团可选自C1、C2和C3的烷基；“C3-10环烷基”指该基团可选自C3、C4、C5、C6、C7、C8、C9和C10的环烷基；“5～6元环烷基”指该基团可选自5元和6元的杂环烷基。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本文中，当部分基团可以发生被取代或氧代时，取代或氧代是相互独立的，包括只有取代无氧代、只有氧代无取代或者取代或氧代同时发生。例如，当环A任选被1、2或3个Ra取代或发生1、2或3个氧代时，包括1)环A上无取代基和无氧代，2)环A上只被1、2或3个Ra取代，3)环A上只发生1、2或3个氧代，4)环A上同时有Ra取代和氧代。
在本申请的部分优选方式中，部分片段结构可以左端与其他结构连接，并且同时可以右端与其他结构连接。当虚线或实线表示连接键时，本领域的技术人员通过阅读本申请可以理解得到，该虚线或实线方向性地表明了片段结构与其他结构的连接状态。例如，如果环A选自
Figure PCTCN2017072567-appb-000053
左向性虚线表明N原子与式(Ⅰ)所示化合物的L基团相连，右向性虚线表明C原子与式(Ⅰ)所示化合物的羰基部分相连；又例如，如果环A选自
Figure PCTCN2017072567-appb-000054
左向性虚线表明C原子与式(Ⅰ)所示化合物的L基团相连，右向性虚线表明N原子与式(Ⅰ)所示化合物的羰基部分相连。所述左向性虚线或实线指从片段结构本身出发，向左上、左或左下方向伸出；所述右向性虚线或实线指从片段结构本身出发，向右上、右或右下方向伸出。
在本申请的部分优选方式中，所述链长度指形成所述开链式基团所用原子个数，所述原子包括不同价态的C原子、N原子、O原子或S原子，例如，L2选自-CH2CH2CH2-时，链长度为3；当L2选自-(CH2)2-O-(CH2)2-时，链长度为5；当L2选自-(CH2)2-CH＝CH-(CH2)2-时，链长度为6。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“巯基”指-SH基团。
术语“氨基”指-NH2基团。
术语“硝基”指-NO2基团。
术语“烷氧基”指-O-烷基。
术语“烷基氨基”指-NH-烷基。
术语“二烷基氨基”指-N(烷基)2。
术语“烷基磺酰基”指-SO2-烷基。
术语“烷硫基”指-S-烷基。
术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“杂烷基”指含有杂原子的烷基结构。除非另有指示，该杂烷基通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的烷基。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。术语“链烯基”指直链烯基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。
术语“非芳香杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、双环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至6元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的盐可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异 构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams & Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2017072567-appb-000055
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括 但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。
卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。本领域任何合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基。对于经过训练的从业者来说，Greene and Wuts的(Protective Groups In Organic Synthesis,Wiley and Sons,1991)是这方面的权威。本申请引用的所有参考文献整体上并入本申请。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH 代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
具体实施方式
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。
参考例1 INT-747的制备
Figure PCTCN2017072567-appb-000056
参考例1A
Figure PCTCN2017072567-appb-000057
向鹅去氧胆酸(60.0克，152.8毫摩尔)的甲醇/醋酸/水/乙酸乙酯(360/120/30/780毫升)溶液中分批加入四丁基溴化铵(81.0克，251.3毫摩尔)和溴化钠(9.0克，87.5毫摩尔)，再在0摄氏度下于30分钟内滴加次氯酸钠(210毫升，3.4摩尔)，在28摄氏度下搅拌16小时后，加入饱和的亚硫酸氢钠溶液(500毫升)淬灭，水层用乙酸乙酯(1000毫升×2)萃取，将合并的有机层再用水(1000毫升×5)洗涤，将有机层用硫酸钠干燥，过滤并旋干，残余物通过重结晶(二氯甲烷，200毫升)得到参考例1A(黄色固体，41克，69％产率)。1H NMR(400MHz,METHANOL-d4)δ3.44-3.60(m,1H),2.99(dd,J＝5.77,12.30Hz,1H),2.54(t,J＝11.29Hz,1H),2.08-2.41(m,3H),2.00-2.08(m,1H),1.75-1.96(m,6H),1.28-1.69(m,9H),1.09-1.27(m,8H),0.97(d,J＝6.53Hz,3H),0.71(s,3H).
参考例1B
Figure PCTCN2017072567-appb-000058
向参考例1A(246.0克，629.9毫摩尔)的甲醇(2升)溶液中一次性加入对甲苯磺酸(10.9克，63.0毫摩尔)，在80摄氏度反应4小时。冷却至室温后，蒸干，用饱和碳酸氢钠溶液(1500毫升)淬灭后，水层用乙酸乙酯(1500毫升×3)萃取，合并的有机层用盐水(1000毫升×3)洗涤后，经硫酸钠干燥，过滤并旋干，残余物通过重结晶(乙酸乙酯，500毫升)得到参考例1B(白色固体，202克，79％产率)。1H NMR(400MHz,CHLOROFORM-d)δ3.66(s,3H),3.55-3.62(m,1H),2.85(dd,J＝6.02,12.55Hz,1H),2.28-2.43(m,2H),2.13-2.26(m,2H),1.64-2.04(m,10H),1.19-1.51(m,11H),1.00-1.17(m,3H),0.86-0.97(m,3H),0.65(s,3H).
参考例1C
Figure PCTCN2017072567-appb-000059
零下78摄氏度，氮气保护下，向三甲基氯硅烷(107.5克，989.5毫摩尔)的四氢呋喃(500毫升)溶液中滴加二异丙基氨基锂(87.4克，815.6毫摩尔)，搅拌40分钟后，再滴加参考例1B(50克，123.6毫摩尔)的四氢呋喃(300毫升)溶液。滴加完毕后在零下78摄氏度下继续搅拌40分钟，再加入三乙胺(182.5克，1.8摩尔)，1小时后，用饱和碳酸氢钠(1000毫升)淬灭，水层用乙酸乙酯(1000毫升×3)萃取。将合并的有机层再用水(100毫升×6)和饱和食盐水(1000毫升×2)洗，将有机层用硫酸钠干燥，过滤并旋干，得到参考例1C(棕黄色油状物，68克，收率100％)可直接用于下一步而无需进一步纯化。1H NMR(400MHz,CHLOROFORM-d)δ4.75(dd,J＝1.38,5.90Hz,1H),3.69(s,3H),3.48-3.59(m,1H),2.13-2.42(m,2H),1.52-2.04(m,10H),1.29-1.48(m,7H),0.99-1.23(m,5H),0.95(d,J＝6.53Hz,3H),0.85(s,3H),0.70(s,3H),0.17-0.20(m,9H),0.13(s,9H).
参考例1D
Figure PCTCN2017072567-appb-000060
向参考例1C(68.0克，123.9毫摩尔)的二氯甲烷(500毫升)溶液中加入无水乙醛(10.1克，229.2 毫摩尔)。零下78摄氏度氮气保护下逐滴加入三氟化硼-乙醚(64.4克，453.4毫摩尔)的二氯甲烷(300毫升)溶液。滴加速度需保持内温为零下78摄氏度，搅拌1小时后，升温至30摄氏度继续搅拌2小时，将上述溶液用饱和碳酸氢钠(1000毫升)淬灭，水层用二氯甲烷(1000毫升×3)萃取，合并的有机层用饱和食盐水(1000毫升×2)洗涤，硫酸钠干燥，过滤并旋干，残余物通过柱色谱纯化得到参考例1D(黄色固体，43克，收率81％)。1H NMR(400MHz,CHLOROFORM-d)δ6.12(q,J＝7.03Hz,1H),3.52-3.66(m,4H),2.54(dd,J＝4.02,13.05Hz,1H),2.13-2.40(m,5H),1.68-1.98(m,7H),1.65(d,J＝7.03Hz,3H),1.00-1.52(m,11H),0.97(s,3H),0.89(d,J＝6.53Hz,3H),0.61(s,3H).
参考例1E
Figure PCTCN2017072567-appb-000061
向参考例1D(212.0克，492.3毫摩尔)的甲醇(500毫升)溶液中加入NaOH(39.4克，984.6毫摩尔)的水(50毫升)溶液，50摄氏度下搅拌2小时。旋干溶剂后，加水(500毫升)，用乙酸乙酯(500毫升×2)萃取，水相用稀HCl调至pH至3，再用二氯甲烷(600毫升×2)萃取，将合并的有机层浓缩，残余物通过重结晶(乙醇，200毫升)纯化得到参考例1E(黄色固体，147克，收率72％)。1H NMR(400MHz,CHLOROFORM-d)δ6.19(q,J＝7.36Hz,1H),3.60-3.74(m,1H),2.58(dd,J＝4.02,13.05Hz,1H),2.40(tt,J＝5.02,10.29Hz,3H),2.19-2.32(m,2H),1.61-2.06(m,10H),1.04-1.54(m,14H),1.01(s,3H),0.95(d,J＝6.53Hz,3H),0.65(s,3H).
参考例1F
Figure PCTCN2017072567-appb-000062
向参考例1E(140.0克，336.1毫摩尔)的NaOH(0.5摩尔)水溶液(600毫升)中一次性加入10％Pd-C(19.9克，134.4毫摩尔)，通入15psi的氢气，在100摄氏度下反应16小时。抽滤，滤液用稀盐酸调pH至3，水层用二氯甲烷(1500毫升×3)萃取，合并的有机层用盐水(1000毫升×3)洗涤后，经硫酸钠干燥，过滤并旋干，得到参考例1F(白色固体，101克，收率72％)可直接用于下一步而无需进一步纯化。1H NMR(400MHz,CHLOROFORM-d)δ3.49-3.60(m,1H),2.70(q,J＝6.02Hz,1H),2.12-2.45(m,4H),1.65-2.02(m,9H),1.29-1.52(m,6H),1.05-1.24(m,8H),0.93(d,J＝6.53Hz,5H),0.81(t,J＝7.53Hz, 3H),0.66(s,3H).
参考化合物INT-747
Figure PCTCN2017072567-appb-000063
向参考例1F(16.0克，38.2毫摩尔)的氢氧化钠(2摩尔，100毫升)溶液中分批加入硼氢化钠(8.7克，229.3毫摩尔)，在100摄氏度搅拌2小时。冷却至室温后加入饱和氯化铵水溶液(150毫升)，用稀盐酸调pH至3，水层用二氯甲烷(300毫升×3)萃取，合并的有机层用盐水(200毫升×3)洗涤后，经硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化得到参考化合物INT-747(白色固体，14.5克，收率90％)。1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s,1H),3.36-3.48(m,1H),2.18-2.47(m,2H),1.56-2.01(m,10H),1.06-1.54(m,15H),0.86-0.97(m,9H),0.66(s,3H).
路线1
Figure PCTCN2017072567-appb-000064
实施例1
Figure PCTCN2017072567-appb-000065
实施例1A
Figure PCTCN2017072567-appb-000066
氮气保护下，向参考化合物INT-747(2.7克，6.4毫摩尔)和甲酸(0.3克，6.4毫摩尔)的四氢呋喃(40毫升)溶液中加入高氯酸(6.0克，60.0毫摩尔)。55摄氏度下搅拌6小时，将上述溶液减压浓缩后用水(100毫升)稀释，水层用乙酸乙酯(100毫升×2)萃取。将合并的有机层用无水硫酸钠干燥，过滤并旋干，残余物通过柱色谱纯化得到实施例1A，为白色固体(2.8克，收率92％)。1H NMR(400MHz,CHLOROFORM-d)δ8.16(s,1H),8.05(s,1H),5.20(br.s.,1H),4.77-4.65(m,1H),2.45-2.34(m,1H),2.31-2.21(m,1H),2.01-1.58(m,11H),1.55-1.30(m,8H),1.22-1.05(m,6H),0.97-0.88(m,9H),0.66(s,3H).
实施例1B
Figure PCTCN2017072567-appb-000067
向实施例1A(100.0毫克，0.2毫摩尔)和醋酸铅(186.0毫克，0.4毫摩尔)的四氯化碳(2毫升)溶液中加入单质碘(106.0毫克，0.4毫摩尔)，反应体系光照下反应12小时。将上述溶液加入硫代硫酸钠溶液(1毫升)淬灭反应，水层用二氯甲烷(10毫升×3)萃取，经无水硫酸钠干燥，过滤并旋干，残余物通过制备薄层板纯化(石油醚：乙酸乙酯＝5：1)得到实施例1B(无色固体，50.0毫克，产率38％)。1H-NMR(CDCl3,400MHz)δ8.14(s,1H),8.03(s,1H),5.19(br.s.,1H),4.62-4.77(m,1H),3.23-3.32(m,1H),3.00-3.12(m,1H),1.96-2.02(m,2H),1.85-1.92(m,2H),1.70-1.82(m,7H),1.66-1.72(m,2H), 1.39-1.45(m,2H),1.23-1.32(m,5H),1.09-1.19(m,6H),0.96(s,3H),0.90-0.93(m,6H),0.67(s,3H).
实施例1
Figure PCTCN2017072567-appb-000068
零度下向6-酮哌啶-3-羧酸甲酯(21.0毫克，134微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入钠氢(7.0毫克，179微摩尔，60％)。半小时后，零度下缓慢滴加实施例1B(50.0毫克，89.5微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。滴加完毕，反应体系缓慢升至室温反应12小时。水(3毫升)和一水合氢氧化锂(4毫克，89.5毫摩尔)加入反应体系，继续搅拌3小时。加入水(10毫升)，反应体系用盐酸(1M)调至pH＝6，二氯甲烷：甲醇＝10:1(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备薄层板纯化(二氯甲烷：甲醇＝10：1)得到实施例1(15毫克，32.4％产率)。1H NMR(400MHz,METHANOL-d4)δ3.67(br.s.,1H),3.58-3.48(m,2H),3.45-3.34(m,2H),3.31-3.27(m,1H),2.87(d,J＝13.1Hz,1H),2.49-2.29(m,2H),2.11(br.s.,2H),2.00-1.35(m,19H),1.30-1.10(m,6H),1.04(d,J＝6.5Hz,3H),0.95-0.90(m,6H),0.72(s,3H).
操作如同实施例1，合成了实施例化合物2-16，如下：
Figure PCTCN2017072567-appb-000069
Figure PCTCN2017072567-appb-000070
Figure PCTCN2017072567-appb-000071
路线2
Figure PCTCN2017072567-appb-000072
实施例17和实施例18
Figure PCTCN2017072567-appb-000073
实施例2A
Figure PCTCN2017072567-appb-000074
向实施例1A(500.0毫克，1毫摩尔)的四氢呋喃(5毫升)溶液中加入三乙胺(153.0毫克，1.5毫摩尔)和氯甲酸乙酯(167.0毫克，1.5毫摩尔)，反应体系在25摄氏度下反应2小时。体系冷却至0摄氏度，硼氢化钠(210.0毫克，5.6毫摩尔)的甲醇(5毫升)溶液慢慢加入反应体系，0摄氏度下反应15分钟，25摄氏度下反应15分钟。用0.2M的稀盐酸(1毫升)淬灭反应，水层用乙酸乙酯(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤并旋干，残余物通过柱色谱(石油醚：乙酸乙酯＝4：1)纯化得到实施例2A(250.0毫克，70％)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.77-4.66(m,1H),3.66-3.57(m,2H),2.06-1.77(m,7H),1.45-1.06(m,21H),0.97-0.88(m,9H),0.66(s,3H).
