WO2016173524A1 - 鹅去氧胆酸衍生物 - Google Patents

鹅去氧胆酸衍生物 Download PDF

Info

Publication number
WO2016173524A1
WO2016173524A1 PCT/CN2016/080635 CN2016080635W WO2016173524A1 WO 2016173524 A1 WO2016173524 A1 WO 2016173524A1 CN 2016080635 W CN2016080635 W CN 2016080635W WO 2016173524 A1 WO2016173524 A1 WO 2016173524A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
tautomer
acceptable salt
compound
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/CN2016/080635
Other languages
English (en)
French (fr)
Inventor
贺海鹰
李鹏
肖华玲
陈正霞
张杨
陈曙辉
胡国平
黎健
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
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Medshine Discovery Inc filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN202010345654.3A priority Critical patent/CN111574577B/zh
Priority to CN201680024495.9A priority patent/CN107531743B/zh
Publication of WO2016173524A1 publication Critical patent/WO2016173524A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • 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
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • 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
    • 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
    • C07J41/0038—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 with an androstane skeleton, including 18- or 19-substituted derivatives, 18-nor derivatives and also derivatives where position 17-beta is substituted by a carbon atom not directly bonded to a further carbon atom and not 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
    • C07J41/0055—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
    • 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
    • C07J41/0066—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 a carbon atom forming 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
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/001—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class spiro-linked
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only
    • C07J71/0047—Nitrogen only at position 2(3)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0073—Sulfur-containing hetero ring
    • C07J71/0094—Sulfur-containing hetero ring containing sulfur and nitrogen
    • 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

Definitions

  • This application relates to the field of medicine.
  • the present application relates to a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and to Preparation of a medicament for treating FXR-related diseases.
  • Nitrification X receptor is an orphan nuclear receptor originally identified from a rat lung cDNA library (BM. Forman, et al., Cell 81:687-693 (1995)), which is associated with insect ecdysone 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 that FXR is abundantly expressed in the lung, intestine, kidney, and adrenal gland (BM. Formanet al., Cell 81:687-693 (1995) and W.
  • 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.
  • An aspect of the application provides a compound of Formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 , R 8 and R 9 are each independently selected from H, halogen, OH, NH 2 , SH, CN, or a C 1-3 alkane optionally substituted by 1, 2, 3, 4 or 5 R Or a C 1-3 alkoxy group, optionally, R 8 and R 9 may be joined together to form a 3- to 6-membered ring; or, R 9 is selected from H, and R 7 and R 8 are formed with the attached carbon atom. a 5- to 6-membered heteroaryl ring or a C 3-6 cycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R;
  • R are each independently selected from halogen, CN, OH, NH 2 , SH, or C 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 , 3, 4 or 5 R';
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me or trifluoromethyl;
  • R 7 , R 8 and R 9 are not H at the same time, and when R 8 is OH, R 7 and R 9 are not simultaneously selected from H, and R 8 or R 9 is not selected from
  • Another aspect of the application provides a compound of Formula II, Formula III or Formula IV, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 5 are each independently selected from H, halogen, OH, NH 2 , SH, CN, or C 1 selected from, optionally substituted by 1, 2, 3, 4 or 5 R. -3 alkyl or C 1-3 alkoxy;
  • R 2 is OH, R 1 and R 3 are not simultaneously selected from H;
  • R 2 and R 3 may be joined together to form a 3 to 6 membered ring;
  • Ring A is selected from a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2, 3, 4 or 5 R;
  • R L is selected from H or is selected from C 1-3 alkyl optionally substituted by 1, 2, or 3 R;
  • R 4 is selected from H or selected from the group consisting of 1, 2, 3, 4, or 5 R: C 1-3 alkyl, C 3-10 cycloalkyl, 3 to 6-membered heterocycloalkyl , 5 to 6-membered aryl or 5 to 6-membered heteroaryl;
  • R is independently selected from halogen, CN, OH, NH 2 , SH, or optionally substituted by 1, 2, 3, 4, or 5 R': C 1-3 alkyl, C 1-3 heteroalkane Base; and/or
  • any one of R L may be joined to R 4 to form a 4 to 6 membered ring optionally substituted by 1, 2, 3, 4, or 5 R;
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me, trifluoromethyl;
  • the number of said "hetero" on each of the above "hetero"-containing groups is 1, 2, 3, 4, or 5.
  • Another aspect of the invention provides a compound of formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 4 is selected from H or a C 1-3 alkyl group optionally substituted by 1, 2, 3, 4 or 5 R, a C 3-10 cycloalkyl group, a 3 to 6-membered heterocycloalkyl group, 5 ⁇ 6-membered aryl or 5- to 6-membered heteroaryl;
  • R 5 is selected from H, halogen, OH, NH 2 , SH, CN, or a C 1-3 alkyl or C 1-3 alkoxy group optionally substituted by 1, 2, 3, 4 or 5 R ;
  • R 6 is selected from H or OH
  • n is selected from 0, 1 or 2;
  • R L is selected from H or from a C 1-3 alkyl group optionally substituted by 1, 2, or 3 R;
  • R are each independently selected from halogen, CN, OH, NH 2 , SH, or optionally substituted by 1, 2 , 3, 4 or 5 R': C 1-3 alkyl, C 1-3 heteroalkane Base and / or
  • any one of R L and R 4 are joined together to form a 4 to 6 membered ring optionally substituted by 1, 2, 3, 4, or 5 R;
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me or trifluoromethyl;
  • R 4 is selected from a C 1-3 alkyl group, R is not selected from OH and NH 2 .
  • compositions comprising a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, tautomers thereof, stereoisomers thereof Or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • Another aspect of the present invention provides a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a combination thereof
  • a disease for the prevention or treatment of a disease that benefits from FXR agonism including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near areas) and benign Prostatic hyperplasia (BPH) or ureteral stones.
  • Another aspect of the present application 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 compound of Formula I, a tautomer thereof, a stereoisomer thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition as described above, which benefits from FXR agonistic diseases, including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near area), and benign prostatic hyperplasia ( BPH) or ureteral stones.
  • FXR agonism comprising administering to a patient a therapeutically effective amount of a compound of Formula I, a tautomer thereof, a stereoisomer thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition as described above, which benefits from FXR agonistic diseases, including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near area), and benign prostatic hyperplasia ( BPH) or ureteral stones.
  • An aspect of the application provides a compound of Formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 7 , R 8 and R 9 are each independently selected from H, halogen, OH, NH 2 , SH, CN, or a C 1-3 alkane optionally substituted by 1, 2, 3, 4 or 5 R Or a C 1-3 alkoxy group, optionally, R 8 and R 9 may be joined together to form a 3- to 6-membered ring; or, R 9 is selected from H, and R 7 and R 8 are formed with the attached carbon atom. a 5- to 6-membered heteroaryl ring or a C 3-6 cycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R;
  • R are each independently selected from halogen, CN, OH, NH 2 , SH, or C 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 , 3, 4 or 5 R';
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me or trifluoromethyl;
  • R 7 , R 8 and R 9 are not H at the same time, and when R 8 is OH, R 7 and R 9 are not simultaneously selected from H, and R 8 or R 9 is not selected from
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , SH, CN, Me, Et,
  • R 7 is selected from H or
  • R 8 and R 9 above are each independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , SH, CN, Me, Et, Alternatively, R 8 and R 9 are joined together to form a C 3-6 cycloalkyl group.
  • R 8 and R 9 above are each independently selected from the group consisting of H, F, OH, Me, Et, Alternatively, R 8 and R 9 are joined together to form a cyclopropyl group, and R 8 and R 9 are not H at the same time.
  • R 9 is selected from H, and R 7 and R 8 form an imidazolyl, pyrazolyl, pyrrolyl group, optionally substituted by 1 or 2 R, with the attached carbon atom.
  • R 9 is selected from H, and R 7 and R 8 are bonded to the attached carbon atom to form optionally substituted by methyl or amino.
  • R 9 is selected from H, and R 7 and R 8 are formed with the attached carbon atom.
  • Another aspect of the application provides a compound of Formula II, Formula III or Formula IV, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 5 are each independently selected from H, halogen, OH, NH 2 , SH, CN, or C 1 selected from, optionally substituted by 1, 2, 3, 4 or 5 R. -3 alkyl or C 1-3 alkoxy;
  • R 2 is OH, R 1 and R 3 are not simultaneously selected from H;
  • R 2 and R 3 may be joined together to form a 3 to 6 membered ring;
  • Ring A is selected from a 5- to 6-membered heteroaryl ring optionally substituted by 1, 2, 3, 4 or 5 R;
  • R L is selected from H or is selected from C 1-3 alkyl optionally substituted by 1, 2, or 3 R;
  • R 4 is selected from H or selected from the group consisting of 1, 2, 3, 4, or 5 R: C 1-3 alkyl, C 3-10 cycloalkyl, 3 to 6-membered heterocycloalkyl , 5 to 6-membered aryl or 5 to 6-membered heteroaryl;
  • R is independently selected from halogen, CN, OH, NH 2 , SH, or optionally substituted by 1, 2, 3, 4, or 5 R': C 1-3 alkyl, C 1-3 heteroalkane Base; and/or
  • any one of R L may be joined to R 4 to form a 4 to 6 membered ring optionally substituted by 1, 2, 3, 4, or 5 R;
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me, trifluoromethyl;
  • the number of said "hetero" on each of the above "hetero"-containing groups is 1, 2, 3, 4, or 5.
  • the above R is selected from the group consisting of halogen, CN, OH, NH 2 , SH, or optionally substituted by 1, 2, 3, 4, or 5 R': C 1-3 alkyl, C 1-3 alkoxy group, C 1-3 alkylamino group.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , SH, Me, Et, CF 3 .
  • R 1 , R 2 , R 3 , and R 5 are each independently selected from the group consisting of H, halogen, OH, NH 2 , SH, CN, Me, Et,
  • R 2 and R 3 are joined together to form a cyclopropyl group.
  • the ring A is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, furyl, optionally substituted by 1 or 2 R.
  • the ring A is selected from the group consisting of methyl substituted
  • the ring A is selected from the group consisting of
  • R 4 is selected from H, or Me, Et, optionally substituted by 1, 2, 3, 4, or 5 R
  • R 4 is selected from H or is selected from Me, Et, which is optionally substituted by 1, 2, 3, 4, or 5 R.
  • R 4 is selected from the group consisting of: H, Me, Et,
  • the structural unit -LR 4 is selected from Selected to be replaced by 1 or 2 R
  • structural unit -LR 4 is selected from
  • the structural unit -LR 4 is selected from the group consisting of:
  • Another aspect of the application provides a compound of formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 4 is selected from H or a C 1-3 alkyl group optionally substituted by 1, 2, 3, 4 or 5 R, a C 3-10 cycloalkyl group, a 3 to 6-membered heterocycloalkyl group, 5 ⁇ 6-membered aryl or 5- to 6-membered heteroaryl;
  • R 5 is selected from H, halogen, OH, NH 2 , SH, CN, or a C 1-3 alkyl or C 1-3 alkoxy group optionally substituted by 1, 2, 3, 4 or 5 R ;
  • R 6 is selected from H or OH
  • n is selected from 0, 1 or 2;
  • R L is selected from H or is selected from a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R, preferably R L is selected from H or C 1-3 alkyl;
  • R are each independently selected from halogen, CN, OH, NH 2 , SH, or optionally substituted by 1, 2 , 3, 4 or 5 R': C 1-3 alkyl, C 1-3 heteroalkane Base and / or
  • any one of R L and R 4 are joined together to form a 4 to 6 membered ring optionally substituted by 1, 2, 3, 4, or 5 R;
  • R' is selected from the group consisting of halogen, CN, OH, NH 2 , SH, Me or trifluoromethyl;
  • R 4 is selected from a C 1-3 alkyl group, R is not selected from OH and NH 2 .
  • the stereoisomer of the compound of formula V is as shown in the following formula V':
  • R is selected from halogen, CN, OH, NH 2 , SH, or C 1-3 optionally substituted by 1, 2 , 3, 4 or 5 R'.
  • R is preferably selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , SH, Me, Et, Or CF 3 .
  • the above R is preferably selected from the group consisting of F, Cl, OH, NH 2 , SH, Me, Et, Or CF 3 .
  • R 5 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , SH, CN, Me, Et,
  • R 5 is selected from H, Me or Et.
  • R 4 above is selected from H, or Me, optionally substituted by 1, 2, 3, 4 or 5 R,
  • R 4 above is preferably selected from H or selected from Me, Et, optionally substituted by 1, 2, 3, 4 or 5 R.
  • R 4 above is more preferably from H, Me, Et,
  • the structural unit - LR 4 is selected from the group consisting of optionally substituted by 1 or 2 R
  • the above structural unit -LR 4 is selected from the group consisting of:
  • compositions comprising a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, tautomers thereof, stereoisomers thereof Or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the compound of the present application or a salt thereof can be administered as an active substance alone, preferably in the form of a pharmaceutical composition thereof.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt, solvate, polymorph thereof, metabolism thereof As an active ingredient, one or more pharmaceutically acceptable carriers.
  • Administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration which provides a medicament for similar use.
  • the pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with a suitable pharmaceutically acceptable carrier, diluent, medium or excipient.
  • the pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration, and the like.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition of the present application can be produced by a method known to those skilled in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art. These carriers enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral pharmaceutical compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core of the dragee may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using enteric coatings.
  • compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • the amount of the compound or composition administered to the patient is not fixed, depending on the drug to be administered, the purpose of administration, such as prevention or treatment; the state of the patient, the manner of administration, and the like.
  • a composition that is sufficient to cure or at least partially inhibit the symptoms of the disease and its complications can be administered to a patient already suffering from the disease.
  • the effective dose will depend on the condition being treated and the judgment of the attending clinician, which will depend, for example, on the severity of the disease, the age, weight, and condition of the patient.
  • composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions can be eliminated by conventional sterilization techniques or by filter sterilization bacteria.
  • the aqueous solution can be packaged as is, or lyophilized, and the lyophilized preparation is mixed with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparation is usually from 3 to 11, more preferably from 5 to 9, most preferably from 7 to 8. It will be appreciated that the use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of a pharmaceutical salt.
  • the compounds of the present application are FXR agonists.
  • the compounds of the present application 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 application.
  • the compounds of the present application 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 level of the subject in need of treatment or treatment prior to administration of a compound of the present application.
  • the compounds of the present application can reduce liver triglyceride production or reduce liver triglyceride secretion by reducing fat absorption.
  • the compounds of the present application also reduce serum triglycerides and hepatic triglycerides.
  • the compounds of the present application can 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 application can be used to prevent or treat liver/biliary diseases of a subject, such as a mammal, particularly a human, such as, but not limited to, cholestatic liver disease, high HDL cholesterol disease, high triglyceride disease, or Fibrotic diseases, such as, but not limited to, 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
  • Bile duct atresia cholestatic liver disease, chronic liver disease, hepatitis infection (type B
  • the compounds of the present application can be used to prevent or treat obesity in a subject, such as a mammal, particularly a human.
  • the compounds of the present application can be used to prevent or treat 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 application can be used to prevent or treat 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 present invention provides a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a combination thereof
  • a disease for the prevention or treatment of a disease that benefits from FXR agonism including cardiovascular disease, liver/biliary system disease, obesity, diabetes, lower urinary tract symptoms (near areas) and benign Prostatic hyperplasia (BPH) or ureteral stones.
  • Another aspect of the present application 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 compound of Formula I, Formula II, Formula III, Formula IV or Formula V, which are mutually An isomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which benefits from FXR agonistic 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 comprising administering to a patient a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, which are mutually An isomer, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which benefits from FXR agonistic diseases, including cardiovascular disease, liver/biliary system disease, obesity, diabetes
  • 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 disease, high HDL cholesterol disease, high triglyceride disease, or fibrotic disease.