实施例2B
Figure PCTCN2017072567-appb-000075
零度下向实施例2A(280.0毫克，605微摩尔)，三苯基磷(476.0毫克，1.8毫摩尔)和咪唑(124.0毫克，1.8毫摩尔)的甲苯(4毫升)和乙腈(1毫升)混合溶液中加入碘(461.0毫克，1.8毫摩尔)，反应体系在25摄氏度下反应3小时。饱和的亚硫酸钠溶液(10毫升)加入反应体系，水层用乙酸乙酯(10毫升×3)萃取，合并有机层并用无水硫酸钠干燥，过滤并旋干，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝20：1)得到实施例2B(250.0毫克，70％)。1H-NMR(CDCl3,400MHz)δ8.16(s,1H),8.07-8.02(m,1H),5.20(br.s.,1H),4.76-4.66(m,1H),3.24-3.08(m,2H),2.01-1.72(m,10H),1.46-1.06(m,17H),0.97-0.89(m,9H),0.66(s,3H).
实施例17和实施例18
Figure PCTCN2017072567-appb-000076
零度下向6-羟基烟酸甲酯(80.0毫克，523微摩尔)的N,N-二甲基甲酰胺(3毫升)溶液加钠氢(21.0毫克，523毫摩尔，60％)。半小时后，零度下滴加实施例2B(150.0毫克，262微摩尔)的N,N-二甲基甲酰胺(5毫升)溶液。滴加完毕，反应体系缓慢升至室温反应12小时。水(3毫升)和一水合氢氧化锂(55毫克，1.31毫摩尔)加入反应体系，继续搅拌3小时。加入水(10毫升)，体系用盐酸(1M)调至pH＝6，用二氯甲烷：甲醇＝10:1(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备薄层板(二氯甲烷：甲醇＝10:1)分离纯化得到实施例17(40毫克，29％)，1H NMR(400MHz,METHANOL-d4)δ8.44(d,J＝2.5Hz,1H),7.97(dd,J＝2.5,9.5Hz,1H),6.55(d,J＝9.5Hz,1H),4.10-3.96(m,2H),3.70-3.63(m,1H),3.37-3.34(m,1H),2.02-1.11(m,27H),0.98(d,J＝6.0Hz,3H),0.95-0.88(m,6H),0.71(s,3H)。以及实施例18(20毫克，14％)，1H NMR(400MHz,METHANOL-d4)δ8.77(s,1H),8.21(dd,J＝1.8,8.8Hz,1H),6.84(d,J＝8.5Hz,1H),4.34(d,J＝2.5Hz,2H),3.78-3.58(m,1H),3.38-3.33(m,1H),2.02-1.22(m,27H),1.01(d,J＝6.5Hz,3H),0.95-0.90(m,6H),0.72(s,3H).
路线3
Figure PCTCN2017072567-appb-000077
实施例19
Figure PCTCN2017072567-appb-000078
实施例3A
Figure PCTCN2017072567-appb-000079
向实施例2A(500.0毫克，1.1毫摩尔)，醋酸铜(99.0毫克，0.6毫摩尔)和醋酸铅(2.4克，11.0毫摩尔)的甲苯(5毫升)溶液中加入吡啶(980.0毫克，12.4毫摩尔)，反应体系110摄氏度下反应12小时。反应体系过滤，滤液浓缩，残余物通过柱色谱纯化(石油醚：乙酸乙酯＝20：1)得到标题化合物(120.0毫克，27.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.05(s,1H),5.71-5.59(m,1H),5.19(br.s.,1H),4.93-4.80(m,2H),4.76-4.67(m,1H),2.12-1.61(m,11H),1.52-1.09(m,13H),1.04(d,J＝6.8Hz,3H),0.97(s,3H),0.91(t,J＝7.4Hz,3H),0.68(s,3H).
实施例3B
Figure PCTCN2017072567-appb-000080
氮气下向实施例3A(100.0毫克，0.2毫摩尔)，碳酸钠(74.0毫克，0.7毫摩尔)和四丁基溴化铵(66.0毫克，0.2毫摩尔)的N,N二甲基甲酰胺(2毫升)溶液中加入醋酸钯(5.0毫克，23.0微摩尔)以及2-碘代苯甲酸甲酯(60.8毫克，0.2毫摩尔)，反应体系85摄氏度下反应12小时。旋干溶剂，水(10毫升)加入反应体系，水层用二氯甲烷(20毫升×3)萃取，合并有机层，有机相用无水硫酸钠干燥，过滤并旋干，残余物通过薄层制备色谱纯化(石油醚：乙酸乙酯＝10：1)得到标题化合物(80.0毫克，61.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.16(s,1H),8.07(s,1H),8.01(s,1H),7.90-7.84(m,1H),7.51(d,J＝7.8Hz,1H),7.41-7.33(m,1H),6.40-6.31(m,1H),6.16(dd,J＝8.8,15.8Hz,1H),5.21(br.s.,1H),4.79-4.63(m,1H),3.94(s,3H),2.29(d,J＝6.8Hz,1H),2.08-1.62(m,11H),1.52-1.20(m,11H),1.15(d,J＝6.5Hz,3H),1.00(s,3H),0.95-0.90(m,3H),0.74(s,3H).
实施例3C
Figure PCTCN2017072567-appb-000081
氮气下向实施例3B(100.0毫克，0.2毫摩尔)的甲醇(3毫升)溶液中加入湿钯碳(50毫克10％)，反应体系在25摄氏度氢气条件(15psi)下反应12小时。反应体系过滤旋干，得到实施例3C(90.0毫克，90.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.18-8.11(m,1H),8.06-8.00(m,1H),7.85-7.81(m,2H),7.35-7.31(m,2H),5.18(br.s.,1H),4.76-4.51(m,1H),2.77-2.64(m,1H),2.54-2.44(m,1H),1.95-1.20(m,25H),1.01(d,J＝6.5Hz,3H),0.95-0.87(m,6H),0.64(s,3H).
实施例19
Figure PCTCN2017072567-appb-000082
向实施例3C(160.0毫克，282.0微摩尔)的四氢呋喃(1毫升)，甲醇(1毫升)和水(1毫升)溶液中加氢氧化锂(59.0毫克，1.4毫摩尔)。反应体系在20摄氏度下反应12小时。水(5毫升)加入反应体系，体系用盐酸(1M)调至pH＝1-2，水相用乙酸乙酯(10毫升×3)萃取体系，合并有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备分离(HCl)分离纯化得到实施例19(80毫克，57％)。1H NMR(400MHz,METHANOL-d4)δ7.93-7.76(m,2H),7.45-7.35(m,2H),3.67(br.s.,1H),3.37-3.35(m,1H),2.84-2.73(m,1H),2.60(d,J＝10.5Hz,1H),2.06-1.27(m,25H),1.09(d,J＝6.3Hz,3H),0.94-0.91(m,6H),0.70(s,3H).
路线4
Figure PCTCN2017072567-appb-000083
实施例20
Figure PCTCN2017072567-appb-000084
向实施例3B(40.0毫克，70.8微摩尔)的四氢呋喃(0.5毫升)，甲醇(0.5毫升)和水(0.5毫升)溶液中加氢氧化锂(15毫克，0.35毫摩尔)。反应体系在20摄氏度下反应12小时。水(5毫升)加入反应体系，体系用盐酸(1M)调至pH＝1-2，水相用乙酸乙酯(10毫升×3)萃取，合并有机层经无水硫酸钠干燥，过滤并旋干。残余物通过薄层制备色谱纯化(二氯甲烷：甲醇＝10：1)得到实施例20(25.0毫克，71.0％)。1H NMR(400MHz,METHANOL-d4)δ8.00(br.s.,1H),7.84(d,J＝7.0Hz,1H),7.55(d,J＝7.5Hz,1H),7.42-7.34(m,1H),6.46-6.32(m,1H),6.19(dd,J＝8.8,15.6Hz,1H),3.72-3.62(m,1H),3.39-3.37(m,1H),2.32(d,J＝6.0Hz,1H),2.07-1.29(m,22H),1.17(d,J＝6.3Hz,3H),0.95-0.89(m,6H),0.78(s, 3H).
路线5
Figure PCTCN2017072567-appb-000085
实施例21
Figure PCTCN2017072567-appb-000086
实施例5A
Figure PCTCN2017072567-appb-000087
参考例1(100.0毫克，0.2毫摩尔)，三乙胺(48.0毫克，0.5毫摩尔)和O,N-二甲基羟基胺盐酸盐(23.0毫克，0.2毫摩尔)的乙腈(2毫升)混合物在25摄氏度搅拌0.5小时后，加入O-苯并三氮唑-N,N,N’,N’-四甲基脲四氟硼酸(95.0毫克，0.3毫摩尔)。将所得混合物在25摄氏度搅拌12小时。真空旋蒸除去溶剂后，残余物通过柱色谱纯化得到实施例5A，为白色固体(90毫克，收率82％)。1H NMR(400MHz,CHLOROFORM-d)δ3.73-3.67(m,4H),3.45-3.36(m,1H),3.18(s,3H),2.51-2.40(m,1H),2.38-2.27(m,1H),2.00-1.89(m,2H),1.87-1.74(m,5H),1.71-1.56(m,5H),1.53-1.31(m,11H),1.23-1.14(m,3H),1.06-0.99(m,1H),0.96(d,J＝6.3Hz,3H),0.93-0.88(m,6H),0.67(s,3H).
实施例5B
Figure PCTCN2017072567-appb-000088
向实施例5A(100.0毫克，0.2毫摩尔)的四氢呋喃(5毫升)溶液在0摄氏度下加入甲基溴化镁(0.4毫升，1.1毫摩尔，3N)的乙醚溶液，并且在0摄氏度下继续搅拌30分钟，然后升至室温搅拌12小时，加入冰水淬灭反应然后用乙酸乙酯(60毫升×2)萃取，水洗后有机相用无水硫酸钠干燥，过滤，真空除去溶剂后，残余物通过制备型TLC纯化得到实施例5B，白色固体(6毫克，收率66％)。1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s.,1H),3.48-3.35(m,1H),2.51-2.41(m,1H),2.39-2.29(m,1H),2.14(s,3H),1.99-1.79(m,5H),1.76-1.56(m,5H),1.51-1.30(m,10H),1.22-1.11(m,3H),1.00(dt,J＝3.3,14.2Hz,1H),0.94-0.87(m,9H),0.66(s,3H).
实施例5C
Figure PCTCN2017072567-appb-000089
将实施例5B(1.0克，2.4毫摩尔)溶1,4-二氧六环(20.0毫升)中，加入1,4-二氢吡喃(2.0克，23.9毫摩尔，2.2毫升)和对甲苯磺酸(90.9毫克，478.0微摩尔)，反应液于三十摄氏度搅拌三十六小时。浓缩除去溶剂，向反应液中加入水(5毫升)，乙酸乙酯萃取(10毫升×3)。有机层经水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩得到粗产物。粗产物经柱层析分离得到实施例5C(450.0毫克，32.1％产率，无色油状物)。1H NMR(400MHz,CHLOROFORM-d)δ4.73(d,J＝3.3Hz,1H),4.56(d,J＝4.3Hz,1H),3.95-3.81(m,2H),3.76-3.72(m,1H),3.55-3.31(m,4H),2.52-2.41(m,1H),2.34(ddd,J＝5.8,9.9,16.0Hz,1H),1.97-1.80(m,7H),1.74-1.67(m,4H),1.55(br.s.,4H),1.41(d,J＝7.3Hz,3H),1.33-1.27(m,3H),1.17-1.08(m,3H),0.90(s,3H),0.88(s,3H),0.69-0.59(m,3H).
实施例5D
Figure PCTCN2017072567-appb-000090
将金属钠(68.2毫克，3.0毫摩尔)溶解于无水乙醇中(5毫升)，冷却至零摄氏度时，缓慢加入实施例5C(170.0毫克，296.8微摩尔，溶于无水乙醇2毫升)，于零摄氏度继续搅拌半小时。然后逐滴加入草酸二乙酯(65.0毫克，445.1微摩尔，60.8微升，溶于无水乙醇1毫升)，反应液于零摄氏度搅拌半小时后升温至二十五摄氏度并继续搅拌三十五小时。向反应液中加入乙醇(6毫升)，浓缩除去溶剂，加入乙酸乙酯(40毫升)，冰浴搅拌下加入两摩尔柠檬酸水溶液(至pH＝5-6)，水相经乙酸乙酯萃取(10毫升×2)。有机层经水洗(10毫升)，食盐水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩得到粗产物。粗产物经柱层析分离得到实施例5D(90.0毫克，44.2％产率)。1H NMR(400MHz,CHLOROFORM-d)δ4.73(d,J＝3.3Hz,1H),4.57(d,J＝4.0Hz,1H),4.36(q,J＝7.0Hz,2H),3.97-3.80(m,2H),3.70(br.s.,1H),3.52-3.34(m,3H),2.54(ddd,J＝5.1,10.3,15.4Hz,1H),2.44-2.29(m,1H),1.98-1.90(m,2H),1.82(br.s.,3H),1.74-1.67(m,4H),1.53(br.s.,7H),1.38(s,3H),1.26(t,J＝7.0Hz,2H),1.16(d,J＝9.8Hz,2H),0.95(d,J＝6.5Hz,2H),0.89(s,3H),0.71-0.59(m,3H)。
实施例5E
Figure PCTCN2017072567-appb-000091
将实施例5D(90.0毫克，131.0微摩尔)溶于乙醇(3.0毫升)，加入盐酸羟胺(27.3毫克，393.0微摩尔)，反应液于八十摄氏度搅拌五小时。浓缩除去溶剂，向反应液中加入水(5毫升)，水相用乙酸乙酯萃取(10毫升×3)萃取。有机层经水洗(10毫升)，无水硫酸钠干燥，过滤，滤液减压并旋干。粗产物无需纯化得到实施例5E(86.0毫克，粗产物，黄色油状物)。1H NMR(400MHz,CHLOROFORM-d)δ6.39(s,1H),4.43(q,J＝7.3Hz,2H),3.72(br.s.,1H),3.43-3.40(m,1H),2.90-2.64(m,2H),2.42(t,J＝6.9Hz,2H),2.00-1.95(m,2H),1.75(d,J＝6.8Hz,3H),1.69(br.s.,4H),1.60(d,J＝3.3Hz,3H),1.48(d,J＝7.5Hz,4H),1.41(s,3H),1.28(br.s.,4H),1.20(d,J＝8.5Hz,3H),0.90(s,3H),0.89-0.88(m,1H),0.65(s,3H).
实施例21
Figure PCTCN2017072567-appb-000092
将实施例5E(115.0毫克，222.9微摩尔)溶于四氢呋喃(1.0毫升)，水(1.0毫升)和甲醇(1.0毫升)中，加入一水合氢氧化锂(93.6毫克，2.2毫摩尔)，反应液于二十五摄氏度搅拌十二小时。反应液用一 摩尔盐酸酸化(至pH＝5-6)，乙酸乙酯萃取(10毫升×3)。有机层经水洗(10毫升),无水硫酸钠干燥并过滤，滤液减压旋干，粗产物经薄层层析色谱分离得到实施例21(28.0毫克，25.8％产率)。1H NMR(400MHz,METHANOL-d4)δ6.41(s,1H),3.67(br.s.,1H),3.31(br.s.,1H),2.94-2.83(m,1H),2.80-2.70(m,1H),2.03(d,J＝12.0Hz,1H),1.96-1.83(m,5H),1.80-1.73(m,2H),1.64(br.s.,1H),1.58-1.50(m,5H),1.48-1.42(m,2H),1.42-1.34(m,3H),1.32-1.27(m,3H),1.24(d,J＝9.5Hz,2H),1.05(d,J＝6.0Hz,3H),0.93(s,3H),0.92-0.89(m,3H),0.71(s,3H).
路线6
Figure PCTCN2017072567-appb-000093
实施例22
Figure PCTCN2017072567-appb-000094
实施例6A
Figure PCTCN2017072567-appb-000095