  • 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.
  • references throughout the specification to “a” or “an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” are meant to include in at least one embodiment.
  • Specific reference elements, structures or features associated with the embodiments are meant to include in at least one embodiment.
  • the appearance of the phrase “a” or “in an embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” refers to the same implementation.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • 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. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). 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 m to n means that m to n carbon atoms are present in the moiety.
  • C 1-3 alkyl means that the alkyl group has 1 to 3 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 , a cycloalkyl group of C 5 , C 6 , C 7 , C 8 , C 9 and C 10
  • 3 to 6-membered heterocycloalkyl means that the group may be selected from the group consisting of 3, 4, 5 and 6 Heterocycloalkyl.
  • substituted or “substituted” means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and substituted.
  • the compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • 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.
  • 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.
  • 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.
  • a structural unit Indicates that it can be substituted at any position on the cyclohexyl or cyclodiene, including
  • the right end of the L group is attached to R 4 .
  • halo or halogen, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • Non-limiting examples of the term include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -CH (CH 3) 2, -CH (CH 3 (CH 2 CH 3 ), -CH(CH 2 CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH (CH 3 )(CH 2 CH 3 ) or the like.
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • C 1-6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • the "alkyl”, “C 1-8 alkyl”, “C 1-6 alkyl” or “C 1-4 alkyl” may be unsubstituted or selected from one or more selected from the group consisting of hydroxyl, halogen or Substituent substitution of an amino group.
  • cycloalkyl refers to an all-carbon cyclic saturated hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, including a monocyclic structure, a fused ring structure, a spiro structure or a bridged ring structure, such as C. 3-10 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Adamantyl and the like.
  • cycloalkyl group may be unsubstituted or independently substituted by one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, aryl, heteroaryl Base, amino, halogen, sulfonyl, sulfinyl, phosphoryl or hydroxy.
  • 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.
  • Aryl includes, but is not limited to, phenyl, naphthyl, anthryl and the like.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and an atomic group containing these hetero atoms, including, for example, oxygen (O), nitrogen (N).
  • heteroalkyl means a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, and a part of carbon atoms and hydrogen atoms are substituted or replaced by the above hetero atom or hetero atomic group.
  • the term “heteroalkyl” by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • heteroalkyl includes "alkoxy”, “alkylamino” and “alkylthio”.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atomic structure selected from the above heteroatoms or heteroatoms, the remaining ring atoms being C, and having at least one aromatic ring.
  • the heteroaryl group includes at least one ring atom selected from the group consisting of N, O, and S.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, Pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • the term “5- or 6-membered heteroaryl” refers to a heteroaryl group having 5 to 6 ring atoms.
  • the "heteroaryl” or “5- or 6-membered heteroaryl group” may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen, or C 1 ⁇ 4 alkyl substituents.
  • heterocycloalkyl refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system group containing at least one ring atom structure selected from the above heteroatoms or heteroatoms, the remaining ring atoms For C.
  • the "heterocycloalkyl group” includes at least one hetero atom selected from N, O, S, S(O)n (where n is 0, 1, or 2) as a ring atom structure, and the remaining ring atoms are C.
  • Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • heterocycloalkyl include oxiranyl, cyclohexylethane, cycloalkylethane, azetidinyl, acetobutyl, thibutane, tetrahydrofuranyl, pyrrolidinyl, Oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, di Hydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxacycloheptyl, thiecycloheptyl, oxa Azabicyclo[2.2.1]heptyl and azas
  • ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl is as defined above.
  • the cycloalkenyl group or the cycloalkynyl group means an alkenyl group or an alkynyl group structure in the ring atom structure of the cycloalkyl group.
  • the heterocyclenyl or heterocycloalkynyl group means a ring atomic structure in which a cycloalkenyl group or a cycloalkynyl group contains at least one hetero atom or a hetero atom group selected from the above, and the remaining ring atoms are C.
  • a cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl group is unsaturated (e.g., having one or more double bonds), but does not have a fully conjugated ⁇ -electron system.
  • 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 present invention prepared from a compound having a particular substituent found herein and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • the acid addition salt can be obtained by contacting a sufficient amount of an acid with a neutral form of such a compound in a neat solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, as well as organic acid salts, salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al). ., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application contain basic and acidic functional groups which can be converted to any base or acid addition salt.
  • 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.
  • Compound The parent form differs from its various salt forms by certain physical properties, such as differences in solubility in polar solvents.
  • the compounds provided herein also exist in the form of a prodrug.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the claimed compounds.
  • prodrugs can be converted to the compounds of the present application by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the present application may exist in unsolvated as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present application.
  • Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and individual isomers are included within the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, 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 Within the scope of this application. 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 this application.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application 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 purity. The desired enantiomer.
  • a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then 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 application 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). All isotopic compositional changes of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of the active substance of the present application, 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, refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are 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.
  • patient refers to any animal, including mammals, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, most preferably a human.
  • terapéuticaally effective amount refers to an amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human causing a biological or medical response. Includes one or more of the following:
  • Prevention of diseases for example, prevention of a disease, disorder or condition in an individual who is susceptible to a disease, disorder or condition but has not experienced or developed a pathology or symptom of the disease.
  • Inhibiting a disease for example, inhibiting a disease, disorder, or condition (ie, preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder, or condition.
  • Relieving a disease for example, alleviating a disease, disorder, or condition (ie, reversing pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder, or condition.
  • the therapeutic dose of a compound of the present application can depend, for example, on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of the compounds of the present application in the pharmaceutical compositions may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration.
  • the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound.
  • Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day.
  • the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof.
  • An effective dose can be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the reactions described herein can be monitored according to any suitable method known in the art.
  • it can be performed by a broad-spectrum method such as nuclear magnetic resonance spectroscopy (for example, 1 H or 13 C), infrared spectroscopy, spectrophotometry (for example, UV-visible light) or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer.
  • a broad-spectrum method such as nuclear magnetic resonance spectroscopy (for example, 1 H or 13 C), infrared spectroscopy, spectrophotometry (for example, UV-visible light) or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer.
  • HPLC high performance liquid chromatography
  • the solvent used in the present application is commercially available.
  • This application uses 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 benzyloxycarbon
  • Example 1E To a solution of the compound of Example 1E (140.0 g, 336.1 mmol) in NaOH (0.5 mol) (600.0 mL), 10% Pd-C (19.9 g, 134.4 mmol), and 15 psi of hydrogen, at 100 The reaction was carried out for 16 hours at a temperature of Celsius. After suction filtration, the filtrate was adjusted to pH 3 with dilute aqueous hydrochloric acid, and the aqueous layer was extracted with methylene chloride (1500.0 ml ⁇ 3).
  • Potassium hydroxide (0.5 g, 8.9 mmol) was added to a mixture of the compound (10.0 mg, 0.06 mmol) of water (2.0 ml) and ethanol (2.0 ml). After stirring at 80 ° C for 24 hours, it was neutralized with 1 mol of hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (100 ml ⁇ 4).
  • Reference Example 1F compound (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, half Formic acid (40.3 g, 874.7 mmol, 33.0 ml) was added dropwise over an hour, and the reaction mixture was stirred at 50 ° C for eleven hours. The solvent was concentrated, and water (35.0 ml) was evaporated.
  • Example 3B The compound of Example 3B (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 for one hour at one hundred degrees Celsius. . Part of the solvent was removed by concentration and extracted with dichloromethane (30 mL ⁇ 3). The aqueous phase was acidified with EtOAc (EtOAc)EtOAc. The compound of Example 3C (3.2 g, 7.9 mmol, 93.5% yield) was obtained without purification.
  • EtOAc EtOAc
  • Example 3D The compound of Example 3D (1.3 g, 3.2 mmol) was added to dichloromethane (30.0 mL), and N,N-dimethyl-4-aminopyridine (78.2 mg, 640.00 ⁇ mol) and EDCI (736.1) Mg, 3.8 mmol), and the reaction was stirred at 30 ° C for 12 hours. Dichloromethane (50 ml) was added to the mixture.
  • Example 37 Preparation of Example 37 to Example 39
  • the procedure of Reference Example 27 was carried out by using the compound of Example 3D as a starting material, which was obtained by the acylation reaction of Scheme 4, and the obtained results are as follows:
  • Example 40 The same operation as in Example 27, using Example 3D as a starting material, the acylation reaction was carried out and purified to give Example 40 as follows:
  • Example 51 Preparation of Example 51 to Example 58
  • the procedure of Example 53 was prepared by Route 7, and the results obtained were as follows:
  • Methyl iodide (8.5 mg, 60.0 ⁇ m) was added to a solution of the compound of Example 62 (23.0 mg, 50.0 ⁇ mol) and potassium carbonate (13.8 mg, 100.1 ⁇ mol) in dimethylformamide (2.0 ml). Mole, 3.7 ⁇ l, and after stirring for 3 hours at 20 ° C, 5 ml of water was added, and extracted with ethyl acetate (10 ml ⁇ 3), and the combined organic layers were washed twice with saturated brine (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.
  • Example 11A The compound of Example 11A (1.1 g, 2.5 mmol) was dissolved in aq. MeOH (14 mL). The crude product after spin-drying gave the compound of Example 12A (200.0 mg, yield 19.0%) by column chromatography.
  • 1 H NMR (400 MHz, CHLOROFORM-d) ⁇ 5.50 (s, 2H) 3.72 (br.s., 1H) 3.36-3.50 (m, 1H) 2.24 - 2.37 (m, 1H) 2.09-2.19 (m, 1H) ) 1.95-2.01(m,1H)1.56-1.95(m,9H)1.43-1.54(m,5H)1.30-1.42(m,5H)1.25-1.27(m,1H)1.13-1.24(m,3H)0.98 -1.07 (m, 1H) 0.89-0.98 (m, 9H) 0.68 (s, 3H).
  • Triethyltrifluoromethylsilyl ether (59.6 mg, 0.4 ml) and tetrabutylammonium fluoride (10.9 mg, 0.04) were added to a solution of the title compound (160.0 mg, 0.3 mmol) in THF (6 ml). The mixture was stirred at 0 ° C for 1 h.
  • Example 66A and the compound of Example 66B (27.0 mg, yield 61.0%) were obtained from the title compound 14A.
  • 1 H NMR 400 MHz, CHLOROFORM-d
  • Example 69 and Example 70 were carried out by the procedure of Example 68, prepared by Route 16, and the results obtained were as follows:
  • Example 72 The compound of Example 72 (10.0 mg, yield 56.0%, purity 90%) was purified by using the compound of Example 18A as the starting material.
  • Example 15A The compound of Example 15A (1.5 g, 2.7 mmol) was dissolved in N-methylpyrrolidone (8.0 ml), and sodium azide (1.5 g, 23.1 mmol) and acetic acid (1.9 g, 32.3 mmol) The solution was stirred at 20 ° C for 20 hours. The reaction was quenched with EtOAc EtOAc (EtOAc) The organic layer was washed with EtOAc (EtOAc m.
  • EtOAc EtOAc
  • Example 19A The compound of Example 19A (1.0 g, 2.1 mmol) was dissolved in tetrahydrofuran (20.0 ml), and triphenylphosphine (1.7 g, 6.3 mmol) and water (1.0 ml) were sequentially added under a nitrogen atmosphere. Stir for 12 hours.
  • Example 19B The compound of Example 19B (50.0 mg, 111.7 ⁇ mol) was dissolved in N,N-dimethylformamide (1.0 mL) and dichloromethane (2.0 mL). , 335.1 micromoles of aqueous solution (1.0 ml) and thiophosgene (15.4 mg, 134.0 micromoles), the reaction solution was reacted at 20 degrees for 30 minutes, water (10 ml) was added, and dichloromethane (10 ml ⁇ 3) ). The organic layer was washed with EtOAc (EtOAc) (EtOAc m.
  • EtOAc EtOAc
  • Example 19B The compound of Example 19B (80.0 mg, 178.7 ⁇ mol) was dissolved in dichloromethane (4.0 mL), then diisopropylethylamine (34.6 mg, 268.1 ⁇ mol) and 2-isopropylisocyanate (27.1 mg). , 268.1 ⁇ mol), and the reaction solution was stirred at 20 °C for 12 hours. The solvent was evaporated to dryness.
  • Example 12A The compound of Example 12A (5.0 g, 11.5 mmol) was dissolved in anhydrous toluene (80.0 mL), then silver carbonate / celite (12.6 g, 46.0 mmol) was added, and the reaction mixture was stirred at 130 ° C. hour. After cooling to room temperature, the solvent was concentrated.
  • Example 21B The compound of Example 21B (100.0 mg, 210.7 ⁇ mol) was dissolved in ethanol (3.00 ml), and hydrazine hydrate (21.1 mg, 421.4 ⁇ mol) was added to the obtained solution, and the reaction mixture was stirred at 80 ° C for 1 hour.
  • Example 21C The compound of Example 21C (65.0 mg, 138.1 ⁇ mol) was dissolved in tetrahydrofuran (4.0 ml), then aqueous sodium hydroxide (55.2 mg, 1.4 mmol) (2.0 ml) was added and the mixture was stirred at 30 ° C for 12 hours. . Acidified to pH 2-3 with 1N diluted hydrochloric acid, ethyl acetate (EtOAc (EtOAc) (EtOAc) The compound of Example 75 (14.0 mg, yield 22.0%) was obtained by chromatography.
  • Example 21C The compound of Example 21C (90.0 mg, 191.2 ⁇ mol) was dissolved in N,N-dimethylformamide (4.0 ml), then dimethyl sulfate (440.0 mg, 3.5 mmol) and potassium carbonate (79.3 mg, 573.6 ⁇ mol), the reaction solution was stirred at 30 ° C for 12 hours. The solvent was removed by EtOAc (EtOAc)EtOAc.
  • Example 22A The compound of Example 22A (20.0 mg, 37.1 ⁇ mol) was used as the starting material, and the ethoxy group was removed from LiOH, followed by thin layer chromatography to give the compound of Example 76 (10.0 mg. Rate 50%).
  • Example 21B After the compound of Example 21B (400.0 mg, 895.6 ⁇ mol) was dissolved in methanol (10.0 ml), sodium borohydride (203.3 mg, 5.4 mmol) was added, and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction was quenched with EtOAc (EtOAc m. The organic layer was washed with EtOAc EtOAc m.
  • Example 21A The compound of Example 21A (10.0 g, 23.1 mmol) was dissolved in pyridine (100 ml), and acetic anhydride (28.3 g, 277.4 mmol) and 4-N,N-dimethylaminopyridine (282.4 mg, 2.3 The mixture was refluxed for 6 hours at 110 ° C. The reaction was quenched by TLC.
  • Example 25B1 compound (35.0 mg, yield 56.0%).
  • 1 H NMR (400MHz, CHLOROFORM- d) ⁇ 5.03-5.14 (m, 1H) 2.31-2.43 (m, 1H) 2.18-2.30 (m, 1H) 2.04 (s, 3H) 1.90-2.00 (m, 1H) 1.72-1.86(m,4H)1.53-1.69(m,4H)1.26-1.51(m,11H)1.19-1.23(m,3H)1.01-1.17(m,5H)0.94-0.99(m,3H)0.85- 0.94 (m, 6H) 0.64 (s, 3H).
  • Example 25B2 compound (15.0 mg, yield 24.0%).
  • 1 H NMR (400 MHz, CHLOROFORM-d) ⁇ 5.04-5.13 (m, 1H) 2.33 - 2.42 (m, 1H) 2.19 - 2.30 (m, 1H) 2.05 - 2.09 (m, 3H) 1.86 - 2.03 (m, 3H)1.73-1.84(m,5H)1.29-1.61(m,12H)1.21(s,3H)1.06-1.15(m,5H)0.90-0.95(m,6H)0.84-0.90(m,3H)0.59- 0.67 (m, 3H).
  • Example 79A The compound of Example 79A was obtained, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Tebbe reagent (0.5 M solution in toluene, 0.1 mmol) was added to a solution of the compound of Example 24A (60.0 mg, 0.1M) in tetrahydrofuran (2.0 mL). After stirring at 0 ° C for 4 hours, it was stirred at 25-30 ° C for 16 hours. 2 ml of a 2 M aqueous solution of sodium hydroxide was added to the reaction mixture, and the mixture was filtered, and the filtrate was evaporated to ethyl acetate (10 ml ⁇ 2). Filter and spin dry under reduced pressure.
  • Example 82B compound (10.0 mg, yield 39%, purity 95%).
  • Example 86 and Example 87 were carried out by the procedure of Example 85, prepared by the route 31, and the obtained result was as follows:
  • Example 33A To a solution of the compound of Example 33A (100.0 mg, 19. The solvent was evaporated to drynessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessnessness
  • Example 33D Dry palladium on carbon (50 mg, water ⁇ 1%) and the compound of Example 33D (600.0 mg, 720.1 micromol) were added to dry 25 mL round bottom flask, then anhydrous methanol (5.0 mL) and tetrahydrofuran (5.0 mL) The reaction system was purged with nitrogen three times, and then hydrogen was exchanged three times. The reaction solution was stirred under a hydrogen atmosphere (15 psi) at 25 ° C for 48 hours.
  • Example 90 The same procedure as Example 2A was carried out to give the compound of Example 90 (20.0 mg, 16.8% yield).
  • 1H NMR 400MHz, CHLOROFORM-d
  • reaction solution was stirred at 50-60 ° C for 20 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, and washed with brine (35 ml ⁇ 2), ethyl acetate (20 ml ⁇ 2), and the organic phase was dried over anhydrous sodium sulfate. 35B compound (1.8 g, yield 94.8%, purity 67%).
  • Example 35B The compound of Example 35B (2.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (20.0 mL). At 0 ° C, lithium tetrahydroaluminum (1.0 g, 27.2 mmol) was added portionwise, and the reaction mixture was stirred at seventy degrees Celsius. hour. After cooling to zero degrees Celsius, water (2 ml) was added dropwise to the reaction mixture, which was extracted with dichloromethane/methanol (10/1, 30 ml ⁇ 3).
  • Example 35D The compound of Example 35D (140.0 mg, 196.06 ⁇ mol) was dissolved in methanol (5.0 ml), p-toluenesulfonic acid monohydrate (37.3 mg, 196.0 micromoles) was added, and the reaction mixture was stirred at twenty degrees Celsius for twelve hours. The solvent was removed by EtOAc (EtOAc)EtOAc.
  • Example 92 Preparation of Example 92 and Example 93
  • the procedure of Reference Example 91 was prepared by Route 35 and the results obtained were as follows:
  • Example 94 The compound of Example 94 (692.0 mg, yield: 67.8%) was obtained by the procedure of the procedure of Example 65.
  • Example 35C The compound of Example 35C (200.0 mg, 357.2 micromoles) was dissolved in dichloromethane (2 mL), triethylamine (72.3 mg, 714.5 micromoles, 99.0 microliters) was added, and monooxalyl chloride was added at 0 degrees Celsius. The ester (97.6 mg, 714.5 micromoles, 79.9 microliters) was dissolved in dichloromethane (1 ml) and the reaction was stirred at 30 ° C for 12 hours. The solvent was removed by EtOAc (EtOAc)EtOAc.
  • Example 96 The compound of Example 96 (40.0 mg, 69.7% yield) was obtained from the crude material.
  • Example 35C (1.3 g, 2.3 mmol) was dissolved in tetrahydrofuran (12 ml), triethylamine (458.4 mg, 4.5 mmol) was added, and chloroethyl isocyanate (478.1 mg, 4.5 mmol) was added dropwise. The reaction solution was stirred at 30 ° C for twelve hours in tetrahydrofuran (3 ml). Water (5 ml) was added, and ethyl acetate (10 ml x 3).
  • Example 39B The compound of Example 39B (360.0 mg, 559.9 ⁇ mol) was used as a starting material.
  • Example 19B The compound of Example 19B (100.0 mg, 223.4 ⁇ mol) was dissolved in dichloromethane (2.0 mL). At 0 ° C, triethylamine (33.9 mg, 335.1 ⁇ mol) was added, followed by the addition of monoethyl chloro oxalate ( 61.0 mg, 446.7 ⁇ mol), and the reaction solution was stirred at 20 ° C for 16 hours. The solvent was removed by EtOAc (EtOAc m.).
  • Example 40A The compound of Example 40A (50.0 mg, 91.2 ⁇ mol) was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (1.0 ml), and lithium hydroxide monohydrate (76.6 mg, 1.8 mmol) was added. Stir for 12 hours at 25 degrees Celsius. The reaction mixture was extracted with methylene chloride / EtOAc (EtOAc (EtOAc) (EtOAc) .
  • Example 99 The procedure of Example 98, prepared by Route 40, was obtained as follows:
  • Triethylamine (153.0 mg, 1.5 mmol) and ethyl chloroformate (167.0 mg, 1.5 mmol) were added to a solution of the compound of Example 2A (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 Celsius, and a solution of sodium borohydride (210.0 mg, 5.5 mmol) in methanol (5 mL) was slowly added to the reaction mixture, and reacted at 0 ° C for 15 minutes and at 25 ° C for 15 minutes. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. Purification of the compound of Example 41A (600.0 mg, crude).
  • Example 41A The compound of Example 41A (280.0 mg, 605.0 ⁇ mol), triphenylphosphine (476.0 mg, 1.8 mmol) and imidazole (124.0 mg, 1.8 mmol) in toluene (4 mL) and acetonitrile (1 mL) Iodine (461.0 mg, 1.8 mmol) was added to the solution, and the reaction was allowed to react at 25 ° C for 3 hours. A saturated aqueous solution of sodium sulfite (10 ml) was added to the reaction mixture, the aqueous layer was evaporated, evaporated, evaporated, evaporated. The title compound 41B (250.0 mg, 70%).
  • Example 102 The compound of Example 102 (200.0 mg, 79.4% yield) was obtained from the title compound.
  • Example 21A The compound of Example 21A (2.0 g, 4.6 mmol) was dissolved in toluic acid (24.4 g, 530.1 mmol, and then chloric acid (4.6 mg, 46.2 micromoles) was added and the reaction mixture was stirred at 25 ° C for 12 hours. The solvent, the residue was purified by column chromatography on silica gel to give compound Example 44A (700.0 mg, 32.9% yield) embodiment.
  • Example 44A The compound of Example 44A (80.0 mg, 173.6 ⁇ mol) was dissolved in dichloromethane (3.0 mL), and then, under 25 ° C, under nitrogen, a solution of pyridinium bromide (55.5 mg, 173.6 ⁇ mol) was added, Stir in Celsius for four hours. Dichloromethane (25 ml) was added to the mixture. The residue was purified by EtOAc EtOAc EtOAc.
  • Example 44B The compound of Example 44B (100.0 mg, 185.3 ⁇ mol) and thiourea (28.2 mg, 370.6 ⁇ mol) were dissolved in pyridine (2.0 ml), and the reaction mixture was stirred at 90 ° C for 12 hours. The solvent was removed, and water (5 ml) was evaporated. The organic layer was washed with water (10 mL) The residue was purified by EtOAc EtOAc EtOAc.
  • 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 ⁇ L 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 microwells of the 384-well plate at 7.5 ul volume 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 ⁇ L 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 ⁇ L per well.
  • the 384 microplate was incubated for 16 hours at 37 ° C, 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) to determine the percent activation efficacy of the compound (Efficacy).
  • the first group is the intravenous group, which is administered with 2mg/kg for the tail vein, (the solvent is 10% HPbCD aqueous solution, the drug solubility is not ideal, then the cosolvent is added); the second group is the oral group, intragastric administration 10 mg/kg, 10 mL/kg (solvent is 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.

Landscapes

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

Abstract

本申请公开了式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐，并公开了其在制备治疗FXR相关疾病药物中的应用。

Description

鹅去氧胆酸衍生物 发明领域
本申请涉及医药领域。具体而言，本申请涉及式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示化合物、其互变异构体、其立体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
尼酯X受体(FXR)是一种最初从大鼠肺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在肺，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 PCTCN2016080635-appb-000001
发明概述
本申请的一方面提供式Ⅰ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000002
其中，
R7、R8和R9分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基，任选地，R8和R9可连接在一起形成一个3～6元环；或者，R9选自H，R7和R8与所连碳原子形成任选被1、2、3、4或5个R取代的5～6元杂芳环或C3-6环烷基；
上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的C1-3烷基、C1-3杂烷基；
上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
条件是，R7、R8和R9不同时为H，并且，当R8为OH时，R7和R9不同时选自H，并且，R8或R9不选自
Figure PCTCN2016080635-appb-000003
本申请的另一方面提供式Ⅱ、式Ⅲ或式Ⅳ所示化合物、其互变异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000004
其中，
R1、R2、R3、R5分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
当R2为OH时，R1和R3不同时选自H；
任选地，R2、R3可连接在一起形成一个3～6元环；
Figure PCTCN2016080635-appb-000005
代表单键或双键；
环A选自任选被1、2、3、4或5个R取代的5～6元杂芳环；
L选自：单键、-C(＝O)、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、 -N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2N(RL)-；
RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基；
R4选自H、或选自任选被1、2、3、4、或5个R取代的：C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
R分别独立地选自卤素、CN、OH、NH2、SH、或任选被1、2、3、4、或5个R’取代的：C1-3烷基、C1-3杂烷基；和/或
任选地，任何一个RL可与R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环；
R’选自卤素、CN、OH、NH2、SH、Me、三氟甲基；
“杂”代表杂原子或杂原子团，选自-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-和/或-S(＝O)2-；
每个上述含“杂”的基团上所述“杂”的数目为1、2、3、4、或5个。
本申请另一方面提供式Ⅴ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000006
其中，
R4选自H、或选自任选被1、2、3、4或5个R取代的C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
R5选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
R6选自H或OH；
n选自0、1或2；
L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(ORL)O-；
上述RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基；
上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的：C1-3 烷基、C1-3杂烷基和/或
任选地，任何一个RL与R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环；
上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
条件是，当R4选自C1-3烷基时，R不选自OH和NH2。
本申请的另一方面提供一种药物组合物，其包含治疗有效量的如式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形剂。
本申请另一方面提供如式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物，其互变异构体、其立体异构体或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。
本申请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所示的化合物，其互变异构体、其立体异构体或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。
发明详述
本申请的一方面提供式Ⅰ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000007
其中，
R7、R8和R9分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基，任选地，R8和R9可连接在一起形成一个3～6元环；或者，R9选自H，R7和R8与所连碳原子形成任选被1、2、3、4或5个R取代的5～6元杂芳环或C3-6环烷基；
上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的C1-3烷基、C1-3杂烷基；
上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
条件是，R7、R8和R9不同时为H，并且，当R8为OH时，R7和R9不同时选自H，并且，R8或R9不选自
Figure PCTCN2016080635-appb-000008
在一个方案中，在式Ⅰ所示化合物中，R7选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
Figure PCTCN2016080635-appb-000009
Figure PCTCN2016080635-appb-000010
在一个方案中，在式Ⅰ所示化合物中，R7选自H或
Figure PCTCN2016080635-appb-000011
在一个方案中，在式Ⅰ所示化合物中，上述R8和R9分别独立地选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
Figure PCTCN2016080635-appb-000012
或者，R8和R9连接在一起形成C3-6环烷基。
在一个方案中，在式Ⅰ所示化合物中，上述R8和R9分别独立地选自H、F、OH、Me、Et、
Figure PCTCN2016080635-appb-000013
Figure PCTCN2016080635-appb-000014
或者，R8和R9连接在一起形成环丙基，且R8和R9不同时为H。
在一个方案中，在式Ⅰ所示化合物中，R9选自H，R7和R8与所连碳原子形成任选被1或2个R取代的咪唑基、吡唑基、吡咯基、噻吩基、恶唑基、噻唑基、呋喃基或环丙基。
在一个方案中，在式Ⅰ所示化合物中，R9选自H，R7和R8与所连碳原子形成任选被甲基或氨基取代的
Figure PCTCN2016080635-appb-000015
在一个方案中，在式Ⅰ所示化合物中，R9选自H，R7和R8与所连碳原子形成
Figure PCTCN2016080635-appb-000016
Figure PCTCN2016080635-appb-000017
本申请的另一方面提供式Ⅱ、式Ⅲ或式Ⅳ所示化合物、其互变异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000018
其中，
R1、R2、R3、R5分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
当R2为OH时，R1和R3不同时选自H；
任选地，R2、R3可连接在一起形成一个3～6元环；
Figure PCTCN2016080635-appb-000019
代表单键或双键；
环A选自任选被1、2、3、4或5个R取代的5～6元杂芳环；
L选自：单键、-C(＝O)、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2N(RL)-；
RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基；
R4选自H、或选自任选被1、2、3、4、或5个R取代的：C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
R分别独立地选自卤素、CN、OH、NH2、SH、或任选被1、2、3、4、或5个R’取代的：C1-3烷基、C1-3杂烷基；和/或
任选地，任何一个RL可与R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环；
R’选自卤素、CN、OH、NH2、SH、Me、三氟甲基；
“杂”代表杂原子或杂原子团，选自-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-和/或-S(＝O)2-；
每个上述含“杂”的基团上所述“杂”的数目为1、2、3、4、或5个。
本发明的一个方案中，上述R选自卤素、CN、OH、NH2、SH、或任选被1、2、3、4、或5个R’取代的：C1-3烷基、C1-3烷氧基、C1-3烷氨基。
本发明的一个方案中，上述R选自F、Cl、Br、I、OH、CN、NH2、SH、Me、Et、
Figure PCTCN2016080635-appb-000020
CF3。
本发明的一个方案中，上述R1、R2、R3、R5分别独立地选自H、卤素、OH、NH2、SH、CN、Me、 Et、
Figure PCTCN2016080635-appb-000021
本发明的一个方案中，上述R2、R3连接在一起形成一个环丙基。
本发明的一个方案中，上述环A选自任选被1或2个R取代的咪唑基、吡唑基、吡咯基、噻吩基、恶唑基、噻唑基、呋喃基。
本发明的一个方案中，上述环A选自被甲基取代的
Figure PCTCN2016080635-appb-000022
本发明的一个方案中，上述环A选自
Figure PCTCN2016080635-appb-000023
本发明的一个方案中，上述R4选自H，或任选被1、2、3、4、或5个R取代的Me、Et、
Figure PCTCN2016080635-appb-000024
Figure PCTCN2016080635-appb-000025
本发明的一个方案中，上述R4选自H，或选自任选被1、2、3、4、或5个R取代的Me、Et、
Figure PCTCN2016080635-appb-000026
Figure PCTCN2016080635-appb-000027
本发明的一个方案中，上述R4选自：H、Me、Et、
Figure PCTCN2016080635-appb-000028
Figure PCTCN2016080635-appb-000029
本发明的一个方案中，上述L选自：单键、-C(＝O)、-C(＝O)S-、-C(＝O)NHS(＝O)2(CH2)0-2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)N(RL)(CH2)0-2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2NH-。