向6-羟基烟酸甲酯(438.7毫克，2.9毫摩尔)，实施例1B(800毫克，1.4毫摩尔)的氯仿(20毫升)溶液加碳酸银(790毫克，2.9毫摩尔)。反应体系在60℃下反应72小时。过滤，浓缩，残余物通过柱分离(石油醚：乙酸乙酯＝10：1)得到标题化合物6A(400毫克，47.9％)。1H NMR(400MHz, CHLOROFORM-d)δ8.82(d,J＝2.3Hz,1H),8.16(s,1H),8.16-8.12(m,1H),8.05(s,1H),6.74(d,J＝8.5Hz,1H),5.21(br.s.,1H),4.80-4.61(m,1H),4.48-4.27(m,2H),3.91(s,3H),2.02-1.63(m,11H),1.46-1.09(m,14H),1.02(d,J＝6.5Hz,3H),0.97(s,3H),0.94-0.89(m,3H),0.68(s,3H)。
实施例22
Figure PCTCN2017072567-appb-000096
向实施例6A(800毫克，1.4毫摩尔)的甲醇(10毫升)溶液加10％的氢氧化钠溶液(甲醇和水的体积比为1:1)(600毫克，15毫摩尔，6毫升)，反应体系在70℃下反应2小时。旋干溶剂，体系用稀盐酸(1M)调至pH＝1-2，并用二氯甲烷:甲醇＝10:1(20毫升×3)萃取，有机层经无水硫酸钠干燥，过滤，浓缩。残余物通过制备色谱纯化得到标题化合物22(460毫克，64％产率)。1H NMR(400MHz,METHANOL-d4)δ8.78(d,J＝1.8Hz,1H),8.21(dd,J＝2.3,8.5Hz,1H),6.84(d,J＝8.8Hz,1H),4.56-4.23(m,2H),3.68(br.s.,1H),3.35-3.34(m,1H),2.04-1.17(m,25H),1.07(d,J＝6.5Hz,3H),0.96-0.89(m,6H),0.74(s,3H).
实施例23-26的制备参考标题化合物22的操作
Figure PCTCN2017072567-appb-000097
Figure PCTCN2017072567-appb-000098
路线7
Figure PCTCN2017072567-appb-000099
实施例27
Figure PCTCN2017072567-appb-000100
向实施例22(100.0毫克，194.7微摩尔)，DCC(60.3毫克，292微摩尔)和DMAP(23.8毫克，194.7微摩尔)的二氯甲烷(5毫升)溶液加甲基磺酰胺(37毫克，389.3微摩尔)。反应体系在25℃下反应12小时。水(5毫升)加入体系，体系用稀盐酸(1M)调至ph＝2，并用二氯甲烷(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤，浓缩。残余物通过制备色谱纯化得到实施例27(25毫克，21.7％产率)。1H NMR(400MHz,METHANOL-d4)δ8.74(d,J＝2.3Hz,1H),8.23(dd,J＝2.3,8.8Hz,1H),7.06-6.87(m,1H),4.57-4.40(m,2H),3.67(br s,1H),3.39(s,3H),2.03-1.27(m,25H),1.07(br d,J＝6.5Hz,3H),0.96-0.90(m,6H),0.73(s,3H)。
实施例28-34的制备参考标题化合物27的操作
Figure PCTCN2017072567-appb-000101
Figure PCTCN2017072567-appb-000102
Figure PCTCN2017072567-appb-000103
路线8
Figure PCTCN2017072567-appb-000104
实施例35
Figure PCTCN2017072567-appb-000105
实施例35的合成以实施例11为原料，操作参考实施例27的合成，收率17.4％，1H NMR(400MHz,METHANOL-d4)δ8.95-8.70(m,2H),8.48(s,1H),4.41-4.27(m,2H),3.67(br s,1H),3.41(s,3H),3.33-3.32(m,1H),2.02-1.16(m,25H),1.08(d,J＝6.3Hz,3H),0.94-0.88(m,6H),0.74(s,3H)。
路线9
Figure PCTCN2017072567-appb-000106
实施例36
Figure PCTCN2017072567-appb-000107
实施例36的合成以实施例23为原料，操作参考实施例27的合成，收率17.5％，1H NMR(400MHz,CHLOROFORM-d)δ＝8.60(d,J＝2.3Hz,1H),8.18(d,J＝2.3Hz,1H),4.56-4.33(m,2H),3.69(br s,1H),3.45(s,3H),1.96-1.15(m,25H),1.01(d,J＝6.5Hz,3H),0.89-0.81(m,6H),0.66(s,3H)。
路线10
Figure PCTCN2017072567-appb-000108
实施例37
Figure PCTCN2017072567-appb-000109
实施例37的合成以实施例23为原料，操作参考实施例27的合成，收率60.8％，1H NMR(400MHz,METHANOL-d4)δ8.55(d,J＝1.8Hz,1H),8.17(d,J＝1.8Hz,1H),4.57-4.38(m,2H),3.87-3.75(m,2H),3.66(br s,1H),3.32-3.20(m,1H),3.11(t,J＝6.9Hz,2H),2.06-1.23(m,25H),1.06(br d,J＝6.5Hz,3H),0.96-0.86(m,6H),0.71(s,3H)。
路线11
Figure PCTCN2017072567-appb-000110
实施例38
Figure PCTCN2017072567-appb-000111
实施例38的合成以实施例22为原料，操作参考实施例27的合成，收率53％，1H NMR(400MHz,METHANOL-d4)8.63–8.62(m,1H),8.09–8.06(m,1H),6.84–6.82(m,1H),4.39–4.28(m,2H),3.82–3.74(m,3H),3.40–3.30(m,1H),3.12–3.08(m,2H),1.99-1.20(m,25H),1.06(d,J＝6.5Hz,3H),0.94-0.90(m,6H),0.73(s,3H)。
路线12
Figure PCTCN2017072567-appb-000112
实施例39
Figure PCTCN2017072567-appb-000113
实施例12A
Figure PCTCN2017072567-appb-000114
甘氨酸盐酸盐(14毫克，112微摩尔)和三乙胺(20.0微升，146微摩尔)的乙酸乙酯(5毫升)溶液在20摄氏度下反应0.5小时。实施例22(50毫克，97微摩尔)和2-乙氧基-1-乙氧碳酰基-1.2-二氢喹啉(36毫克，146微摩尔)加入体系。反应体系在65摄氏度下反应10小时。水(5毫升)加入体系中，水相用乙酸乙酯(15毫升×2)萃取。合并有机相，有机相依次用0.5N氢氧化钠水溶液(15毫升)，水(15毫升)0.5N盐酸(15毫升)和水(15毫升)洗涤。有机层经无水硫酸钠干燥，过滤并旋干。粗品通过制备分离(TFA)分离纯化得到实施例12A(25毫克，43.9％)。1H NMR(400MHz,CDCl3)8.66–8.65(m,1H),8.08–8.05(m,1H),6.81–6.67(m,1H),6.68(s,1H),4.42–4.24(m,2H),4.35–4.24(m,2H),3.81(s,3H),3.72–3.71(m,1H),3.46–3.44(m,1H),1.99-1.20(m,25H),1.03(d,J＝6.5Hz,3H),0.92-0.88(m,6H),0.68(s,3H).
实施例39
Figure PCTCN2017072567-appb-000115
向实施例12A(25.0毫克，42.7微摩尔)的四氢呋喃(3毫升)，甲醇(1毫升)和水(2毫升)溶液中加氢氧化锂(8.9毫克，213.7微摩尔)。反应体系在30摄氏度下反应4小时。体系用盐酸(1M)调至pH＝5，水相用乙酸乙酯(20毫升×2)萃取体系，合并有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备TLC分离，得到实施例39(24毫克，98％)。1H NMR(400MHz,METHANOL-d4)8.66–8.65(m,1H),8.11–8.02(m,1H),6.84–6.82(m,1H),4.48–4.29(m,2H),4.09–4.08(m,3H),3.66–3.65(m,1H),1.99-1.20(m,25H),1.06(d,J＝6.5Hz,3H),0.92-0.88(m,6H),0.72(s,3H).
路线13
Figure PCTCN2017072567-appb-000116
实施例40
Figure PCTCN2017072567-appb-000117
实施例13A
Figure PCTCN2017072567-appb-000118
以实施例2B为原料，实施例13A的操作参考实施例6A的合成，收率16.3％，1H NMR(400MHz,CHLOROFORM-d)δ8.69(d,J＝2.0Hz,1H),8.21(d,J＝2.0Hz,1H),8.16(s,1H),8.05(s,1H),5.20(br s,1H),4.72(br s,1H),4.46-4.36(m,2H),3.92(s,3H),2.06-1.66(m,15H),1.31-1.04(m,10H),0.97-0.81(m,9H),0.67(s,3H)。
实施例40
Figure PCTCN2017072567-appb-000119
实施例40的操作参考实施例22的合成，收率96.4％，1H NMR(400MHz,METHANOL-d4)δ＝8.74(d, J＝2.0Hz,1H),8.29(d,J＝1.8Hz,1H),4.51(t,J＝6.4Hz,2H),3.72(br s,1H),3.43-3.39(m,1H),2.11-1.23(m,27H),1.07(d,J＝6.5Hz,3H),1.00-0.93(m,6H),0.77(s,3H)。
路线14
Figure PCTCN2017072567-appb-000120
实施例14A
Figure PCTCN2017072567-appb-000121
向参考例1(40.0克，95.1毫摩尔)的甲醇(500毫升)溶液中加入对甲苯磺酸(4.0克，21.0毫摩尔)。反应体系在70℃下反应3小时。旋干溶剂，体系用二氯甲烷(500毫升)稀释，有机相依次经饱和碳酸钠水溶液(3x100毫升)、水溶液(100毫升)和饱和食盐水(100毫升)洗涤，经无水硫酸钠干燥，过滤，浓缩。无需纯化得到实施例14A(41克，100％产率)，可直接用于下步反应。
实施例14B
Figure PCTCN2017072567-appb-000122
将实施例14A(41克，95.1毫摩尔)溶于无水四氢呋喃(300毫升)溶液中，氮气保护下升温至50度，缓慢滴加甲基溴化镁(800毫升，1M)的四氢呋喃溶液，滴加完毕后将反应液冷却至室温并搅拌过夜，反应结束后，加入环己烷(25毫升)，过滤，滤渣溶于3N的盐酸(800毫升)水溶液和二氯甲烷(200毫升)的混合溶液中，继续搅拌30分钟，反应结束后，将有机相与水相分离，水相继续用二氯甲烷(2x 200毫升)萃取，合并有机相并依次经水溶液(100毫升)和饱和食盐水(100毫升)洗涤，经无水硫酸钠干燥，过滤，浓缩。无需纯化得到实施例14B(51克，100％产率)，可直接用于下步反应。
实施例14C
Figure PCTCN2017072567-appb-000123
将乙酸酐(9.9毫升，105.1毫摩尔)，吡啶(1.6毫升，19.8毫摩尔)以及4-二甲基氨基吡啶(0.8克，6.6毫摩尔)加入到实施例14B(51克，95.1毫摩尔)的无水四氢呋喃(300毫升)溶液中，反应液在室温下搅拌过夜，反应结束后，用水溶液(100毫升)稀释，水相用二氯甲烷(3x 150毫升)萃取，合并有机相并用饱和食盐水(100毫升)洗涤，经无水硫酸钠干燥，过滤，浓缩。无需纯化得到实施例14C(55克，100％产率)，可直接用于下步反应。1H-NMR(CDC13)δ0.66(3H,s,CH3-I8)；0.77(3Η,s,CH3-26)；1.00(3Η,d,CH3-21)；1.20(3Η,s,CH3-19)；1.96(3Η,s,AcO),2.18-2.31(1Η,m,CH-22)；3.70(1Η,m,CH-7)；4.55(1Η,m,CH-3)；6.11(1Η,dd,＝6.2Hz,J 2＝8.3Hz；CH-23)；7.14-7.36(10Η,m,Ph).
实施例14D
Figure PCTCN2017072567-appb-000124
高碘酸钠(13.2克，61.9毫摩尔)溶于水(13毫升)和2N的硫酸水溶液(1.7毫升)中，搅拌15分钟后，反应液冷却至0度并加入三氯化钌(71.3毫克，0.4毫摩尔)，反应液继续搅拌至颜色变为亮黄色。向反应液中加入乙酸乙酯(27毫升)和乙腈(20毫升)并继续搅拌5分钟。0度下向上述反应液中加入实施例14C(4克，6.9毫摩尔)，待反应结束后，过滤，滤液泼入水中，并用乙酸乙酯(3x100毫升)萃取，合并有机相并用饱和硫代硫酸钠(200毫升)洗涤，无水硫酸钠干燥，过滤，滤液旋干后经硅胶柱层析分离得到实施例14D(2.7克，89％收率)。1H-NMR(CDC13)δ0.71(3H,s,CH3-I8)；0.86-1.07(9Η,m,CH3-19,CH3-21,C-24)；2.03(3Η,s,AcO)；4.48-4.61(1Η,m,CH-3).
实施例14E
Figure PCTCN2017072567-appb-000125
将三乙胺(6.7毫升，3.4毫摩尔)加入到实施例14D(1克，2.2毫摩尔)和氯甲酸异丁酯(3.5毫升，2.7毫摩尔)的四氢呋喃(20毫升)中，1小时后反应结束，反应液过滤，0度下向滤液中分批加入硼氢化钠(847毫克，22.4毫摩尔)，待反应结束后，加入水(3毫升)来淬灭反应，并在室温下继续搅拌2小时，随后用3N的稀盐酸水溶液酸化，并用乙酸乙酯(3x 15毫升)萃取，并有机相并用饱和食盐水(15毫升)洗涤，无水硫酸钠干燥，过滤，滤液旋干后经硅胶柱层析分离得到实施例14E(800毫克，85％收率)。1H-NMR(CDCI3)δ0.67(3H,s,CH3-I8)；0.86-0.97(9Η,m,CH3-19,CH3-21,CH3-24)；2.03(3Η,s,AcO)；3.72(3Η,m,(2Η,m,CH-7,CH-23)；4.48-4.61(1Η,m,CH-3).
实施例41
Figure PCTCN2017072567-appb-000126
零度下向实施例14E(100毫克，230.1微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入钠氢(18.4毫克，460.1微摩尔，60％)。半小时后，零度下缓慢滴加甲基-4-氯吡啶-2-甲酸酯(78.9毫克，460.1微摩尔)的N,N-二甲基甲酰胺(2毫升)溶液。滴加完毕，反应体系缓慢升至室温反应12小时。加入水(10毫升)，反应体系用盐酸(1M)调至pH＝6，二氯甲烷(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤并旋干。向残余物的甲醇溶液(1毫升)加10％的氢氧化钠溶液(甲醇和水的体积比为1:1)(50毫克，1.3毫摩尔，0.5毫升)，反应体系在70℃下反应2小时。旋干溶剂，体系用稀盐酸(1M) 调至pH＝1-2，并用二氯甲烷:甲醇＝10:1(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤，浓缩。残余物通过制备色谱纯化得到实施例41(5毫克，4％产率)。1H NMR(400MHz,METHANOL-d4)δ8.67(br d,J＝6.5Hz,1H),7.99(d,J＝2.5Hz,1H),7.69(br d,J＝6.5Hz,1H),4.50(br d,J＝6.5Hz,2H),3.78-3.59(m,1H),3.32-3.30(m,1H),2.18-1.17(m,25H),1.10(d,J＝6.5Hz,3H),0.95-0.89(m,6H),0.76(s,3H)。
路线15
Figure PCTCN2017072567-appb-000127
实施例42
Figure PCTCN2017072567-appb-000128
向实施例16D(100.0毫克，245.9微摩尔)和5-氨基吡啶-3-甲酸(50.0毫克，295微摩尔)的DMF(5毫升)溶液中加入1,3-二环己基碳二亚胺(101.5毫克，492微摩尔)和4-二甲基氨基吡啶(1.5毫克，12.3微摩尔)。反应体系在30摄氏度下反应16小时。氢氧化锂(10.3毫克，246微摩尔)的水(2.0毫升)溶液加入体系。反应体系在30摄氏度下反应2小时.体系用盐酸(1M)调至pH＝4，水相用二氯甲烷/甲醇(10:1)(20毫升×3)萃取体系，合并有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备分离(HCl)分离纯化得到实施例42(20毫克，15.4％)。1H NMR(400MHz,METHANOL-d4)9.14–9.13(m,1H),8.90–8.89(m,1H),8.71–8.70(m,1H),3.68(s,1H),3.40–3.30(m,1H),2.64–2.61(m,1H),2.15–2.06(m,2H),1.99-1.20(m,25H),1.07(d,J＝6.5Hz,3H),0.95-0.91(m,6H),0.78(s,3H).
路线16
Figure PCTCN2017072567-appb-000129
实施例43
Figure PCTCN2017072567-appb-000130
实施例16A
Figure PCTCN2017072567-appb-000131
将参考例1F(10.0克，23.9毫摩尔)溶于四氢呋喃(60.0毫升)，加入高氯酸(240.0毫克，2.4毫摩尔，144.6微升)(大约10滴)，于三十摄氏度下，半小时内逐滴加入甲酸(40.3克，874.7毫摩尔，33.0毫升)，反应液于五十摄氏度搅拌十一点五小时。浓缩除去溶剂，向反应液中加入水(35.0毫升)，乙酸乙酯萃取(30.0毫升×3)。有机层经水洗(10.0毫升×2)，无水硫酸钠干燥，过滤和浓缩得到 粗产物。粗产物经柱层析分离得到实施例16A(7.0克，15.7毫摩尔，65.6％产率，白色固体)。1H NMR(400MHz,CHLOROFORM-d)δ＝8.01(s,1H),4.86-4.73(m,1H),2.82-2.67(m,1H),2.47-2.35(m,2H),2.33-2.16(m,2H),2.05-1.93(m,2H),1.89(d,J＝13.1Hz,2H),1.82(dd,J＝5.5,16.8Hz,2H),1.75(dd,J＝6.5,14.1Hz,3H),1.71(br.s.,1H),1.58-1.30(m,7H),1.26(s,3H),1.23-1.02(m,4H),0.95(d,J＝6.5Hz,3H),0.83(t,J＝7.4Hz,3H),0.68(s,3H).
实施例16B
Figure PCTCN2017072567-appb-000132
零摄氏度下将实施例16A(5.8克，13.0毫摩尔)溶于三氟乙酸(40.0毫升)和三氟乙酸酐(20.5克，97.4毫摩尔)，待固体溶解后，分批加入亚硝酸钠(2.7克，39.0毫摩尔)，于零摄氏度继续搅拌一小时够，升温至四十摄氏度继续搅拌一小时。待反应液冷至三十摄氏度，在零摄氏度下，用零点五摩尔氢氧化钠水溶液中和(pH＝7-8)。反应液用乙酸乙酯萃取(40毫升×3)，有机层经水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩。粗产物经色谱柱(硅胶)分离得到实施例16B(3.5克，8.5毫摩尔，93.0％产率，淡黄色油状物)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.59-3.47(m,1H),2.69(q,J＝6.2Hz,1H),2.42-2.31(m,2H),2.29-2.15(m,2H),2.01-1.88(m,2H),1.86-1.68(m,7H),1.61-1.45(m,6H),1.26(t,J＝7.2Hz,5H),1.19-1.12(m,5H),1.02-0.91(m,1H),0.80(t,J＝7.4Hz,3H),0.71-0.64(m,3H).
实施例16C
Figure PCTCN2017072567-appb-000133
将实施例16B(3.5克，8.5毫摩尔)溶于甲醇(100.0毫升)，加入氢氧化钾水溶液(70.0克，1.3mol，溶于水100.0毫升)，反应液于一百摄氏度搅拌十二小时。浓缩除去部分溶剂，二氯甲烷萃取(30毫升×3)。水相经一摩尔盐酸酸化(pH＝3-4)，用乙酸乙酯萃取(30毫升×3)，有机层经水洗(20毫升)，无水硫酸钠干燥，过滤和浓缩得到粗产物。无需纯化得到实施例16C(3.2克，7.9毫摩尔，93.5％产率，黄色油状物)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.65-3.50(m,1H),2.71(d,J＝5.8Hz,1H),2.48(dd,J＝2.6,14.9Hz,1H),2.43-2.31(m,2H),2.22-2.15(m,1H),2.07-1.98(m,2H),1.95-1.86(m,3H),1.82-1.70(m,6H),1.53-1.46(m,3H),1.19-1.10(m,6H),1.02(d,J＝6.3Hz,3H),0.86(d,J＝10.3Hz,5H),0.69(s,3H)。
实施例16D
Figure PCTCN2017072567-appb-000134
向氢氧化钠水溶液(949.2毫克，23.7毫摩尔，溶于水10.00毫升)加入实施例16C(3.2克，7.9毫摩尔)，反应液加热到八十摄氏度，分批加入硼氢化钠(1.8克，47.5毫摩尔)，反应液于一百摄氏度搅拌十二小时。逐滴加入甲醇(6毫升)，浓缩除去部分溶剂，反应液用一摩尔盐酸酸化(pH＝5-6)，乙酸乙酯萃取(40毫升×3)，有机层经水洗(20毫升)，无水硫酸钠干燥，过滤和浓缩，粗产物无需分离得到实施例16D(3.1克，7.6毫摩尔，96.4％产率，白色固体)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.70(br.s.,1H),3.46-3.36(m,1H),2.52-2.39(m,1H),2.02-1.88(m,3H),1.85-1.77(m,4H),1.71-1.59(m,3H),1.53-1.44(m,4H),1.41-1.37(m,1H),1.36-1.27(m,4H),1.24-1.13(m,4H),1.04(d,J＝6.5Hz,3H),0.92-0.88(m,6H),0.73-0.69(m,3H)。
实施例16E
Figure PCTCN2017072567-appb-000135
氮气保护下向实施例16D(100毫克，245.8微摩尔)的乙腈(2毫升)溶液中加入三乙胺(49.8毫克，491.9毫摩尔，68.2微升)以及N,O-二甲基羟胺盐酸盐(24.0毫克，245.9微摩尔)。25摄氏度搅拌30分钟，然后加入O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(98.7毫克，307.4微摩尔)继续搅拌11.5小时。反应液泼入冷水中(30毫升)，乙酸乙酯萃取(40毫升×3)，有机层经水洗(20毫升)，无水硫酸钠干燥，过滤和浓缩，粗产物无需分离得到实施例16E(90毫克，91.4％产率，白色固体)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.76(s,3H),3.70(br.s.,1H),3.46-3.36(m,1H),2.79(s,3H),2.43-2.39(m,1H),2.24–2.18(m,1H),2.00-1.97(m,41H),1.03-0.88(m,10H),0.73(s,3H)。
实施例16F
Figure PCTCN2017072567-appb-000136
零下78摄氏度下，向四氢铝锂(6.3毫克，168.9微摩尔)的四氢呋喃(2毫升)溶液中加入实施例16E (50毫克，111.2微摩尔)，并且在零下78摄氏度下搅拌2小时，反应结束后，加入水(0.006毫升)，反应液过滤，滤饼烘干就得到实施例16F(50毫克，100％，白色固体)。1H NMR(400MHz,CHLOROFORM-d)δ＝9.76(s.,1H),3.70(br.s.,1H),3.46-3.36(m,1H),2.43-2.39(m,1H),2.24–2.18(m,1H),2.00-1.97(m,41H),1.03-0.88(m,10H),0.73(s,3H)。
实施例16G
Figure PCTCN2017072567-appb-000137
向实施例16F(150.0毫克，0.3毫摩尔)和5-氨基吡啶-3-甲酸甲酯(64.0毫克，0.4毫摩尔)的乙酸乙酯(5毫升)溶液中加入三氟乙酸(57微升，0.8毫摩尔)和三乙酰基硼氢化钠(146.0毫克，0.7毫摩尔)，反应体系在20摄氏度下反应16小时。乙酸乙酯(30毫升)加入反应体系，体系用饱和碳酸氢钠(20毫升×2)和饱和食盐水(20毫升×1)洗涤，有机层经无水硫酸钠干燥，过滤并旋干得到粗品。粗品经制备分离(TFA)得到实施例16G(60.0毫克，29.7％)。1H NMR(400MHz,CHLOROFORM-d)8.44-8.43(m,1H),8.43-8.42(m,1H),7.92-7.91(m,1H),4.01(s,3H),3.72–3.71(m,1H),3.49–3.48(m,1H),3.28–3.13(m,2H),1.99-1.20(m,25H),1.01(d,J＝6.5Hz,3H),0.95-0.87(m,6H),0.67(s,3H).
实施例43
Figure PCTCN2017072567-appb-000138
向实施例16G(60.0毫克，113.9微摩尔)的四氢呋喃(2毫升)，甲醇(1毫升)和水(2毫升)溶液中加氢氧化锂(60.0毫克，1.43毫摩尔)。反应体系在40摄氏度下反应1小时。体系用盐酸(1M)调至pH＝4，水相用二氯甲烷/甲醇(10:1)(20毫升×3)萃取体系，合并有机层经无水硫酸钠干燥，过滤并旋干。残余物通过制备分离(HCl)分离纯化得到实施例43(40毫克，68％)。1H NMR(400MHz,METHANOL-d4)8.30–8.29(m,1H),8.03–8.02(m,1H),7.59–7.58(m,1H),3.70-3.65(m,1H),3.40–3.30(m,1H),3.12–3.07(m,2H),1.99-1.20(m,25H),1.05(d,J＝6.5Hz,3H),0.95-0.87(m,6H),0.72(s,3H).
路线17
Figure PCTCN2017072567-appb-000139
实施例44
Figure PCTCN2017072567-appb-000140
向实施例22(50.0毫克，97.3微摩尔)的甲醇(5毫升)溶液加浓硫酸(368.0毫克，3.8毫摩尔)。反应体系在70℃下反应12小时。水(5毫升)加入体系，体系用氢氧化钠(1M)调至ph＝7，并用二氯甲烷(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤，浓缩。残余物通过制备色谱纯化得到标题化合物44(15毫克，29.2％产率)。1H NMR(400MHz,METHANOL-d4)δ8.76(d,J＝2.0Hz,1H),8.18(dd,J＝2.5,8.8Hz,1H),6.82(d,J＝8.8Hz,1H),4.49-4.28(m,2H),3.89(s,3H),3.65(br s,1H),3.28(br s,1H),2.03-1.15(m,25H),1.04(d,J＝6.5Hz,3H),0.93-0.86(m,6H),0.71(s,3H)
路线18
Figure PCTCN2017072567-appb-000141
实施例45
Figure PCTCN2017072567-appb-000142
实施例18A
Figure PCTCN2017072567-appb-000143
实施例18A的合成以实施例23为原料，操作参考实施例12A的合成，收率79.7％，1H NMR(400MHz,CHLOROFORM-d)δ8.48(d,J＝2.3Hz,1H),8.08(d,J＝2.3Hz,1H),7.26(s,1H),6.55(t,J＝4.8Hz,1H),4.57-4.38(m,2H),4.24(d,J＝5.0Hz,2H),3.81(s,3H),3.71(s,1H),3.46-3.36(m,1H),2.05-1.12(m,33H),1.06-0.84(m,14H),0.68(s,3H)。
实施例45
Figure PCTCN2017072567-appb-000144
实施例45的操作参考实施例39的合成，收率56.8％，1H NMR(400MHz,METHANOL-d4)δ8.80-8.72(m,1H),8.48(d,J＝2.0Hz,1H),8.10(d,J＝2.0Hz,1H),4.50-4.33(m,2H),3.99(d,J＝4.5Hz,2H),3.56(s,1H),1.98-1.03(m,31H),1.01-0.87(m,5H),0.84-0.74(m,10H),0.62(s,3H)。
实施例1：体外评价
FXR生化实验
实验目的：
通过均相邻近发光放大实验(alphascreen)检测化合物对FXR结合反应的激活作用。
实验材料:
1.蛋白：谷胱甘肽-S-转移酶标记的FXR人源蛋白(Invitrogen)
2.共激活因子：生物素标记的类固醇受体辅活化子(Anaspec)
3.检测试剂：均相邻近发光放大实验(alphascreen)检测试剂盒(PerkinElmer)
实验方法：
1.化合物稀释：将待测化合物制备为40μM的DMSO溶液，随后将化合物3倍稀释至10个浓度点。参照化合物制备为400μM的DMSO溶液，随后以1.5倍稀释至10个浓度点。将稀释好的DMSO溶液以每孔150nL的体积加入384孔板的微孔中。
2.将谷胱甘肽-S-转移酶标记的FXR人源蛋白和生物素标记的类固醇受体辅活化子配置浓度分别为0.4nM和30nM的混合溶液。以每孔15μL的体积加入384孔板的微孔中。室温孵育1小时。
4.将均相邻近发光放大实验(alphascreen)检测试剂盒中的受体小球混合液稀释125倍，以每孔7.5μL体积加入384孔板的微孔中。实验过程避光操作。室温孵育1小时。
5.将均相邻近发光放大实验(alphascreen)检测试剂盒中的供体小球混合液稀释125倍，以每孔7.5μL体积加入384孔板的微孔中。实验过程避光操作。室温孵育1小时。
6.EC50测试：采用Envision于680nm波长处激发，读取520-620nm处的吸收信号。
7.分析数据:用Prism 5.0来分析数据，计算化合物的激活作用EC50值。再将化合物的最高信号值与参照化合物的最高信号值作比值得出化合物的激活效力百分数(Efficacy)。
FXR细胞实验
实验目的：
通过β-内酰胺酶报告基因技术检测化合物对细胞功能活性的影响。
实验材料:
1.细胞系：FXR HEK 293T DA
2.细胞培养基：DMEM培养基添加10％血清和Penicillin/Streptomycin(1×)
3.检测试剂：
Figure PCTCN2017072567-appb-000145
报告基因检测试剂盒(Invitrogen)
实验方法：
1.化合物稀释：将待测化合物制备为100μM的DMSO溶液，随后将化合物3倍稀释至10个浓度点。参照化合物制备为100μM的DMSO溶液，随后以1.3倍稀释至10个浓度点。将稀释好的DMSO溶液以每孔200nL的体积加入384孔板的微孔中。
2.细胞接种：将FXR HEK 293T DA细胞复苏，用培养基重悬，稀释至密度为5×105个/mL，以每孔40ul的体积加入384孔板的微孔中。
3.将384微孔板于37℃,5％CO2条件下培养16小时。
4.将6μL的1mM LiveBLAzerTM-FRET B/G(CCF4-AM)底物与60μL的B溶液和934μL的C溶液混合，以每孔8μL的体积加入384孔板的微孔中。
5.将384微孔板室温避光孵育2小时。
6.EC50测试：采用Envision于409nm波长处激发，读取460和530nm处的吸收信号。
7.分析数据:用Prism 5.0来分析数据，计算化合物的激活作用EC50值。再将测试化合物的最高信号值与参照化合物(鹅去氧胆酸，CDCA)的最高信号值作比值得出化合物的激活效力百分数(Efficacy)。
表1 检测生化实验测试结果以及细胞实验测试结果EC50：
Figure PCTCN2017072567-appb-000146
Figure PCTCN2017072567-appb-000147
结论：本发明化合物对FXR受体的激动作用显著，在细胞水平上对FXR受体的激动作用也比较显著。
实验例2：体内研究
单独给药小鼠药代：
12只C57BL/6J雄性小鼠随机分为两组，6只每组。第一组为静脉组，为尾静脉脉注射给药2mg/kg、2mL/kg(溶媒为10％HPbCD水溶液，药物溶解度不理想时，则会加入助溶剂)；第二组为口服组，灌胃给药10mg/kg、10mL/kg(溶媒为0.5％HPMC水溶液)。静脉组给药后0.083、0.25、0.5、1、2、4、6、8和24小时采集血浆(K2-EDTA为抗凝)样品；口服组给药后0.25、0.5、1、2、4、6、8和24小时采集血浆样品。每组6只动物，一个时间点采集3个动物血样，第1批3只动物与第2批3只动物交错采样。使用LC-MS/MS进行血浆样品分析。获得血浆浓度与时间作图，并使用Phoenix WinNonlin 6.3计算PK参数。
表2
Figure PCTCN2017072567-appb-000148
结论：如表2中所示，相同剂量口服给药后化合物11的峰值浓度以及药物暴露量高于对照化合物INT-747。相同剂量口服给药后化合物22的峰值浓度与对照化合物INT-747接近，药物暴露量高于对照化合物INT-747。相同剂量口服给药后化合物23的峰值浓度高于对照化合物INT-747，药物暴露量也高于对照化合物INT-747。
盒式给药小鼠肝血比实验：
6只C57BL/6J雄性小鼠为一组，为口服组，制剂中含有5种研发药物，灌胃给药2mg/kg/化合物(溶媒为0.5％HPMC水溶液)。5个化合物首先分别溶于溶媒中，通过超声或者斡旋，分别形成1mg/mL溶液(澄清溶液或者混悬液)，然后五种化合物溶液等体积混合(1:1:1:1:1,v:v:v:v:v)于一个玻璃瓶中。灌胃口服给药后，3只动物于给药后0.5小时采集血浆和肝组织样品；另外3只动物于给药后3小时采集相应样品。肝组织采集后，使用冰冷匀浆缓冲液(甲醇:15mM PBS缓冲液(pH 7.4)＝1:2，v:v)按 照肝重量:匀浆缓冲液体积＝1:3进行匀浆。使用提前开发的五合一的LC-MS/MS分析方法进行血浆和肝组织样品分析。获得血浆浓度以及肝组织匀浆液浓度，并使用Excel计算肝组织与血浆浓度比值。
表3
Figure PCTCN2017072567-appb-000149
注：ND表示未检测到。
结论：如表3中所示，口服给予相同剂量本发明化合物后，实施例22在0.5小时以及3小时药物肝脏中的浓度均高于对照化合物，0.5小时以及3小时肝/血浓度比也高于对照化合物。实施例26在0.5小时药物肝脏中的浓度均高于对照化合物，0.5小时以及3小时肝/血浓度比高于对照化合物。