本发明的一个方案中，上述L选自：单键、-C(＝O)、-C(＝O)S-、-C(＝O)NHS(＝O)2-、-C(＝O)NHS(＝O)2CH2-、-C(＝O)NHS(＝O)2(CH2)2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)O-、-NHC(＝O)OCH2-、-NHC(＝O)O(CH2)2-、-NHC(＝O)NH-、-NHC(＝O)NHCH2-、-NHC(＝O)NH(CH2)2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2NH-。
本发明的一个方案中，上述RL和R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环时，结构单元-L-R4选自任选被1或2个R取代的
Figure PCTCN2016080635-appb-000030
本发明的一个方案中，上述RL和R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环时，结构单元-L-R4选自
Figure PCTCN2016080635-appb-000031
本发明的一个方案中，上述结构单元-L-R4选自：
Figure PCTCN2016080635-appb-000032
Figure PCTCN2016080635-appb-000033
本申请的另一方面提供式Ⅴ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐：
Figure PCTCN2016080635-appb-000034
其中，
R4选自H、或选自任选被1、2、3、4或5个R取代的C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
R5选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
R6选自H或OH；
n选自0、1或2；
L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(ORL)O-；
上述RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基，优选RL选自H或C1-3烷基；
上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的：C1-3烷基、C1-3杂烷基和/或
任选地，任何一个RL与R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环；
上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
条件是，当R4选自C1-3烷基时，R不选自OH和NH2。
在一个方案中，所述式Ⅴ所示化合物的立体异构体如下式Ⅴ’所示：
Figure PCTCN2016080635-appb-000035
在一个方案中，在式Ⅴ所示化合物中，上述R选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的C1-3烷基、C1-3烷氧基或C1-3烷氨基。
在一个方案中，在式Ⅴ所示化合物中，上述R优选自F、Cl、Br、I、OH、CN、NH2、SH、Me、Et、
Figure PCTCN2016080635-appb-000036
或CF3。
在一个方案中，在式Ⅴ所示化合物中，上述R优选自F、Cl、OH、NH2、SH、Me、Et、
Figure PCTCN2016080635-appb-000037
或CF3。
在一个方案中，在式Ⅴ所示化合物中，R5选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
Figure PCTCN2016080635-appb-000038
在一个方案中，在式Ⅴ所示化合物中，R5选自H、Me或Et。
在一个方案中，在式Ⅴ所示化合物中，上述R4选自H，或任选被1、2、3、4或5个R取代的Me、
Figure PCTCN2016080635-appb-000039
在一个方案中，在式Ⅴ所示化合物中，上述R4优选自H，或选自任选被1、2、3、4或5个R取代的 Me、Et、
Figure PCTCN2016080635-appb-000040
Figure PCTCN2016080635-appb-000041
在一个方案中，在式Ⅴ所示化合物中，上述R4更优选自H、Me、Et、
Figure PCTCN2016080635-appb-000042
Figure PCTCN2016080635-appb-000043
在一个方案中，在式Ⅴ所示化合物中，上述L选自单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2(CH2)0-2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)N(RL)(CH2)0-2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2NH-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(ORL)O-。
在一个方案中，在式Ⅴ所示化合物中，上述L优选自单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2-、-C(＝O)NHS(＝O)2CH2-、-C(＝O)NHS(＝O)2(CH2)2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O-、-NHC(＝O)OCH2-、-NHC(＝O)O(CH2)2-、-NHC(＝O)NH-、-NHC(＝O)NHCH2-、-NHC(＝O)NH(CH2)2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2NH-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(CH3)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(OMe)O-。
在一个方案中，在式Ⅴ所示化合物中，上述RL和R4连接在一起形成一个任选被1、2、3、4或5个R 取代的4～6元环时，结构单元-L-R4选自任选被1或2个R取代的
Figure PCTCN2016080635-appb-000044
Figure PCTCN2016080635-appb-000045
在一个方案中，在式Ⅴ所示化合物中，上述RL和R4连接在一起形成一个任选被1、2、3、4或5个R取代的4～6元环时，结构单元-L-R4优选自
Figure PCTCN2016080635-appb-000046
Figure PCTCN2016080635-appb-000047
在一个方案中，在式Ⅴ所示化合物中，上述结构单元-L-R4选自：
Figure PCTCN2016080635-appb-000048
Figure PCTCN2016080635-appb-000049
如下所述化合物：
Figure PCTCN2016080635-appb-000050
Figure PCTCN2016080635-appb-000051
Figure PCTCN2016080635-appb-000052
Figure PCTCN2016080635-appb-000053
Figure PCTCN2016080635-appb-000054
Figure PCTCN2016080635-appb-000055
Figure PCTCN2016080635-appb-000056
药物组合物
本申请另一方面提供一种药物组合物，其包含治疗有效量的如式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形剂。
本申请的化合物或其盐可以作为活性物质单独给药，优选以其药物组合物的形式给药。
另一方面，本申请提供了药物组合物，其含有通式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物或其药学上可接受的盐、溶剂化物、多晶型、代谢物作为活性成分，以及一种或多种药学上可接受的载体。
本申请化合物或其药学上可接受的盐的给药可以以纯的形式或适宜的药物组合物的形式通过提供类似用途的药物的任何可接受的给药方式来进行。本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的载体、稀释剂、介质或赋形剂相组合而制备。本申请的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
本申请的化合物或其药学上可接受的盐或其药物组合物的典型的给药途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药等。优选的给药途径是口服给药。
本申请的药物组合物可以采用本领域普通技术人员所知悉的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在优选的实施方案中，药物组合物是口服形式的。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服药物组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预胶化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对糖衣剂的核心进行包衣，尤其使用肠溶包衣。
本申请的药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
给予患者的化合物或组合物的量不固定，取决于给予的药物、给药的目的例如预防或治疗；患者的状态、给药的方式等。在治疗应用时，可给予已患疾病的患者足够治愈或至少部分抑制疾病及其并发症症状的量的组合物。有效剂量应取决于所治疗的疾病状态和主治临床医师的判断，该判断取决于例如疾病的严重程度、患者的年龄、体重和一般状况等因素。
给予患者的组合物可以是上述药用组合物形式。可通过常规灭菌技术或可过滤灭菌，将这些组合物灭 菌。可将水溶液包装原样使用，或冻干，给药前，将冻干制剂与无菌水性载体混合。化合物制剂的pH通常为3～11，更优选5～9，最优选7～8。可以理解，使用某些前述赋形剂、载体或稳定剂会导致形成药物盐。
治疗用途
本申请的化合物是FXR激动剂。本申请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申请的化合物。
本申请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。本申请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，本申请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。本申请化合物还可以降低血清甘油三脂和肝甘油三脂。
本申请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。
本申请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HDL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。
本申请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。
本申请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。
本申请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。
本申请另一方面提供如式Ⅰ、式Ⅱ、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物，其互变异构体、其立体异构体或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。
本申请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、式Ⅲ、式Ⅳ或式Ⅴ所示的化合物，其互变异构体、其立体异构体或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HDL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。
定义和说明
除非另有说明，本申请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。在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其它方法、部件、材料等的情况下可实现实施方案。
除非本申请中另外要求，在说明书和权利要求书中，词语“包括(comprise)”及其英文变体例如“包括(comprises)”和“包括(comprising)”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提到的“一个方案”或“一实施方案”或“实施方案”或“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“一个方案”或“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本申请说明书和附加的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包括“催化剂”的反应包括一种催化剂，或两种或多种催化剂。还应当理解，术语“或”通常以其包括“和/或”的含义而使用，除非文中另外明确地规定。
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，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)。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。
本文所用的Cm～n指该部分中具有m～n个碳原子。例如，“C1-3烷基”指该烷基具有1～3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；“3～6元杂环烷基” 指该基团可选自3元、4元、5元和6元的杂环烷基。
术语“取代”或“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，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。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
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。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如“A-L-Z”中L代表单键时，表示该结构A与Z直接相连，实际上是A-Z。
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 PCTCN2016080635-appb-000057
表示其可在环己基或者环基二烯上的任意一个位置发生取代，包括
Figure PCTCN2016080635-appb-000058
Figure PCTCN2016080635-appb-000059
在本申请的部分优选方式中，所述L基团的右端与R4相连。例如，L可以选自-C(＝O)S-，在本申请的部分优选方式中，-C(＝O)S-的右端与R4相连，即S原子与R4相连；又例如，L可以选自-OC(＝O)N(RL)-，在本申请的部分优选方式中，-OC(＝O)N(RL)-的右端与R4相连，即N原子与R4相连；又例如，L可以选自-N(RL)C(＝O)N(RL)(C(RL)2)0-2-，在本申请的部分优选方式中，-N(RL)C(＝O)N(RL)(C(RL)2)0-2-的右端与R4相连，即“C(＝O)N(RL)(C(RL)2)0-2”部分中的N原子与R4相连。
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。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。该术语的非限制性实例包括甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、 -CH2CH(CH3)(CH2CH3)等。术语“C1～8烷基”指具有1～8个碳原子的烷基。术语“C1～6烷基”指具有1～6个碳原子的烷基。术语“C1～4烷基”指具有1～4个碳原子的烷基。所述“烷基”、“C1～8烷基”、“C1～6烷基”或“C1～4烷基”可以是非取代的或是被一个或多个选自羟基、卤素或氨基的取代基取代。
本文所用的术语“环烷基”是指仅由碳原子和氢原子组成的全碳的环状饱和烃基团，包括单环结构、稠和并环结构、螺环结构或桥环结构，例如C3-10环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、
Figure PCTCN2016080635-appb-000060
金刚烷基等。所述“环烷基”可以是未取代的或被一个或多个取代基独立地取代，所述的取代基包括但不限于烷基、烷氧基、氰基、羟基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基或羟基。
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”包括但不限于苯基、萘基和蒽基等。
术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-；每个上述含“杂”的基团上所述“杂”的数目可选地为1、2、3、4或5个。
术语“杂烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团中，部分碳原子和氢原子被上述杂原子或杂原子团取代或替代。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于或杂烷基的任何内部位置(包括该烃基附着于分子其余部分的位置)。除非另有规定，术语“杂烷基”包括“烷氧基”、“烷氨基”和“烷硫基”。“杂烷基”的实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3、-OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-NHCH3、-NHCH2CH3、-NHCH2CH2CH3、-NHCH(CH3)2、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH(CH3)2。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
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上述杂原子或杂原子团的环原子结构，其余环原子为C，并且具有至少一个芳香环。优选地，所述杂芳基包括至少一个选自N、O、S的环原子。杂芳基的包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、异噁唑基、1,2,4-噁二唑基、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“5元或6元杂芳基”是指具有5～6个环原子的杂芳基。所述“杂芳基”或“5 元或6元杂芳基”可以是非取代的或是被一个或多个选自羟基、卤素或C1～4烷基的取代基取代。
术语“杂环烷基”是指无芳香性的单环、稠合多环、桥环或螺环体系基团，其中含有至少一个选自上述杂原子或杂原子团的环原子结构，其余环原子为C。优选地，所述“杂环烷基”包括至少一个子选自N、O、S、S(O)n(其中n为0、1或2)的杂原子作为环原子结构，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。“杂环烷基”的非限制性实例包括环氧乙烷基、环硫乙烷基、环氮乙烷基、吖丁啶基、噁丁环基、噻丁环基、四氢呋喃基、吡咯烷基、噁唑烷基、四氢吡唑基、吡咯啉基、二氢呋喃基、二氢噻吩基、哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、二氢吡啶基、四氢吡啶基、二氢吡喃基、四氢吡喃基、二氢噻喃基、氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基、氧杂氮杂双环[2.2.1]庚基和氮杂螺[3.3]庚基、
Figure PCTCN2016080635-appb-000061
Figure PCTCN2016080635-appb-000062
等。术语“5元或6元杂环烷基”是指具有5～6个环原子的杂环烷基。
除非另有规定，“环”表示环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。其中环烷基、杂环烷基、芳基或杂芳基如前文所定义。其中，环烯基或环炔基是指在环烷基的环原子结构中包括烯基或炔基结构。杂环烯基或杂环炔基是指在环烯基或环炔基中，其中含有至少一个选自上述杂原子或杂原子团的环原子结构，其余环原子为C。环烯基、杂环烯基、环炔基、杂环炔基是不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。
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”是指本申请化合物的盐，由本申请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。当本申请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。当本申请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。药学上可接受的酸加成盐的实例包括无机酸盐，以及有机酸盐，还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本申请的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
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。
除了盐的形式，本申请所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本申请的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本申请的化合物。
本申请的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本申请的范围之内。
本申请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申请的范围之内。
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申请的范围之内。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请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申请的范围之内。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，均包括在本申请的范围之内。
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。如果想得到本申请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分步结晶法或色谱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)。
本申请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)。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“药学上可接受的载体”是指能够递送本申请有效量活性物质、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。对于本申请中的口服剂型，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。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
本文中使用的短语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：
(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。
(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。
(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请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申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合 成步骤或者反应流程进行修改或选择。
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。
可按照本领域中已知的任何合适的方法，监测本文中所述反应。例如，可通过广谱方法例如核磁共振波谱(例如1H或13C)、红外光谱、分光光度测定(例如UV-可见光)或质谱，或通过色谱例如高效液相色谱(HPLC)或薄层层析监测产物形成。
本申请所使用的溶剂可经市售获得。本申请采用下述缩略词：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；TFAA代表三氟乙酸酐；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；PTSA代表对甲基苯磺酸；TMSCl代表三甲基氯硅烷；BF3-Et2O代表三氟化硼乙醚；Ac2O代表醋酸酐；DMAP代表N,N-二甲基氨基吡啶；EDCI代表1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐；TEA代表三乙胺；TBTU代表O,N-二甲基羟基胺盐酸盐；MeMgBr代表甲基溴化镁；Burgess reagent代表伯吉斯试剂；Bu2OSn代表氧化二丁基锡；TMSN3代表三甲基硅基叠氮；DHP代表3,4-二氢吡喃；PCC代表吡啶铬酸盐；AcCl代表乙酰氯；TMSCF3代表三甲基三氟甲基硅醚；TBAF代表四丁基氟化铵；Pb(OAc)4代表四乙酸铅；P(OEt)3代表三乙基亚磷酸酯；Pyridine代表吡啶；PPh3代表三苯基磷；Thiophosgene代表硫光气；DAST代表二乙胺基三氟化硫；Et2Zn代表二乙基锌；Ph3PCH2OCH3Cl代表甲氧甲基三苯基氯化磷；n-BuLi代表正丁基锂；PhSO2Cl代表苯基磺酰氯；MsCl代表甲烷磺酰氯；TMSNCO代表三甲基硅基异氰酸酯。
化合物经手工或者
Figure PCTCN2016080635-appb-000063
软件命名，市售化合物采用供应商目录名称。
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 PCTCN2016080635-appb-000064
参考例1A
Figure PCTCN2016080635-appb-000065
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，41.0克，69.0％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 PCTCN2016080635-appb-000066
向参考例1A化合物(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 PCTCN2016080635-appb-000067
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(500.0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化合物(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 PCTCN2016080635-appb-000068
向参考例1C化合物(68.0克，123.9毫摩尔)的二氯甲烷(500.0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，43.0克，收率81.0％)。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 PCTCN2016080635-appb-000069
向参考例1D化合物(212.0克，492.3毫摩尔)的甲醇(500.0毫升)溶液中加入NaOH(39.4克，984.6毫摩尔)的水(50.0毫升)溶液，50摄氏度下搅拌2小时。旋干溶剂后，加水(500.0毫升)，用乙酸乙酯(500.0毫升×2)萃取，水相用稀HCl调至pH至3，再用二氯甲烷(600.0毫升×2)萃取，将合并的有机层浓缩，残余物通过重结晶(乙醇，200.0毫升)纯化得到参考例1E(黄色固体，147.0克，收率72.0％)。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 PCTCN2016080635-appb-000070
向参考例1E化合物(140.0克，336.1毫摩尔)的NaOH(0.5摩尔)水溶液(600.0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(1500.0毫升×3)萃取，合并的有机层用盐水(1000.0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，101.0克，收率72.0％)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).
参考例1 INT-747
Figure PCTCN2016080635-appb-000071
向参考例1F化合物(16.0克，38.2毫摩尔)的氢氧化钠(2摩尔，100.0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(150.0毫升)，用稀盐酸调pH至3，水层用二氯甲烷(300.0毫升×3)萃取，合并的有机层用盐水(200.0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例1(白色固体，14.5克，收率90.0％)。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 PCTCN2016080635-appb-000072
实施例1
Figure PCTCN2016080635-appb-000073
实施例1A
氮气保护下，向参考例1化合物(1.0克，2.4毫摩尔)和N,N-二甲基氨基吡啶(30.0毫克，0.2毫摩 尔)的吡啶溶液(10.0毫升)中加入乙酸酐(1.0克，9.5毫摩尔)，在40摄氏度下搅拌12小时后，加入水(100.0毫升)淬灭，水层用乙酸乙酯(100.0毫升×2)萃取，有机层依次用1摩尔的盐酸水溶液和饱和食盐水洗涤，将合并的有机层用硫酸钠干燥，过滤并旋干，残余物通过柱色谱纯化得到实施例1A化合物(1.1克，92.0％产率)。
实施例1B
Figure PCTCN2016080635-appb-000075
实施例1A化合物(0.1克，0.2毫摩尔)和羰基二咪唑(60.0毫克，0.4毫摩尔)的乙腈(3毫升)混合物在25摄氏度反应0.5小时，然后加入硫氢化钠(40.0毫克，0.8毫摩尔)，25摄氏度下继续反应12小时。减压浓缩后用水(80.0毫升)稀释，稀盐酸调pH至3，水层用乙酸乙酯(100.0毫升×2)萃取，合并的有机层用水(100.0毫升)、盐水(100.0毫升)洗涤后，经硫酸钠干燥，过滤并旋干，残余物通过制备TLC板纯化得到标题实施例1B化合物(40.0毫克，收率39.0％)。1H NMR(400MHz,DMSO-d6)δ4.98(br.s.,1H),4.52-4.34(m,1H),2.38-2.13(m,2H),2.04-1.85(m,7H),1.84-1.49(m,9H),1.38(d,J＝8.5Hz,5H),1.26-0.99(m,10H),0.95-0.71(m,9H),0.60(s,3H).
实施例1
Figure PCTCN2016080635-appb-000076
氮气保护下，向实施例1B化合物(30.0毫克，0.06毫摩尔)的水(2.0毫升)和乙醇(2.0毫升)混合物中加入氢氧化钾(0.5克，8.9毫摩尔)。80摄氏度下搅拌24小时后，用1摩尔盐酸中和，水层用乙酸乙酯(100毫升×4)萃取。将合并的有机层用硫酸钠干燥，过滤并旋干，残余物通过制备TLC板纯化得到实施例1化合物(20.0毫克，收率62.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.48-3.35(m,1H),2.47-2.33(m,1H),2.30-2.17(m,1H),2.00-1.72(m,7H),1.70-1.55(m,3H),1.52-1.26(m,11H),1.22-1.10(m,3H),1.04-0.86(m,10H),0.65(s,3H).
路线2
Figure PCTCN2016080635-appb-000077
实施例2
Figure PCTCN2016080635-appb-000078
实施例2A
Figure PCTCN2016080635-appb-000079
氮气保护下，向参考例1化合物(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)中加入高氯酸(6.0克，60.0毫摩尔)。55摄氏度下搅拌6小时后，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2A化合物(2.8克，收率92.0％)。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2B
Figure PCTCN2016080635-appb-000080
氮气保护下向实施例2A化合物(100毫克，0.2毫摩尔)和甲基磺酰胺(18.0毫克)的二氯甲烷溶液(5.0毫升)中加入1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(44毫克，0.2毫摩尔)和N,N-二甲基氨基吡啶(3.8毫克，0.03毫摩尔)，混合物在25摄氏度反应4小时。加入二氯甲烷(120毫升)稀释，用水洗涤，有机相用无水硫酸钠干燥后，真空干燥除去溶液，残余物通过柱色谱纯化得到实施例2B化合物(60.0毫克，收率54.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.52(s,1H),8.05-8.01(m,1H),4.75-4.62(m,1H),3.72(br.s.,1H),3.31(s,3H),2.43-2.34(m,1H),2.29-2.20(m,1H),1.99-1.62(m,10H),1.54-1.32(m,10H),1.23-1.03(m,5H),0.97-0.88(m,9H),0.66(s,3H).
实施例2
Figure PCTCN2016080635-appb-000081
将实施例2B化合物(60.0毫克，0.1毫摩尔)和甲醇钠(6.0毫克，0.1毫摩尔)的甲醇(3毫升)溶液在25摄氏度下搅拌1小时，稀酸调pH＝1，水相用乙酸乙酯(20毫升×3)萃取，有机相用无水硫酸钠干燥，真空除去溶剂，残余物通过制备型TLC板纯化得到实施例2化合物(20.0毫克，收率38.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.85(s,1H),3.71(br.s.,1H),3.47-3.39(m,1H),3.33-3.28(m,3H),2.43-2.33(m,1H),2.24(ddd,J＝6.3,9.7,15.7Hz,1H),1.96(d,J＝11.8Hz,1H),1.88-1.76(m,5H),1.72-1.57(m,5H),1.53-1.32(m,12H),1.22-1.13(m,3H),1.06-0.98(m,1H),0.97-0.88(m,9H),0.66(s,3H).
实施例3-至实施例26的制备参考实施例2的操作，通过路线2制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000082
Figure PCTCN2016080635-appb-000083
Figure PCTCN2016080635-appb-000084
Figure PCTCN2016080635-appb-000085
Figure PCTCN2016080635-appb-000086
Figure PCTCN2016080635-appb-000087
Figure PCTCN2016080635-appb-000088
路线3
Figure PCTCN2016080635-appb-000089
实施例27
Figure PCTCN2016080635-appb-000090
实施例3A
Figure PCTCN2016080635-appb-000091
将参考例1F化合物(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3A化合物(7.0克，15.7毫摩尔，65.6％产率)。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3B
Figure PCTCN2016080635-appb-000092
零摄氏度下将实施例3A化合物(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3B化合物(3.5克，8.5毫摩尔，93.0％产率)。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3C
Figure PCTCN2016080635-appb-000093
将实施例3B化合物(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3C化合物(3.2克，7.9毫摩尔，93.5％产率)。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3D
Figure PCTCN2016080635-appb-000094
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3C化合物(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3D(3.1克，7.6毫摩尔，96.4％产率)。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27
Figure PCTCN2016080635-appb-000095
将实施例3D化合物(1.3克，3.2毫摩尔)加入到二氯甲烷中(30.0毫升)，在加入N，N-二甲基-4-氨基吡啶(78.2毫克，640.00微摩尔)和EDCI(736.1毫克，3.8毫摩尔)，反应液于三十摄氏度搅拌十二小时。向反应液中加入二氯甲烷(50毫升)，有机层经水洗(10毫升×2)，无水硫酸钠干燥，过滤和浓缩。粗产物经柱层析分离得到实施例27化合物(660.0毫克，1.4毫摩尔，42.6％产率)。1H NMR(400MHz,CHLOROFORM-d)δ＝8.81(br.s.,1H),3.71(br.s.,1H),3.48-3.38(m,1H),3.31(s,3H),2.48(d,J＝12.3Hz,1H),2.06-1.94(m,3H),1.88-1.75(m,5H),1.70-1.58(m,5H),1.53-1.40(m,5H),1.35-1.17(m,7H),1.03(d,J＝6.0Hz,3H),0.92-0.89(m,5H),0.74-0.67(m,3H).
实施例28至实施例36的制备参考实施例27的操作，通过路线3制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000096
Figure PCTCN2016080635-appb-000097
Figure PCTCN2016080635-appb-000098
路线4
Figure PCTCN2016080635-appb-000099
实施例37至实施例39的制备参考实施例27的操作，以实施例3D化合物为原料，通过路线4发生酰化反应制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000100
路线5
Figure PCTCN2016080635-appb-000101
操作同实施例27，以实施例3D为原料，进行酰化反应经纯化得到实施例40如下：
Figure PCTCN2016080635-appb-000102
路线6
Figure PCTCN2016080635-appb-000103
实施例50
Figure PCTCN2016080635-appb-000104
实施例6A
Figure PCTCN2016080635-appb-000105
向实施例2A化合物(300.0毫克，629.0微摩尔)的甲苯溶液(5.0毫升)中加入氯化亚砜(1.3克，11.0毫摩尔)在100摄氏度下反应2小时。然后将溶液旋转蒸发干并用10毫升四氢呋喃溶解后再次旋干。将所得产物溶于10毫升四氢呋喃中，在0～10摄氏度下向其加入叠氮钠(122.8毫克，1.9毫摩尔)的水溶液(5.0毫升)，在10摄氏度下反应2小时后，用冰水(20毫升)淬灭反应，水层用乙酸乙酯(30毫升)萃取。将合并的有机层用硫酸钠干燥，过滤并旋干后得到红色油状产物大约300毫克，将其溶解于2毫升无水甲苯，取一半溶液加入(S)-3-羟基四氢呋喃(500.0毫克，5.7毫摩尔)并在100摄氏度下反应10小时。反应结束后蒸干溶剂，用水(20毫升)淬灭反应，水层用乙酸乙酯(20毫升)萃取。将合并的有机层用硫酸钠干燥，过滤并旋干。粗品用制备薄层色谱板分离(石油醚:乙酸乙酯＝3:1)，得到实施例6A化合物(150.0毫克，240.3微摩尔，收率80.1％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ8.17(s,1H),8.06(s,1H),5.33-5.17(m,2H),4.79-4.54(m,2H),4.02-3.77(m,5H),2.25-2.12(m,1H),2.08-1.71(m,10H),1.68-1.61(m,1H),1.55-1.41(m,6H),1.37-1.07(m,12H),0.99-0.90(m,10H),0.68(s,3H).
实施例50
Figure PCTCN2016080635-appb-000106
向实施例6A化合物(150.0毫克，267微摩尔)的四氢呋喃/水(5毫升/3毫升)溶液中加入一水合氢氧化锂(11.2毫克，267微摩尔)在40摄氏度下反应5小时。反应结束后，乙酸乙酯(15毫升)萃取， 将合并的有机层用硫酸钠干燥，过滤并旋干得到的粗品用制备薄层色谱板分离(二氯甲烷:乙酸乙酯＝1:1)，得到实施例50化合物(49.0毫克，收率34.2％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d)δ5.27(br.s.,1H),4.64(br.s.,1H),3.99-3.80(m,6H),3.75-3.65(m,1H),3.47-3.37(m,1H),3.33-3.02(m,2H),2.24-2.12(m,1H),2.08-1.65(m,10H),1.55-1.38(m,7H),1.37-1.13(m,10H),1.09-1.01(m,1H),0.98(d,J＝6.3Hz,3H),0.95-0.87(m,6H),0.68(s,3H).
实施例41至实施例49的制备参考实施例50的操作，通过路线6制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000107
Figure PCTCN2016080635-appb-000108
Figure PCTCN2016080635-appb-000109
路线7
Figure PCTCN2016080635-appb-000110
实施例53
Figure PCTCN2016080635-appb-000111
实施例7A
Figure PCTCN2016080635-appb-000112
向实施例2A化合物(300.0毫克，629.4微摩尔)的甲苯溶液(5.0毫升)中加入氯化亚砜(1.3克，11.0毫摩尔)在100摄氏度下反应2小时。然后将溶液旋干用10毫升四氢呋喃溶解并再次旋干。将所得产物溶于10毫升四氢呋喃中，在0～10摄氏度下向其加入叠氮钠(122.8毫克，1.9毫摩尔)的水溶液(5.0毫升)。在10摄氏度下反应2小时后，用冰水(20毫升)淬灭反应，水层用乙酸乙酯(30毫升)萃取。 将合并的有机层用硫酸钠干燥，过滤并蒸发得到红色油状产物大约300毫克，将其溶解于2毫升无水甲苯，取一半溶液在100摄氏度加热1小时，然后旋干溶剂，将产物溶解于二氯甲烷/四氢呋喃(1毫升/1毫升)的混合溶液中分别加入(3S)-3-羟基吡咯(500.0毫克，4.1毫摩尔，盐酸盐)和三乙胺(453.9毫克，4.5毫摩尔)，10摄氏度反应10小时。反应结束后，加水(30毫升)淬灭反应，乙酸乙酯(30毫升)萃取，将合并的有机层用硫酸钠干燥，过滤并旋干得到的粗品用柱层析分离(二氯甲烷:甲醇＝20:1)，得到实施例7A化合物(160.0毫克，收率86.2％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ＝8.16(s,1H),8.05(s,1H),5.20(br.s.,1H),4.78-4.67(m,1H),4.48(br.s.,1H),4.16(br.s.,1H),3.54-3.26(m,5H),3.18-3.06(m,1H),2.70(br.s.,1H),2.04-1.39(m,19H),1.24-1.04(m,7H),1.01-0.95(m,6H),0.91(t,J＝7.4Hz,3H),0.70-0.62(m,3H).
实施例53
Figure PCTCN2016080635-appb-000113
向实施例7A化合物(150.0毫克，267.5微摩尔)的四氢呋喃/水(5毫升/3毫升)溶液中加入一水合氢氧化锂(33.7毫克，802.5微摩尔)，在40摄氏度下反应5小时。反应结束后，用乙酸乙酯(20毫升)萃取，将合并的有机层用硫酸钠干燥，过滤并旋干得到的粗品用制备薄层色谱板分离(二氯甲烷:甲烷＝20:1)，得到实施例53化合物(90.0毫克，收率34％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d)δ5.47(s,1H),4.37(br.s.,1H),3.63(br.s.,1H),3.47-3.34(m,3H),3.28-2.98(m,3H),2.08-1.01(m,29H),1.00-0.83(m,10H),0.68(s,3H).
实施例51至实施例58的制备参实施例53的操作，通过路线7制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000114
Figure PCTCN2016080635-appb-000115
Figure PCTCN2016080635-appb-000116
路线8
Figure PCTCN2016080635-appb-000117
实施例59
Figure PCTCN2016080635-appb-000118
实施例8A
Figure PCTCN2016080635-appb-000119
参考例1化合物(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8A化合物，(90.2毫克，收率82.1％)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.73-3.67(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59
Figure PCTCN2016080635-appb-000120
向实施例8A化合物(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59化合物(6.0毫克，收率66.0％)。1H NMR(400MHz,CHLOROFORM-d)δ＝3.71(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).
路线9
Figure PCTCN2016080635-appb-000121
实施例60
Figure PCTCN2016080635-appb-000122
实施例9A
Figure PCTCN2016080635-appb-000123
丙二酸单甲酯钾盐(2.4克，15.1毫摩尔)和氯化镁(479.4毫克，5.0毫摩尔)的四氢呋喃溶液(20毫升)于60摄氏度搅拌3小时，冷却至20摄氏度；于实施例2A化合物(2.4克，5.0毫摩尔)的四氢呋喃溶液(8毫升)加入羰基二咪唑(816.5毫克，5.0毫摩尔)的四氢呋喃溶液(8毫升)并在25摄氏度下搅拌2小时；然后将此溶液加入的之前的反应液中并于35摄氏度下搅拌10小时。反应结束后，减压旋干四氢呋喃，用乙酸乙酯萃取(100毫升×3)，将合并的有机层用饱和食盐水(10毫升)洗2次，有机相用 无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱层析分离(石油醚:乙酸乙酯＝20:1)纯化得到实施例9A化合物(2.2g，4.1毫摩尔，81.9％收率)。1H NMR(400MHz,CHLOROFORM-d)δ＝8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.76-4.66(m,1H),3.76-3.72(m,3H),3.45(s,2H),2.61-2.40(m,2H),2.01-1.57(m,11H),1.53-1.36(m,6H),1.34-1.03(m,12H),0.99-0.94(m,3H),0.93-0.87(m,6H),0.65(s,3H).