Claims (16)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017072567-appb-100001
    其中，
    环A选自5～12元芳基、含有1～2个杂原子的5～12元杂芳基、含有1～2个杂原子的5～6元非芳香杂环基或5～6元环烷基，所述环A任选被1、2或3个Ra取代或发生1、2或3个氧代，所述杂原子选自N、O或S；
    L选自C1-8烷基、C1-8杂烷基或C2-8链烯基，所述L任选被1、2或3个Rb取代或任选发生1、2或3个氧代；
    L1选自O、N(Rd)、N(Rd)S(＝O)2或N(Rd)S(＝O)；
    R1选自H、C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基，所述C1-6烷基、C1-6杂烷基、5～6元芳基、4～6元杂芳基、C3-6环烷基或3～6元杂环烷基任选被1、2或3个Rc取代或任选发生1、2或3个氧代；
    Ra、Rb、Rc和Rd各自独立地选自H、F、Cl、Br、I、OH、CN、NO2、NH2、COOH、S(＝O)2OH、C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基或C1-3烷基硫基，所述C1-3烷基氨基、N,N-二(C1-3烷基)氨基、C1-3烷基、C1-3烷基氧基或C1-3烷基硫基任选被1、2或3个R’取代；
    R’选自F、Cl、Br、I、OH、NH2、NO2、CN、COOH、Me、Et、CH2F、CHF2、CF3、CH3O、CH3S、NH(CH3)或N(CH3)2；
  2. 根据权利要求1所述化合或其药学上可接受的盐，其中，Ra、Rb、Rc和Rd各自独立地选自H、F、Cl、Br、I、COOH、S(＝O)2OH、Me、CF3、CHF2、CH2F、Et、OMe、NH(CH3)或N(CH3)2。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，环A选自苯基、吡啶基、吡啶-2(1H)-酮基、嘧啶基、吡唑基、咪唑基、噁唑基、噻唑基、噻吩基、吡咯烷基、哌啶基、吗啉基、哌嗪基、异噁唑基、异噻唑基、双环[1.1.1]戊烷基、苯并噁唑基、苯并[d]异噁唑基、吲唑基、吲哚基、喹啉基、异喹啉基、喹唑啉基、1H-吡咯并[2,3-B]吡啶基、中氮茚基、苯并噻唑基或苯并噻吩基，所述环A任选被1、2或3个Ra取代。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2017072567-appb-100002
    Figure PCTCN2017072567-appb-100003
    Figure PCTCN2017072567-appb-100004
    所述环A任选被1、2或3个Ra取代。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2017072567-appb-100005
    Figure PCTCN2017072567-appb-100006
    Figure PCTCN2017072567-appb-100007
  6. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，L选自C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷氨基、C1-4烷基-C(＝O)NH-、C2-4烷烯基或C1-3烷基-O-C1-3烷基，所述L任选被1、2或3个Rb取代。
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，L选自
    Figure PCTCN2017072567-appb-100008
    Figure PCTCN2017072567-appb-100009
    所述L任选被1、2或3个Rb取代。
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，L选自
    Figure PCTCN2017072567-appb-100010
    Figure PCTCN2017072567-appb-100011
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，L选自
    Figure PCTCN2017072567-appb-100012
    Figure PCTCN2017072567-appb-100013
  10. 根据权利要求1或9所述化合物或其药学上可接受的盐，其中，L1选自O、NH、NHS(＝O)2和NHS(＝O)。
  11. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R1选自H、C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基，所述C1-3烷基、C3-6环烷基、苯基、吡啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基或噻吩基任选被1、2或3个Rc取代，所述Rc如前所定义。
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其中，R1选自H、Me、
    Figure PCTCN2017072567-appb-100014
    Figure PCTCN2017072567-appb-100015
  13. 根据权利要求1所述化合物，其选自：
    Figure PCTCN2017072567-appb-100016
    Figure PCTCN2017072567-appb-100017
    Figure PCTCN2017072567-appb-100018
    Figure PCTCN2017072567-appb-100019
    Figure PCTCN2017072567-appb-100020
    Figure PCTCN2017072567-appb-100021
    Figure PCTCN2017072567-appb-100022
  14. 一种药物组合物，其含有治疗有效量的根据权利要求1～13任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  15. 根据权利要求1～13任意一项所述的化合物或其药学上可接受的盐或根据权利要求14所述的药物组合物在制备治疗法尼酯X受体相关各种病症、胆汁淤积性肝疾病、纤维变性疾病、高胆固醇疾病、高甘油三酯疾病及心血管疾病的药物中的应用。
  16. 根据权利要求1～13任意一项所述的化合物或其药学上可接受的盐或根据权利要求14所述的药物组合物在制备治疗非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化(PBC)、胆汁淤积性肝病、慢性肝病、C型肝炎感染、酒精性肝病、肝纤维变性、原发性硬化性胆管炎(PSC)、胆结石、胆管闭锁、下尿路症状与良性前列腺增生(BPH)、输尿管结石、肥胖、二型糖尿病、动脉粥样硬化、动脉硬化症、高胆固醇血症和高血脂症导致的肝功能损害的药物中的应用。
PCT/CN2017/072567 2016-01-28 2017-01-25 甾体类衍生物fxr激动剂 Ceased WO2017129125A1 (zh)