实施例60
Figure PCTCN2016080635-appb-000124
氯化氢(200.0毫克，375.4微摩尔)的甲醇(0.7毫升)溶液于零下30摄氏度下加入氢氧化钠(25.0毫克)的甲醇和水的混合溶剂中(5毫升/0.3毫升)。搅拌30分钟后，上述混合溶液于零下30摄氏度下加入到盐酸羟胺(52.2毫克，750.9微摩尔)和氢氧化钠(45毫克)的甲醇和水(0.6毫升/0.6毫升)的混合溶液中，继续搅拌1小时，加入36.5％的盐酸(0.6毫升)然后升温至80摄氏度搅拌10小时。反应液浓缩，用二氯甲烷萃取(10毫升×3)，将合并的有机层用饱和食盐水(10毫升)洗2次，有机相用无水硫酸钠干燥，过滤并蒸发，残余物通过制备板(二氯甲烷:甲醇＝10:1)纯化得到实施例60化合物(20.00毫克，43.5微摩尔，11.6％收率)。1H NMR(400MHz,CHLOROFORM-d)δppm5.64(s,1H),3.71(br.s.,1H),3.47-3.36(m,1H),2.75-2.47(m,2H),2.01-1.57(m,11H),1.49-1.28(m,1H),1.54-1.27(m,12H),1.25-1.09(m,4H),1.05-0.80(m,11H),0.66(s,3H).
实施例61
Figure PCTCN2016080635-appb-000125
20摄氏度氮气保护下，向实施例62化合物(23.0毫克，50.0微摩尔)和碳酸钾(13.8毫克，100.1微摩尔)的二甲基甲酰胺(2.0毫升)溶液加入碘甲烷(8.5毫克，60.0微摩尔，3.7微升)，在20摄氏度下搅拌3小时后，加入水5毫升，用乙酸乙酯萃取(10毫升×3)，将合并的有机层用饱和食盐水(10毫升)洗2次，有机相用无水硫酸钠干燥，过滤并蒸发，残余物通过制备板(乙酸乙酯:石油醚＝10:1)纯化得到实施例61化合物(9.0毫克，34.2％产率)。1HNMR(400MHz,CHLOROFORM-d)δppm0.66(s,3H)0.89-1.00(m,13H)1.17-1.54(m,28H)1.55-1.93(m,18H)2.47-2.75(m,2H)3.71(br.s.,1H)3.95(s,3H)5.59(s,1H).
路线10
Figure PCTCN2016080635-appb-000126
实施例62
Figure PCTCN2016080635-appb-000127
实施例10A
Figure PCTCN2016080635-appb-000128
将实施例9A化合物(200.0毫克，365.8微摩尔)溶于乙醇(3毫升)，在0摄氏度下，一分钟内滴加完一水合肼(23.8毫克，475.6微摩尔，溶于乙醇2毫升)，滴毕，移除冰浴，反应液于25摄氏度搅拌四小时。浓缩除去溶剂，残留物经薄层色谱柱层析分离得到实施例10A化合物(90.0毫克，184.9微摩尔，50.6％产率)。1H NMR(400MHz,CHLOROFORM-d)δ＝8.17(d,J＝4.8Hz,2H),5.21(br.s.,1H),3.49(d,J＝5.5Hz,1H),3.44-3.35(m,1H),3.33-3.22(m,1H),2.00(d,J＝12.3Hz,1H),1.91-1.79(m,4H),1.77-1.69(m,4H),1.65-1.57(m,11H),1.55-1.48(m,3H),1.45(s,3H),1.29(br.s.,18H),1.20-1.12(m,6H),1.06-0.96(m,9H),0.71-0.63(m,3H).
实施例62
Figure PCTCN2016080635-appb-000129
将实施例10A化合物(90.0毫克，184.9微摩尔)溶于四氢呋喃(1.0毫升)，甲醇(1.0毫升)和水(1.0 毫升)中，加入一水合氢氧化锂(77.6毫克，1.9毫摩尔)，反应液于25摄氏度搅拌十二小时。反应液用1摩尔盐酸中和到pH＝5-6，溶液用乙酸乙酯萃取(10毫升×3)。所得有机层经水洗(10毫升)，无水硫酸钠干燥和浓缩。残留物经薄层色谱柱层析分离得到实施例62化合物(68.0毫克，148.3微摩尔，80.2％产率)。1H NMR(400MHz,METHANOL-d4)＝5.50(s,1H),3.67(br.s.,1H),3.33(br.s.,1H),2.68-2.56(m,1H),2.50-2.39(m,1H),2.03(s,2H),1.95-1.72(m,8H),1.68-1.49(m,8H),1.47(s,2H),1.37-1.33(m,4H),1.27-1.19(m,5H),1.05-1.00(m,4H),0.93(br.s.,5H),0.90(br.s.,5H),0.70(s,3H).
路线11
Figure PCTCN2016080635-appb-000130
实施例63
Figure PCTCN2016080635-appb-000131
实施例11A
Figure PCTCN2016080635-appb-000132
参考例1化合物(35.0克，83.2毫摩尔)以及对甲苯磺酸(1.4克，8.3毫摩尔)的甲醇(350毫升)混合物在80摄氏度下搅拌2小时。冷却过滤，旋干溶剂后，残余物通过硅胶色谱法纯化得到化合物11A，(30克，收率82％)。1H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.66(s,3H),3.46-3.34(m,1H),2.41-2.29(m,1H),2.27-2.14(m,1H),1.99-1.29(m,24H),1.21-1.09(m,3H),1.05-0.85(m,10H),0.72-0.60(m,3H).
实施例11B
Figure PCTCN2016080635-appb-000133
向实施例11A化合物(200.0毫克，460.0微摩尔)的甲醇(10毫升)溶液中加水合肼(515.0毫克，10.3毫摩尔)，反应体系25℃下反应12h。旋干溶剂，残余物用乙酸乙酯溶液(5毫升)洗涤得到实施例11B化合物(120.0毫克，60.2％产率)。1H NMR(400MHz,CHLOROFORM-d)δ6.75(br.s.,1H),3.71(br.s.,1H),3.45-3.36(m,1H),2.26-2.17(m,1H),2.09-2.02(m,1H),1.59-1.10(m,25H),0.94-0.89(m,9H),0.66(s,3H).
实施例63
Figure PCTCN2016080635-appb-000134
20℃氮气保护下，向化合物11B化合物(180.0毫克，414.1微摩尔)和羰基二咪唑(100.7毫克，621.2微摩尔)的二甲基甲酰胺(2.00毫升)、四氢呋喃(2毫升)溶液加入三乙胺(83.8毫克，828.2微摩尔，114.8微升)，在70摄氏度搅拌12小时后，冷却到20摄氏度，加入水20毫升，加入乙酸乙酯(20毫升)，用乙酸乙酯萃取(10毫升×3)，将合并的有机层用饱和食盐水(10毫升)洗一次，有机相用无水硫酸钠干燥，过滤并蒸发，残余物通过过柱(二氯甲烷:甲醇＝50:1)纯化得到实施例63化合物(72.0毫克，35.9％产率)。1HNMR(400MHz,CHLOROFORM-d)δppm0.67(s,3H)0.79-1.11(m,11H)1.11-1.24(m,4H)1.28-1.99(m,26H)2.40-2.51(m,1H)2.55-2.66(m,1H)3.34-3.48(m,1H)3.72(br.s.,1H)。
路线12
Figure PCTCN2016080635-appb-000135
实施例64
Figure PCTCN2016080635-appb-000136
实施例12A
Figure PCTCN2016080635-appb-000137
将实施例11A化合物(1.1克，2.5毫摩尔)溶在氨甲醇(14毫升)溶液中，60-70摄氏度搅拌18小时。旋干后的粗品通过柱层析得到实施例12A化合物(200.0毫克，产率19.0％)。1H NMR(400MHz,CHLOROFORM-d)δ＝5.50(s,2H)3.72(br.s.,1H)3.36-3.50(m,1H)2.24-2.37(m,1H)2.09-2.19(m,1H)1.95-2.01(m,1H)1.56-1.95(m,9H)1.43-1.54(m,5H)1.30-1.42(m,5H)1.25-1.27(m,1H)1.13-1.24(m,3H)0.98-1.07(m,1H)0.89-0.98(m,9H)0.68(s,3H).
实施例12B
Figure PCTCN2016080635-appb-000138
0摄氏度下，将Burgess试剂(85.0毫克，357.5微摩尔)加到化合物12A(150.0毫克，357.4微摩尔)的四氢呋喃(3毫升)溶液中。反应液在10-15摄氏度下搅拌3小时后用饱和食盐水(15毫升×2)洗涤，并用乙酸乙酯(10毫升×2)萃取。有机相用无水硫酸钠干燥后过滤，滤液真空旋干。粗品经薄层析制备板分离得到实施例12B化合物(30.0毫克，产率21.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.64-3.76(m,1H)3.34-3.50(m,1H)2.34-2.46(m,1H)2.22-2.34(m,1H)1.94-2.02(m,1H)1.85-1.91(m,2H)1.81(br.s.,4H)1.66-1.71(m,2H)1.56-1.63(m,2H)1.41-1.54(m,5H)1.31-1.41(m,4H)1.28-1.31(m,1H)1.14-1.24(m,3H)0.99-1.07(m,1H)0.97(d,J＝6.53Hz,3H)0.84-0.95(m,6H)0.69(s,3H).
实施例64
Figure PCTCN2016080635-appb-000139
将氧化二丁基锡(40.0毫克，74.7微摩尔)和三甲基硅基叠氮(52.0毫克，451.4微摩尔)加入到实施例12B化合物(30.0毫克，74.7微摩尔)的甲苯(2毫升)溶液中，并在100-110摄氏度搅拌18小时。反应完成后，反应液冷却至25-30摄氏度，用饱和食盐水(15毫升×2)洗涤，并用乙酸乙酯(8毫升×2)萃取。有机相用无水硫酸钠干燥后过滤，滤液真空旋干。粗品通过薄层析制备板分离得到实施例64化合物(7.0毫克，产率21.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.65-3.81(m,1H)3.33-3.39(m,1H)2.96-3.07(m,1H)2.83-2.95(m,1H)2.03-2.08(m,1H)1.72-2.02(m,6H)1.29-1.70(m,15H)1.12-1.21(m,2H)1.05-1.10(m,3H)0.97-1.04(m,1H)0.94(s,6H)0.70(s,3H).
路线13
Figure PCTCN2016080635-appb-000140
实施例65
Figure PCTCN2016080635-appb-000141
实施例13A
Figure PCTCN2016080635-appb-000142
将3,4-二氢吡喃(1.6克，18.4毫摩尔)，实施例12A化合物(1.0克，2.3毫摩尔)以及对甲苯磺酸(35.9毫克，0.2毫摩尔)的1,4-二氧六环(20毫升)混合物在25摄氏度下搅拌0.5小时。冷却并旋干后，残余物用乙酸乙酯萃取，依次用水、饱和食盐水洗涤，有机相旋干，通过硅胶色谱法纯化得到实施例13A化合物(1.3克，收率94％)。1H NMR(400MHz,CHLOROFORM-d)δ4.72(br.s.,1H),3.92(dd,J＝6.3,10.8Hz,1H), 3.79-3.58(m,4H),3.53-3.36(m,2H),2.40-2.30(m,1H),2.21(ddd,J＝6.5,9.2,15.4Hz,1H),1.98-1.08(m,34H),1.06-0.75(m,13H),0.64(s,3H).
实施例13B
Figure PCTCN2016080635-appb-000143
实施例13A化合物(500毫克，0.8毫摩尔)的四氢呋喃(5毫升)溶液在0摄氏度下加入四氢铝锂(94.4毫克，2.5毫摩尔)，该混合物于0摄氏度下继续搅拌1小时后，加入94.4毫升水，过滤，滤液用乙酸乙酯稀释，碳酸氢钠水溶液洗涤，有机相旋干后得到实施例13B化合物(400毫克，收率84％)，直接用于下步反应。1H NMR(400MHz,CHLOROFORM-d)δ4.74(d,J＝3.01Hz,1H),3.84-3.97(m,1H),3.56-3.73(m,4H),3.37-3.54(m,3H),1.29-2.02(m,34H),1.06-1.20(m,5H),0.83-0.98(m,10H),0.66(s,3H).
实施例13C
Figure PCTCN2016080635-appb-000144
向实施例13B化合物(230.0毫克，400.1微摩尔)的二氯甲烷(10毫升)溶液中一次性加入吡啶铬酸盐(215.0毫克，997.4微摩尔)，混合液在18摄氏度下反应2小时。反应液过滤并旋干后，残余物通过制备板纯化得到实施例13C化合物(60.0毫克，26.0％产率)。1HNMR(400MHz,CHLOROFORM-d)δ9.76(br.s.,1H),4.66-4.77(m,1H),3.64-3.98(m,3H),3.32-3.58(m,3H),2.26-2.52(m,3H),1.06-2.00(m,37H),0.76-1.02(m,9H),0.64(s,3H).
实施例13D
Figure PCTCN2016080635-appb-000145
向实施例13C化合物(150.0毫克，233.3微摩尔)的乙醇溶液(500毫升)中加入氰化钠(11.4毫克， 233.3毫摩尔)，氯化铵(12.5毫克，233.3毫摩尔)，碳酸铵(22.4毫克，233.3毫摩尔)以及氨水(4.6毫升)。在60摄氏度下搅拌6小时，将反应液倒入冰水(50毫升)中，水层用乙酸乙酯(50毫升×3)萃取。将合并的有机层再用饱和食盐水(50毫升×2)洗，将有机层用硫酸钠干燥，过滤并蒸发，残余物通过制备板纯化得到实施例13D化合物(80.0毫克，收率72.1％)。1H NMR(400MHz,CHLOROFORM-d)δ8.50(br.s.,1H),6.15-6.36(m,1H),4.74(d,J＝3.01Hz,1H),4.08(t,J＝5.52Hz,1H),3.93(d,J＝4.52Hz,1H),3.65-3.74(m,1H),3.39-3.55(m,6H),1.00-2.01(m,38H),0.82-0.98(m,9H),0.60-0.69(m,3H).
实施例65
Figure PCTCN2016080635-appb-000146
0摄氏度下向乙酰氯(320.5毫克，4.1毫摩尔)的甲醇(2毫升)溶液中滴加实施例13D化合物(75.0毫克，116.7微摩尔)的甲醇(1毫升)溶液。0摄氏度下搅拌4小时，将反应液旋干，残余物通过制备板纯化得到实施例65化合物(55.0毫克，收率99.0％)。1H NMR(400MHz,METHANOL-d4)δ4.03-4.11(m,1H),3.65(br.s.,1H),3.35(s,1H),1.96-2.04(m,1H),1.67-1.95(m,7H),1.42-1.66(m,9H),1.24-1.41(m,5H),1.00-1.24(m,5H),0.94-1.00(m,3H),0.84-0.94(m,6H),0.70(s,3H).
路线14
Figure PCTCN2016080635-appb-000147
实施例66A和66B
Figure PCTCN2016080635-appb-000148
实施例14A
Figure PCTCN2016080635-appb-000149
于实施例13C化合物(160.0毫克，0.3毫摩尔)的四氢呋喃(6毫升)溶液中加入三甲基三氟甲基硅醚(59.6毫克，0.4毫升)和四丁基氟化铵(10.9毫克，0.04毫摩尔)，在0摄氏度下搅拌1小时，真空除去溶剂后，残余物通过硅胶柱层析法纯化得到实施例14A化合物，(60.0毫克，收率33.1％)。1H NMR(400MHz,CHLOROFORM-d)δ4.73(d,J＝3.8Hz,1H),4.03-3.78(m,2H),3.70(br.s.,1H),3.58-3.35(m,2H),2.00-1.28(m,28H),1.22-1.01(m,5H),0.98-0.84(m,9H),0.71-0.60(m,3H).
实施例66A和66B
Figure PCTCN2016080635-appb-000150
操作如同实施例65，以标题化合物14A为原料，纯化得到实施例66A化合物和实施例66B化合物(27.0毫克，收率61.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.92(dd,J＝4.0,9.0Hz,1H),3.71(br.s.,1H),3.46-3.35(m,1H),2.86-2.65(m,1H),2.14(dt,J＝3.8,12.8Hz,1H),1.98(d,J＝11.8Hz,1H),1.81-1.63(m,6H),1.54-1.08(m,18H),1.05-0.87(m,10H),0.67(s,3H).和68B(10.0毫克，收率23.0％)。1H NMR(400MHz,CHLOROFORM-d)δ4.00-3.80(m,1H),3.70(br.s.,1H),3.48-3.34(m,1H),2.72(br.s.,1H),2.04-1.29(m,26H),1.23-1.07(m,4H),1.05-0.86(m,10H),0.67(d,J＝4.5Hz,3H).
路线15
Figure PCTCN2016080635-appb-000151
实施例67
Figure PCTCN2016080635-appb-000152
实施例15A
Figure PCTCN2016080635-appb-000153
向实施例2A化合物(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毫克，0.4毫摩尔)，反应体系光照下反应12小时。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15A化合物(50.0毫克，产率38.0％)。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15B
Figure PCTCN2016080635-appb-000154
实施例15A化合物(100.0毫克，179微摩尔)的三乙基亚磷酸酯(149.0毫克，895微摩尔)混合物在160摄氏度下搅拌6小时。用水(5毫升)稀释后，用乙酸乙酯(10毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并旋干，残余物通过制备薄层板纯化(石油醚：乙酸乙酯＝1：1)得到实施例15B化合物(90.0毫克，收率84.1％)。1H-NMR(CDCl3,400MHz)δ8.12(s,1H),8.01(s,1H),5.16(br.s.,1H),4.62-4.73(m,1H),4.03-4.08(m,4H),1.82-1.97(m,3H),1.67-1.81(m,7H),1.55-1.65(m,2H),1.38-1.53(m,6H),1.29(t,J＝7.0Hz,9H),1.19-1.26(m,3H),1.01-1.18(m,6H),0.86-0.91(m,6H),0.63(s,3H).
实施例67
Figure PCTCN2016080635-appb-000155
参考实施例53，以化合物15B(40.0毫克，70.3微摩尔)为原料，得到实施例67化合物(30.0毫克，收率79.0％)。1H-NMR(CDCl3,400MHz)δ4.06-4.14(m,4H),3.71(br.s.,1H),3.42(d,J＝8.0Hz,1H),1.88-2.01(m,2H),1.74-1.87(m,6H),1.62-1.73(m,3H),1.37-1.55(m,8H),1.33(s,6H),1.22-1.31(m,3H),1.12-1.21(m,4H),0.97-1.06(m,1H),0.94(d,J＝6.8Hz,3H),0.87-0.92(m,6H),0.67(s,3H).
路线16
Figure PCTCN2016080635-appb-000156
实施例68
Figure PCTCN2016080635-appb-000157
实施例16A
Figure PCTCN2016080635-appb-000158
零度下向N-叔丁氧羰基-1,2,5-噻二唑啉1,1-二氧化物(20.0毫克，89.5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)。半小时后，滴加实施例15A化合物(50.0毫克，89.5微摩尔)的N,N-二甲基甲酰胺(1毫升)溶液。滴加完毕后，反应体系缓慢升至室温后再反应1小时。用水(5毫升)淬灭反应，水层用乙酸乙酯(10毫升×3)萃取，合并有机层，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＝1：1)得到化合物16A化合物(30.0毫克，收率57.5％)。1H-NMR(CDCl3,400MHz)δ8.15(s,1H),5.30(s,1H),5.18(br.s.,1H),3.90(t,J＝6.5Hz,2H),3.78(s,2H),3.02-3.07(m,2H),1.97(d,J＝12.0Hz,2H),1.79-1.88(m,5H),1.64(br.s.,5H),1.30(d,J＝7.0Hz,6H),1.03-1.15(m,7H),0.94(s,3H),0.89(d,J＝8.0Hz,6H),0.65(s,3H).
实施例68
Figure PCTCN2016080635-appb-000159
参考实施例53，实施例16A化合物为原料(30.0毫克，57微摩尔)得到实施例68化合物(20.0毫克，67.1％产率)。1H-NMR(CDCl3,400MHz)δ4.22(br.s.,1H),3.71(br.s.,1H),3.52(q,J＝6.5Hz,2H),3.39-3.47(m,2H),3.31-3.38(m,1H),2.97-3.10(m,2H),1.87-2.01(m,2H),1.80(d,J＝8.8Hz,4H),1.67(br.s.,3H),1.40-1.52(m,5H),1.25-1.39(m,7H),1.12-1.24(m,4H),0.99(d,J＝6.5Hz,3H),0.88-0.93(m,6H),0.68(s,3H).
实施例69和实施例70的制备参考实施例68的操作，通过路线16制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000160
Figure PCTCN2016080635-appb-000161
路线17
Figure PCTCN2016080635-appb-000162
实施例71
Figure PCTCN2016080635-appb-000163
实施例17A
Figure PCTCN2016080635-appb-000164
25摄氏度下，将碳酸银(197.5毫克，716.2微摩尔)加入至实施例15A化合物(200.0毫克，200.0微摩尔)的丙酮(2.8毫升)和水(150.0微升)的混合物溶液中。在25度下，搅拌30分钟，随后升温至80度，继续搅拌12小时。薄层色谱(石油醚：乙酸乙酯＝2：1)检测发现有极性增大的新化合物生成。将反应悬浊液过滤，滤液减压除去溶剂得到剩余物。剩余物用薄层制备板(石油醚：乙酸乙酯＝2：1)纯化得到实施例17A化合物(46.0毫克，27.2％收率，95％纯度)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.20(br.s.,1H),4.80-4.62(m,1H),3.77-3.58(m,1H),2.07-1.95(m,1H),1.94-1.67(m,8H),1.53-1.40(m,5H),1.38-1.02(m,13H),0.99-0.87(m,9H),0.67(s,3H).
实施例17B
Figure PCTCN2016080635-appb-000165
向实施例17A化合物(40.0毫克，89.2微摩尔)的甲苯(3毫升)溶液加乙基异氰酸酯(13.0毫克，178.4微摩尔)，反应体系在110摄氏度下搅拌12小时。旋干溶剂，残余物通过制备薄层板纯化(石油醚：乙酸乙酯＝2：1)得到实施例17B化合物(5毫克，9.7％产率)。1H-NMR(CDCl3,400MHz)δ8.15(s,1H),8.03-8.07(m,1H),5.19(br.s.,1H),4.64-4.77(m,1H),3.96(q,J＝7.1Hz,2H),3.13-3.25(m,2H),1.89-2.02(m,2H),1.70-1.89(m,8H),1.56-1.66(m,4H),1.35-1.55(m,7H),1.27-1.33(m,4H),1.11-1.14(m,3H),0.94-0.97(m,6H),0.88-0.92(m,3H),0.66(s,3H).
实施例71
Figure PCTCN2016080635-appb-000166
参考实施例53，以实施例17B化合物为原料，纯化得到实施例71化合物(5.0毫克，收率53.0％)。1H-NMR(CDCl3,400MHz)δ＝4.60(br.s.,1H),4.00-4.15(m,2H),3.71(d,J＝1.8Hz,1H),3.36-3.45(m,1H),3.16-3.27(m,2H),1.89-2.00(m,2H),1.74-1.85(m,5H),1.56-1.67(m,5H),1.40-1.51(m,6H),1.26-1.36(m,7H),1.14(s,3H),0.97(d,J＝6.3Hz,3H),0.89-0.93(m,6H),0.67(s,3H).
路线18
Figure PCTCN2016080635-appb-000167
实施例72
Figure PCTCN2016080635-appb-000168
实施例18A
Figure PCTCN2016080635-appb-000169
在0摄氏度下，将甲酸(8.2毫克，8.2微摩尔)滴入装有氯磺酸异氰酸酯(24.1毫克，24.1微摩尔)的圆底烧瓶中，在0度下搅拌5分钟，有白色固体产生。向反应体系中加入二氯甲烷(3.0毫升)，并继续在0摄氏度下搅拌1小时，随后升温至25度，继续搅拌4小时。将反应液降至0度，将实施例17A化合物(50.0毫克，111.5微摩尔)和吡啶(13.5毫克，13.5微摩尔)的混合物加入至反应体系中。反应混合物升温至25度，继续搅拌12小时，减压蒸出溶剂，剩余物用薄层制备板(石油醚：乙酸乙酯＝2：1)纯化，得到实施例18A化合物(18.0毫克，收率29.0％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d) δ＝8.15(s,1H),8.04(s,1H),5.20(br.s.,1H),4.79-4.65(m，3H),4.34-4.15(m,2H),2.07-1.69(m,11H),1.68-1.37(m,12H),1.35-1.04(m,13H),1.02-0.81(m,12H),0.73-0.61(m,4H).
实施例72
Figure PCTCN2016080635-appb-000170
参考如同实施例53，以实施例18A化合物为原料，纯化得到实施例72化合物(10.0毫克，收率56.0％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ＝4.82(br.s.,2H),4.33-4.15(m,2H),3.71(br.s.,1H),3.49-3.33(m,1H),2.00-1.87(m,4H),1.84-1.73(m,5H),1.71-1.56(m,12H),1.53-1.38(m,11H),0.99(d,J＝7.0Hz,5H),0.85(d,J＝7.5Hz,10H),0.69-0.66(m,1H).
路线19
Figure PCTCN2016080635-appb-000171
实施例73
Figure PCTCN2016080635-appb-000172
实施例19A
Figure PCTCN2016080635-appb-000173
将实施例15A化合物(1.5克，2.7毫摩尔)溶于N-甲基吡咯烷酮(8.0毫升)，依次加入叠氮钠(1.5克，23.1毫摩尔)和醋酸(1.9克，32.3毫摩尔)，反应液于20摄氏度搅拌20小时。加入饱和碳酸氢钠水溶液(5毫升)淬灭反应，用乙酸乙酯萃取(20毫升×3)。有机层经水洗涤(10毫升×4)，无水硫酸钠干燥，过滤和浓缩，所得残留物经柱层析(硅胶)分离得到实施例19A化合物(1.2克，产率89.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.77-4.65(m,1H),3.35(ddd,J＝4.8,8.2,12.4Hz,1H),3.20(td,J＝7.9,12.2Hz,1H),1.99-1.70(m,10H),1.51-1.42(m,3H),1.18-1.08(m,5H),0.67(s,3H).
实施例19B
Figure PCTCN2016080635-appb-000174
将实施例19A化合物(1.0克，2.1毫摩尔)溶于四氢呋喃(20.0毫升)，在氮气保护下，依次加入三苯基膦(1.7克，6.3毫摩尔)和水(1.0毫升)，反应液20度搅拌十二小时。浓缩除去溶剂，所得残留物经薄层层析色谱得到实施例19B化合物(500.0毫克，产率50.3％)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.20(br.s.,1H),4.77-4.65(m,1H),3.02(br.s.,1H),2.89(br.s.,1H),2.01-1.70(m,14H),1.60-1.47(m,13H),1.21-1.13(m,18H),0.96(s,8H),0.79(d,J＝2.5Hz,7H),0.68(s,3H).
实施例19C
Figure PCTCN2016080635-appb-000175
将实施例19B化合物(50.0毫克，111.7微摩尔)溶于N，N-二甲基甲酰胺(1.0毫升)和二氯甲烷(2.0毫升)，在0度下，依次加入碳酸氢钠(28.2毫克，335.1微摩尔)的水溶液(1.0毫升)和硫光气(15.4毫 克，134.0微摩尔)，反应液于20度反应三十分钟，加入水(10毫升)，二氯甲烷萃取(10毫升×3)。有机层依次用水(10毫升)和饱和食盐水(10毫升)洗涤，经无水硫酸钠干燥，过滤浓缩，所得残留物溶于四氢呋喃(4.0毫升)中，在20摄氏度，依次加入(3R)-3-羟基吡咯盐酸盐(11.7毫克，94.5微摩尔)和三乙胺(13.6毫克，134.0微摩尔)，反应液于80摄氏度搅拌4小时。浓缩除去溶剂，向残留物中加入水(5毫升)，乙酸乙酯萃取(10毫升×3)。有机层经水洗涤(10毫升)，无水硫酸钠干燥，过滤和浓缩，残留物经薄层层析色谱分离得到实施例19C化合物(40.0毫克，产率62.0％)。1H NMR(400MHz,METHANOL-d4)δ8.22(s,1H),8.08(s,1H),5.21(br.s.,1H),4.73-4.60(m,1H),4.44(br.s.,1H),3.77-3.57(m,3H),3.53-3.42(m,1H),2.11-1.85(m,7H),1.75(d,J＝11.0Hz,3H),1.62-1.45(m,7H),1.26-1.10(m,10H),1.08-1.02(m,5H),0.88-0.81(m,6H),0.74(s,3H).
实施例73
Figure PCTCN2016080635-appb-000176
参考实施例53，以实施例19C化合物为原料，纯化得到实施例73化合物(27.0毫克，产率71％)。1H NMR(400MHz,CHLOROFORM-d)δ5.27(t,J＝4.5Hz,1H),4.52(br.s.,1H),3.69(br.s.,5H),3.60-3.48(m,1H),3.45-3.33(m,1H),2.13-2.05(m,2H),2.01-1.89（m,2H),1.86-1.57(m,9H),1.52-1.28(m,12H),1.20-1.15(m,2H),1.00(d,J＝6.3Hz,4H),0.89-0.85(m,5H),0.60(br.s.,3H).
路线20
Figure PCTCN2016080635-appb-000177
实施例74
Figure PCTCN2016080635-appb-000178
实施例20A
Figure PCTCN2016080635-appb-000179
将实施例19B化合物(80.0毫克，178.7微摩尔)溶于二氯甲烷(4.0毫升)，然后依次加入二异丙基乙胺(34.6毫克，268.1微摩尔)和2-异丙基异氰酸酯(27.1毫克，268.1微摩尔)，反应液于20度搅拌12小时。浓缩除去溶剂，所得残留物经薄层层析色谱分离得到实施例20A化合物(60.0毫克，产率58.0％)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.78-4.63(m,1H),3.53-3.19(m,2H),1.98(d,J＝12.3Hz,1H),1.92-1.84(m,2H),1.82-1.60(m,8H),1.53-1.40(m,6H),1.24(d,J＝6.5Hz,7H),1.21-1.08(m,7H),0.98(d,J＝6.5Hz,3H),0.95(s,3H),0.87(d,J＝4.0Hz,4H),0.80-0.76(m,1H),0.65(s,3H).
实施例74
Figure PCTCN2016080635-appb-000180
参考实施例53，以实施例20A化合物为原料，得到实施例74化合物(48.0毫克，产率85.0％)。1H NMR(400MHz,METHANOL-d4)δ3.67(br.s.,1H),3.56(br.s.,1H),3.36(br.s.,1H),2.03(d,J＝12.0Hz,1H),2.00-1.82(m,4H),1.81-1.72(m,3H),1.65-1.48(m,7H),1.44-1.28(m,8H),1.19(d,J＝6.5Hz,6H),1.03(d,J＝6.3Hz,3H),0.93-0.86(m,5H),0.73(s,3H).
路线21
Figure PCTCN2016080635-appb-000181
实施例75
Figure PCTCN2016080635-appb-000182
实施例21A
Figure PCTCN2016080635-appb-000183
将实施例12A化合物(5.0克，11.5毫摩尔)溶于无水甲苯(80.0毫升)中，然后加入碳酸银/硅藻土(12.6克，46.0毫摩尔)，反应液于130摄氏度下搅拌十二小时。冷至室温后，浓缩除去溶剂。残留物经柱层析(硅胶)得到实施例21A化合物(3.6克，产率69.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.78(br.s.,1H),3.67(s,3H),3.07(t,J＝14.6Hz,1H),2.47-2.31(m,2H),2.28-2.09(m,3H),2.06-1.87(m,4H),1.75-1.17(m,21H),1.00(s,3H),0.95-0.83(m,10H),0.70(s,3H).