Priority Applications (18)

Application Number Priority Date Filing Date Title
JP2018539427A JP6924765B2 (ja) 2016-01-28 2017-01-25 ステロイド誘導体ｆｘｒ作動薬
BR112018015474-1A BR112018015474B1 (pt) 2016-01-28 2017-01-25 Compostos agonistas de fxr derivados de esteroide, composição farmacêutica que compreende os mesmos e usos terapêuticos dos ditos compostos
MYPI2018702594A MY196292A (en) 2016-01-28 2017-01-25 Steroid Derivative Fxr Agonist
SG11201806348PA SG11201806348PA (en) 2016-01-28 2017-01-25 Steroid derivative fxr agonist
US16/072,839 US10875888B2 (en) 2016-01-28 2017-01-25 Steroid derivative FXR agonist
AU2017213032A AU2017213032B2 (en) 2016-01-28 2017-01-25 Steroid derivative FXR agonist
PH1/2018/550120A PH12018550120B1 (en) 2016-01-28 2017-01-25 Steroid derivative fxr agonist
CN201780007715.1A CN109071593B (zh) 2016-01-28 2017-01-25 甾体类衍生物fxr激动剂
MX2018009175A MX391812B (es) 2016-01-28 2017-01-25 Agonista fxr derivado de esteroides.
EP17743740.7A EP3409684B1 (en) 2016-01-28 2017-01-25 Steroid derivative fxr agonist
KR1020187024701A KR102788843B1 (ko) 2016-01-28 2017-01-25 스테로이드 유도체 fxr 작용체
NZ745250A NZ745250B2 (en) 2017-01-25 Steroid derivative fxr agonist
CA3012396A CA3012396C (en) 2016-01-28 2017-01-25 Steroid derivative fxr agonist
EA201891690A EA038580B9 (ru) 2016-05-18 2017-01-25 Агонист fxr, представляющий собой производное стероидов
IL260795A IL260795B (en) 2016-01-28 2018-07-26 A steroidal derivative of an fxr receptor agonist
ZA2018/05231A ZA201805231B (en) 2016-01-28 2018-08-03 Steroid derivative fxr agonist
US17/069,691 US11667667B2 (en) 2016-01-28 2020-10-13 Steroid derivative FXR agonist
AU2021202018A AU2021202018B2 (en) 2016-01-28 2021-03-31 Steroid derivative fxr agonist

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201610061293.3 2016-01-28
CN201610061293 2016-01-28
CN201610331759 2016-05-18
CN201610331759.7 2016-05-18

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US16/072,839 A-371-Of-International US10875888B2 (en) 2016-01-28 2017-01-25 Steroid derivative FXR agonist
US17/069,691 Continuation US11667667B2 (en) 2016-01-28 2020-10-13 Steroid derivative FXR agonist

Publications (1)

Publication Number Publication Date
WO2017129125A1 true WO2017129125A1 (zh) 2017-08-03

Family

ID=59397430

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/072567 Ceased WO2017129125A1 (zh) 2016-01-28 2017-01-25 甾体类衍生物fxr激动剂

Country Status (15)

Country Link
US (2) US10875888B2 (zh)
EP (1) EP3409684B1 (zh)
JP (1) JP6924765B2 (zh)
KR (1) KR102788843B1 (zh)
CN (1) CN109071593B (zh)
AU (2) AU2017213032B2 (zh)
CA (1) CA3012396C (zh)
CL (1) CL2018002009A1 (zh)
IL (1) IL260795B (zh)
MX (1) MX391812B (zh)
MY (1) MY196292A (zh)
PH (1) PH12018550120B1 (zh)
SG (2) SG11201806348PA (zh)
WO (1) WO2017129125A1 (zh)
ZA (1) ZA201805231B (zh)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107383139A (zh) * 2017-08-09 2017-11-24 杭州和泽医药科技有限公司 一种3α‑羟基‑7‑氧代‑5β‑胆烷酸新衍生物制备奥贝胆酸的方法
CN107722000A (zh) * 2017-11-03 2018-02-23 中国药科大学 9位－取代的小檗碱衍生物的制备及其医药用途
CN107987116A (zh) * 2018-01-17 2018-05-04 中国药科大学 一类鹅去氧胆酸衍生物、其制备方法和医药用途
WO2019020067A1 (zh) * 2017-07-26 2019-01-31 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的制备方法
WO2019020068A1 (zh) * 2017-07-26 2019-01-31 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的结晶或无定型物、其制备方法和用途
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10246483B2 (en) 2015-02-11 2019-04-02 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10266560B2 (en) 2014-11-06 2019-04-23 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10323061B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10323060B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
US10364267B2 (en) 2016-02-23 2019-07-30 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10457703B2 (en) 2015-03-31 2019-10-29 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
US10519191B2 (en) 2014-11-26 2019-12-31 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10584145B2 (en) 2016-11-29 2020-03-10 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
CN110878113A (zh) * 2019-11-07 2020-03-13 成都贝诺科成生物科技有限公司 一种具有抗菌活性的胆酸衍生物及其药用组合物
US10676500B2 (en) 2017-04-07 2020-06-09 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
EP3705487A4 (en) * 2017-11-02 2021-08-04 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. METHOD FOR PREPARING A CHOLIC ACID COMPOUND
CN113861258A (zh) * 2021-09-05 2021-12-31 中国海洋大学 一种马尾藻甾醇的合成方法
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment
US11578097B2 (en) 2014-11-26 2023-02-14 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof
CN115785183A (zh) * 2020-04-23 2023-03-14 江西青峰药业有限公司 一种3α,7α-二羟基-6α-乙基-5β-胆烷-24-醛的制备方法及其应用
CN116178473A (zh) * 2018-12-10 2023-05-30 江西青峰药业有限公司 一种奥贝胆酸的制备方法
RU2800751C2 (ru) * 2017-07-26 2023-07-27 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3409684B1 (en) * 2016-01-28 2024-01-03 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Steroid derivative fxr agonist
CN109134572A (zh) * 2017-06-19 2019-01-04 中国科学院上海药物研究所 胆酸衍生物及其制备方法和用途
WO2023048528A1 (ko) * 2021-09-24 2023-03-30 (주)샤페론 염증복합체 억제제를 유효성분으로 하는 아토피 피부염 예방, 개선 또는 치료용 약학 조성물
WO2023048526A1 (ko) * 2021-09-24 2023-03-30 (주)샤페론 염증복합체 억제제를 유효성분으로 함유하는, 비알코올성 지방간염, 간 섬유화의 예방, 개선 또는 치료용 약학적 조성물
CN118660883A (zh) 2021-11-15 2024-09-17 海湃泰克(北京)生物医药科技有限公司 多环化合物及其方法
IT202200011705A1 (it) * 2022-06-01 2023-12-01 Prec Bio Therapeutics S R L Derivati del colesterolo e loro usi
CN116497082B (zh) * 2023-06-27 2023-09-29 华南理工大学 一种化学-酶法合成3α,7α,24R-三羟基胆甾醇的方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (en) 1998-12-23 2000-06-29 Glaxo Group Limited Assays for ligands for nuclear receptors
WO2002072598A1 (en) * 2001-03-12 2002-09-19 Roberto Pellicciari Steroids as agonists for fxr
WO2005082925A2 (en) 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
WO2016086218A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016086134A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016161003A1 (en) * 2015-03-31 2016-10-06 Enanta Phamraceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016173397A1 (zh) * 2015-04-28 2016-11-03 上海翰森生物医药科技有限公司 胆酸衍生物及其制备方法和医药用途
CN106083978A (zh) * 2015-04-28 2016-11-09 上海迪诺医药科技有限公司 磺酰基氨基羰基衍生物、其药物组合物及应用

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150004894A (ko) * 2012-05-01 2015-01-13 카타베이시스 파마슈티칼즈, 인코포레이티드 스타틴 및 ｆｘｒ 작용제의 지방산 컨쥬게이트들； 조성물 및 이용 방법
CA2912139C (en) * 2013-05-14 2021-04-20 Roberto Pellicciari 11-hydroxyl-derivatives of bile acids and amino acid conjugates thereof as farnesoid x receptor modulators
CA2957332A1 (en) * 2014-08-20 2016-02-25 F. Hoffmann-La Roche Ag In vitro method and apparatus for analysing the behaviour of substances in simulated physiological environment
HK1244708A1 (zh) * 2014-11-26 2018-08-17 英安塔制药有限公司 作爲fxr/tgr5激动剂的胆汁酸类似物及其使用方法
EP3409684B1 (en) * 2016-01-28 2024-01-03 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Steroid derivative fxr agonist
WO2017147137A1 (en) * 2016-02-23 2017-08-31 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as fxr/tgr5 agonists and methods of use thereof
EP3436316A4 (en) * 2016-03-31 2020-03-04 B/E Aerospace, Inc. SYSTEM AND METHODS FOR PROTECTING A PASSENGER IN AN OBLIQUE MOUNTED AIRPLANE SEAT

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (en) 1998-12-23 2000-06-29 Glaxo Group Limited Assays for ligands for nuclear receptors
WO2002072598A1 (en) * 2001-03-12 2002-09-19 Roberto Pellicciari Steroids as agonists for fxr
WO2005082925A2 (en) 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
WO2016086218A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016086134A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016161003A1 (en) * 2015-03-31 2016-10-06 Enanta Phamraceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
WO2016173397A1 (zh) * 2015-04-28 2016-11-03 上海翰森生物医药科技有限公司 胆酸衍生物及其制备方法和医药用途
CN106083978A (zh) * 2015-04-28 2016-11-09 上海迪诺医药科技有限公司 磺酰基氨基羰基衍生物、其药物组合物及应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Protective Groups In Organic Synthesis", 1991, WILEY AND SONS
"Remington: The Science and Practice of Pharmacy", 2005, LIPPINCOTT, WILLIAMS & WILKINS
BM. FORMAN ET AL., CELL, vol. 81, 1995, pages 687 - 693
BM. FORMAN, CELL, vol. 81, 1995, pages 687 - 693
DJ. MANGELSDORF ET AL., CELL, vol. 83, 1995, pages 841 - 850
MAEHR, J. CHEM. ED., vol. 62, 1985, pages 114 - 120
W. SEOL ET AL., MOL. ENDOCRINNOL., vol. 9, 1995, pages 72 - 85

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10266560B2 (en) 2014-11-06 2019-04-23 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10696713B2 (en) 2014-11-26 2020-06-30 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US12281140B2 (en) 2014-11-26 2025-04-22 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10968249B2 (en) 2014-11-26 2021-04-06 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US11718641B2 (en) 2014-11-26 2023-08-08 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US11578097B2 (en) 2014-11-26 2023-02-14 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10519191B2 (en) 2014-11-26 2019-12-31 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10246483B2 (en) 2015-02-11 2019-04-02 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US11040998B2 (en) 2015-03-31 2021-06-22 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10457703B2 (en) 2015-03-31 2019-10-29 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US11958879B2 (en) 2015-03-31 2024-04-16 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10364267B2 (en) 2016-02-23 2019-07-30 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
US10323060B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
US10323061B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10584145B2 (en) 2016-11-29 2020-03-10 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
US10947264B2 (en) 2016-11-29 2021-03-16 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
US10961272B2 (en) 2017-04-07 2021-03-30 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
US10676500B2 (en) 2017-04-07 2020-06-09 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
WO2019020068A1 (zh) * 2017-07-26 2019-01-31 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的结晶或无定型物、其制备方法和用途
JP7308811B2 (ja) 2017-07-26 2023-07-14 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド ステロイド系誘導体ｆｘｒアゴニストの製造方法
WO2019020067A1 (zh) * 2017-07-26 2019-01-31 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的制备方法
RU2800751C2 (ru) * 2017-07-26 2023-07-27 Чиа Тай Тяньцин Фармасьютикал Груп Ко., Лтд. Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение
CN110869381B (zh) * 2017-07-26 2021-11-19 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的制备方法
JP2020528067A (ja) * 2017-07-26 2020-09-17 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. ステロイド系誘導体ｆｘｒアゴニストの結晶又は非晶質、その製造方法及び使用
EP3660031A4 (en) * 2017-07-26 2021-03-31 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. CRYSTALLINE OR AMORPHIC FORM OF STEROID DERIVATIVE FXR AGONIST, METHOD OF MANUFACTURING THEREOF AND USE THEREOF
CN110869381A (zh) * 2017-07-26 2020-03-06 正大天晴药业集团股份有限公司 甾体类衍生物fxr激动剂的制备方法
EP3660030A4 (en) * 2017-07-26 2021-04-21 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. METHOD OF MANUFACTURING STEROID-DERIVATIVE FXR AGONISTS
JP7244487B2 (ja) 2017-07-26 2023-03-22 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド ステロイド系誘導体ｆｘｒアゴニストの結晶又は非晶質、その製造方法及び使用
US11059853B2 (en) 2017-07-26 2021-07-13 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Crystalline or amorphous form of steroid derivative FXR agonist, preparation method therefor and use thereof
US11059854B2 (en) 2017-07-26 2021-07-13 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing steroid derivative FXR agonist
JP2020528068A (ja) * 2017-07-26 2020-09-17 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッドChia Tai Tianqing Pharmaceutical Group Co., Ltd. ステロイド系誘導体ｆｘｒアゴニストの製造方法
AU2018305612B2 (en) * 2017-07-26 2022-04-14 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Crystalline or amorphous form of steroid derivative FXR agonist, preparation method therefor and use thereof
CN107383139A (zh) * 2017-08-09 2017-11-24 杭州和泽医药科技有限公司 一种3α‑羟基‑7‑氧代‑5β‑胆烷酸新衍生物制备奥贝胆酸的方法
EP3705487A4 (en) * 2017-11-02 2021-08-04 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. METHOD FOR PREPARING A CHOLIC ACID COMPOUND
CN107722000A (zh) * 2017-11-03 2018-02-23 中国药科大学 9位－取代的小檗碱衍生物的制备及其医药用途
CN107987116A (zh) * 2018-01-17 2018-05-04 中国药科大学 一类鹅去氧胆酸衍生物、其制备方法和医药用途
CN107987116B (zh) * 2018-01-17 2021-01-05 中国药科大学 一类鹅去氧胆酸衍生物、其制备方法和医药用途
CN116178473A (zh) * 2018-12-10 2023-05-30 江西青峰药业有限公司 一种奥贝胆酸的制备方法
WO2021009332A1 (en) 2019-07-18 2021-01-21 Enyo Pharma Method for decreasing adverse-effects of interferon
CN110878113B (zh) * 2019-11-07 2021-02-02 成都贝诺科成生物科技有限公司 一种具有抗菌活性的胆酸衍生物及其药用组合物
CN110878113A (zh) * 2019-11-07 2020-03-13 成都贝诺科成生物科技有限公司 一种具有抗菌活性的胆酸衍生物及其药用组合物
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
CN115785183A (zh) * 2020-04-23 2023-03-14 江西青峰药业有限公司 一种3α,7α-二羟基-6α-乙基-5β-胆烷-24-醛的制备方法及其应用
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment
CN113861258A (zh) * 2021-09-05 2021-12-31 中国海洋大学 一种马尾藻甾醇的合成方法

Also Published As

Publication number Publication date
CA3012396C (en) 2024-03-26
CN109071593B (zh) 2021-01-15
JP6924765B2 (ja) 2021-08-25
US11667667B2 (en) 2023-06-06
CN109071593A (zh) 2018-12-21
KR20180100703A (ko) 2018-09-11
AU2017213032B2 (en) 2021-01-07
MX391812B (es) 2025-03-21
PH12018550120A1 (en) 2019-03-18
BR112018015474A2 (zh) 2018-12-18
SG10201913768TA (en) 2020-03-30
AU2017213032A1 (en) 2018-08-30
NZ745250A (en) 2024-08-30
SG11201806348PA (en) 2018-08-30
ZA201805231B (en) 2022-03-30
EP3409684A4 (en) 2019-10-09
JP2019503392A (ja) 2019-02-07
KR102788843B1 (ko) 2025-03-28
MY196292A (en) 2023-03-24
AU2021202018B2 (en) 2022-04-07
CL2018002009A1 (es) 2018-11-05
MX2018009175A (es) 2018-11-29
US20190382437A1 (en) 2019-12-19
IL260795B (en) 2021-04-29
US20210040140A1 (en) 2021-02-11
CA3012396A1 (en) 2017-08-03
PH12018550120B1 (en) 2023-03-15
EP3409684B1 (en) 2024-01-03
US10875888B2 (en) 2020-12-29
AU2021202018A1 (en) 2021-04-29
EP3409684A1 (en) 2018-12-05

Similar Documents

Publication Publication Date Title
CN109071593B (zh) 甾体类衍生物fxr激动剂
CN107531743B (zh) 鹅去氧胆酸衍生物
JP6857124B2 (ja) Ｆｘｒ／ｔｇｒ５アゴニストとしての胆汁酸誘導体およびその使用方法
CN106518946A (zh) 磺酰脲衍生物、其药物组合物及应用
CN106999551A (zh) 作为fxr/tgr5激动剂的胆汁酸类似物和其使用方法
TW202134248A (zh) Sstr5拮抗劑
WO2015135449A1 (zh) 五环三萜类化合物及其制备方法、药物组合物和用途
WO2023198172A1 (zh) 噁二唑化合物、包含其的药物组合物及其用途
TWI893404B (zh) 雙官能基化合物及包含該雙官能基化合物之醫藥組成物，及其用於製備治療雄激素受體相關疾病之藥物的用途
JP7244487B2 (ja) ステロイド系誘導体ｆｘｒアゴニストの結晶又は非晶質、その製造方法及び使用
HK1259152A1 (zh) 甾体类衍生物fxr激动剂
HK1259152B (zh) 甾体类衍生物fxr激动剂
EA038580B1 (ru) Агонист fxr, представляющий собой производное стероидов
BR112018015474B1 (pt) Compostos agonistas de fxr derivados de esteroide, composição farmacêutica que compreende os mesmos e usos terapêuticos dos ditos compostos
CN116789636B (zh) 双功能化合物及其制备方法、药物组合物和用途
CA3080091A1 (en) Amorphous pyrrolidine derivative as ppar agonist and preparation method thereof
RU2800751C2 (ru) Кристаллическая или аморфная форма агонистов fxr, представляющих собой производные стероидов, способ их получения и их применение
JP2025537627A (ja) セレン含有複素環式化合物およびその使用
WO2025180517A1 (zh) 含sf5类喹啉衍生物及其作为p2x7拮抗剂的用途
CN114315815A (zh) 用于调节fxr活性的化合物及其应用
HK40029010A (zh) 含有羧酸基团的苯并氮杂环类化合物及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17743740

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 3012396

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 11201806348P

Country of ref document: SG

Ref document number: 12018550120

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: MX/A/2018/009175

Country of ref document: MX

Ref document number: 260795

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2018539427

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112018015474

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 201891690

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 20187024701

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2017743740

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2017213032

Country of ref document: AU

Date of ref document: 20170125

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017743740

Country of ref document: EP

Effective date: 20180828

ENP Entry into the national phase

Ref document number: 112018015474

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20180727