实施例21B
Figure PCTCN2016080635-appb-000184
在氮气保护下，向钠氢(40.0毫克，1.7毫摩尔)的无水甲苯悬浊液(20毫升)中滴加实施例21A化合物(601.4毫克，1.4毫摩尔)的甲苯溶液(3毫升)，然后再逐滴加入甲酸乙酯(308.9毫克，4.2毫摩尔)的甲苯溶液(2毫升)，20摄氏度搅拌1小时。然后加入无水乙醇(76.8毫克，1.7毫摩尔)，继续搅拌11小时。将反应液倒入冰水中，乙酸乙酯萃取(20毫升×3)，合并的有机相经饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤和浓缩得到实施例21B化合物(500.0毫克，72.0％产率)。1H NMR(400MHz,CHLOROFORM-d)δ14.29(br.s.,1H),8.20(s,1H),4.14(q,J＝7.0Hz,3H),3.79(br.s.,1H),3.68(s,1H),3.41-3.29(m,1H),2.27-2.16(m,2H),1.88-1.76(m,2H),1.56-1.30(m,15H),1.20-1.11(m,4H),1.05(s,3H),0.99-0.90(m,9H),0.69(s,3H).
实施例21C
Figure PCTCN2016080635-appb-000185
将实施例21B化合物(100.0毫克，210.7微摩尔)溶于乙醇(3.00毫升)，向所得溶液中加入水合肼(21.1毫克，421.4微摩尔)，反应液在80摄氏度下搅拌1小时。浓缩除去溶剂，所得残留物经薄层层析色谱分离得到标题化合物21C(65.0毫克，产率62.0％，白色固体)。1H NMR(400MHz,CHLOROFORM-d)δ7.32(br.s.,1H),4.11(q,J＝7.1Hz,3H),3.81(br.s.,1H),3.55-3.44(m,1H),2.78(d,J＝15.8Hz,1H),2.62(dd,J＝6.9,17.7Hz,1H),2.43-2.26(m,1H),2.23-2.09(m,3H),1.96-1.73(m,7H),1.67-1.52(m,4H),1.46-1.35(m,3H),1.30-1.20(m,7H),1.10-1.03(m,5H),0.89(d,J＝6.3Hz,4H),0.66(s,3H).
实施例75
Figure PCTCN2016080635-appb-000186
将实施例21C化合物(65.0毫克，138.1微摩尔)溶于四氢呋喃(4.0毫升)中，然后加入氢氧化钠(55.2毫克，1.4毫摩尔)的水溶液(2.0毫升)，反应液于30摄氏度搅拌12小时。用1N的稀盐酸酸化至pH为2-3，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，所得残留物经薄层层析色谱分离得到实施例75化合物(14.0毫克，产率22.0％)。1H NMR(400MHz,METHANOL-d4)δ7.22(s,1H),3.77(br.s.,1H),3.62(dd,J＝10.8,17.6Hz,1H),2.82(d,J＝15.8Hz,1H),2.58(dd,J＝7.4,17.7Hz,1H),2.40-2.26(m,1H),2.23-2.08(m,2H),1.99-1.73(m,6H),1.69-1.47(m,4H),1.46-1.24(m,8H),1.12(s, 4H),1.00(t,J＝7.3Hz,3H),0.94(d,J＝6.5Hz,3H),0.72(s,3H).
路线22
Figure PCTCN2016080635-appb-000187
实施例76
Figure PCTCN2016080635-appb-000188
实施例22A
Figure PCTCN2016080635-appb-000189
将实施例21C化合物(90.0毫克，191.2微摩尔)溶于N，N-二甲基甲酰胺(4.0毫升)，然后加入硫酸二甲酯(440.0毫克，3.5毫摩尔)和碳酸钾(79.3毫克，573.6微摩尔)，反应液于30摄氏度搅拌12小时。浓缩除去溶剂，所得残留经薄层层析色谱分离得到实施例22A的混合物(20.0毫克，19.0％产率，白色固体)。1H NMR(400MHz,METHANOL-d4)δ7.15(s,1H),4.18-4.06(m，2H),3.78(s,3H),3.56(dt,J＝10.7,17.0Hz,1H),2.78(dd,J＝6.7,15.9Hz,1H),2.52(td,J＝6.3,17.7Hz,1H),2.41-2.27(m,1H),2.18(s,1H),1.98-1.52(m,11H),1.43-1.32(m,5H),1.25(t,J＝7.0Hz,4H),0.71(s,3H).
实施例76
Figure PCTCN2016080635-appb-000190
参考实施例53的操作方法，以实施例22A化合物(20.0毫克，37.1微摩尔)为原料，用LiOH脱除乙氧基，后经薄层层析色谱分离得到实施例76化合物(10.0毫克，产率50％)。1H NMR(400MHz,CHLOROFORM-d)δ7.17(s,1H),6.96(s,1H),3.81(s,3H),3.70(s,1H),2.74(d,J＝15.8Hz,1H),2.67-2.58(m,1H),2.58-2.20(m,3H),2.13(d,J＝15.8Hz,1H),1.94-1.69(m,5H),1.65-1.48(m,4H),1.48-1.22(m,10H),1.15-0.79(m,15H),0.67(s,3H).
路线23
Figure PCTCN2016080635-appb-000191
实施例77
Figure PCTCN2016080635-appb-000192
实施例23A
Figure PCTCN2016080635-appb-000193
将实施例21B化合物(400.0毫克，895.6微摩尔)溶于甲醇(10.0毫升)后，再加入硼氢化钠(203.3 毫克，5.4毫摩尔)，反应液于0摄氏度下搅拌1小时。加入饱和氯化铵溶液(5毫升)淬灭反应，浓缩除去溶剂，向残留物中加入水(5毫升)，用乙酸乙酯萃取(10毫升×3)。有机层经水洗涤(10毫升)，无水硫酸钠干燥，过滤和浓缩，所得残留物经薄层层析色谱得到实施例23A化合物(120.0毫克，产率28.0％，无色油状物)。1H NMR(400MHz,CHLOROFORM-d)δ4.10(q,J＝7.1Hz,2H),3.68(br.s.,1H),3.64(s,1H),3.38(tt,J＝5.1,10.0Hz,1H),2.39-2.27(m,1H),2.23-2.13(m,1H),1.98-1.84(m,3H),1.65-1.54(m,3H),1.45-1.36(m,5H),1.31-1.24(m,6H),1.17-1.10(m,3H),0.90(s,3H),0.67-0.61(m,3H).
实施例77
Figure PCTCN2016080635-appb-000194
以实施例23A化合物为原料(100.0毫克，208.9微摩尔)，参考实施例65的制备方法，经薄层层析色谱分离得到实施例77化合物(20.0毫克，产率20.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s.,1H),3.62(t,J＝5.6Hz,2H),3.47-3.36(m,1H),1.98(d,J＝12.0Hz,1H),1.92-1.75(m,5H),1.69-1.56(m,8H),1.51-1.39(m,9H),1.19-1.06(m,7H),0.95-0.92(m,4H),0.89-0.85(m,8H),0.82-0.76(m,2H),0.67(s,3H).
路线24
Figure PCTCN2016080635-appb-000195
实施例78
Figure PCTCN2016080635-appb-000196
实施例24A
Figure PCTCN2016080635-appb-000197
实施例21A化合物(10.0克，23.1毫摩尔)溶于吡啶(100毫升)中，加入醋酐(28.3克，277.4毫摩尔)和4-N，N-二甲基氨基吡啶(282.4毫克，2.3毫摩尔)，110摄氏度回流6小时，TLC检测反应结束，浓缩除去溶剂，所得残留物经薄层层析色谱分离得到实施例24A化合物(9.2克，产率84.0％)。1H NMR(400MHz,CHLOROFORM-d)δ5.19(br.s.,1H),3.68(s,3H),2.81(t,J＝14.3Hz,1H),2.49-2.39(m,1H),2.35-1.99(m,9H),1.94-1.73(m,5H),1.71-1.08(m,15H),1.09-1.00(m,3H),0.99-0.84(m,6H),0.75-0.63(m,3H).
实施例24B
Figure PCTCN2016080635-appb-000198
将二乙胺基三氟化硫(132.4毫克，821.6微摩尔)滴加到实施例24A化合物(130.0毫克，273.9微摩尔)的二氯甲烷(3.0毫升)溶液中，并在25-30摄氏度搅拌18小时。反应完成后，反应液用冰水淬灭，乙酸乙酯(10毫升×2)萃取、有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥、过滤，减压浓缩得到粗品。粗品经薄层层析制备板(石油醚/乙酸乙酯＝10/1)分离纯化得到实施例24B化合物(75.0毫克，产率50.1％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ0.67(s,3H)0.88-0.97(m,6H)0.97-1.04(m,3H)1.05-1.23(m,5H)1.32-1.41(m,3H)1.43-1.54(m,3H)1.57-1.69(m,6H)1.78-1.90(m,6H)1.96-2.04(m,1H)2.07-2.12(m,3H)2.12-2.31(m,2H)2.32-2.43(m,1H)3.68(s,3H)5.09-5.19(m,1H).
实施例78
Figure PCTCN2016080635-appb-000199
操作同标题化合物53，以化合物24B为原料(75.0毫克，151.0微摩尔)，反应处理并纯化得到标题化合物78(55.0毫克，产率74.0％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ0.69(s,3H)0.90-0.99(m, 9H)1.13-1.25(m,3H)1.31-1.54(m,10H)1.55-1.79(m,5H)1.80-1.87(m,3H)1.87-1.97(m,2H)1.97-2.03(m,1H)2.20-2.53(m,3H)3.75(br.s.,1H).
路线25
Figure PCTCN2016080635-appb-000200
实施例79A和79B
Figure PCTCN2016080635-appb-000201
实施例25A
Figure PCTCN2016080635-appb-000202
将一水合氢氧化锂(35.3毫克，1.5毫摩)加入到实施例24A化合物(100.0毫克，0.2毫摩尔)的甲醇(2毫升)和水(0.5毫升)的混合溶液中，20-25摄氏度搅拌18小时。待反应完成后，反应液用2M稀盐酸酸化后，用饱和食盐水(15毫升×2)洗涤，并用乙酸乙酯(10毫升×2)萃取，无水硫酸钠干燥过滤，滤液减压旋干。粗品经薄层层析制备板分离(二氯甲烷/甲醇＝20/1)得到实施例25A化合物(60.0毫克，产率88.0％)。1H NMR(400MHz,CHLOROFORM-d)δ＝5.17(br.s.,1H)2.70-2.89(m,1H)2.34-2.49(m,2H)2.23(d,J＝3.51Hz,3H)2.06(s,3H)1.98-2.05(m,2H)1.74-1.90(m,5H)1.60-1.70(m,1H)1.29-1.58(m,8H) 1.08-1.24(m,5H)1.01-1.06(m,3H)0.86-0.97(m,6H)0.63-0.72(m,3H).
实施例25B
Figure PCTCN2016080635-appb-000203
0摄氏度氮气保护下，将甲基溴化镁(0.4毫升，651.2微摩，3N)的乙醚溶液滴加到实施例25A化合物(60.0毫克，130.2微摩)的四氢呋喃(4毫升)溶液中并搅拌2小时。反应完成后，用饱和氯化铵溶液淬灭，乙酸乙酯(10毫升×2)萃取。有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥过滤并减压浓缩。粗品经薄层层析制备板分离(二氯甲烷/甲醇＝20/1)得到实施例25B化合物。
实施例25B1化合物(35.0毫克，产率56.0％)。1H NMR(400MHz,CHLOROFORM-d)δ5.03-5.14(m,1H)2.31-2.43(m,1H)2.18-2.30(m,1H)2.04(s,3H)1.90-2.00(m,1H)1.72-1.86(m,4H)1.53-1.69(m,4H)1.26-1.51(m,11H)1.19-1.23(m,3H)1.01-1.17(m,5H)0.94-0.99(m,3H)0.85-0.94(m,6H)0.64(s,3H).
实施例25B2化合物(15.0毫克，产率24.0％)。1H NMR(400MHz,CHLOROFORM-d)δ5.04-5.13(m,1H)2.33-2.42(m,1H)2.19-2.30(m,1H)2.05-2.09(m,3H)1.86-2.03(m,3H)1.73-1.84(m,5H)1.29-1.61(m,12H)1.21(s,3H)1.06-1.15(m,5H)0.90-0.95(m,6H)0.84-0.90(m,3H)0.59-0.67(m,3H).
实施例79A和79B
Figure PCTCN2016080635-appb-000204
将氢氧化钠(1.5克，37.5毫摩)加入到实施例25B1化合物(35.0毫克，73.4微摩)的甲醇(2.0毫升)溶液中，70-80摄氏度搅拌55小时。反应完成后，用2N的稀盐酸酸化至pH值约等于5，乙酸乙酯(8毫升×2)萃取，有机相用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，减压蒸干。粗品经薄层层析板(二氯甲烷/甲醇＝15/1)纯化得到实施例79A化合物(20.0毫克，产率63.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.66-3.77(m,1H)2.33-2.44(m,1H)2.19-2.30(m,1H)1.76-1.99(m,4H)1.53-1.73(m,5H)1.29-1.51(m,12H)1.25-1.27(m,1H)1.10-1.23(m,6H)0.79-1.01(m,9H)0.66(s,3H).
操作同实施例79A化合物，以实施例25B2化合物(15.0毫克，31.5微摩)为原料，粗品经薄层层析(二氯甲烷/甲醇＝15/1)纯化得到实施例79B化合物(6.0毫克，产率44.0％)。1H NMR(400MHz,CHLOROFORM-d)δ3.62-3.72(m,1H),2.33-2.46(m,1H),2.19-2.30(m,1H),1.87-2.08(m,3H),1.72-1.86(m,3H),1.52-1.69(m,3H),1.27-1.52(m,13H),1.19(s,3H),1.02-1.15(m,3H),0.87-0.95(m,9H),0.65(s,3H).
路线26
Figure PCTCN2016080635-appb-000205
实施例80
Figure PCTCN2016080635-appb-000206
实施例26A
Figure PCTCN2016080635-appb-000207
0摄氏度氮气保护下，将Tebbe试剂(0.5M甲苯溶液，0.1毫摩)加入到实施例24A化合物(60.0毫克，0.1微摩)的四氢呋喃(2.0毫升)溶液中。0摄氏度搅拌4小时后，升至25-30摄氏度搅拌16小时。将2毫升2M的氢氧化钠水溶液加到反应液中并过滤，滤液用乙酸乙酯(10毫升×2)萃取，有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥，过滤，减压旋干。粗品经薄层层析(石油醚/乙酸乙酯＝5/1)纯化，得到实施例26A化合物(33.0毫克，产率55.0％)。1H NMR(400MHz,CHLOROFORM-d)δ5.02-5.19(m,1H)4.56 (br.s.,2H)3.67(s,3H)2.42-2.56(m,1H)2.31-2.42(m,1H)2.20-2.29(m,1H)2.10-2.20(m,1H)2.07(s,3H)1.72-2.04(m,8H)1.58-1.71(m,2H)1.47-1.57(m,2H)1.30-1.47(m,5H)1.02-1.24(m,6H)0.83-0.99(m,9H)0.67(s,3H).
实施例26B
Figure PCTCN2016080635-appb-000208
氮气保护下，将二乙基锌(22.9毫克，185.8微摩)和二碘甲烷(79.6毫克，297.2微摩)依次加入到实施例26A化合物(40.0毫克，92.9微摩)的甲苯(2.0毫升)溶液中。25-30摄氏度搅拌0.5小时，此过程中反应液逐步变为白色悬浊液。之后用氧气置换氮气，此过程中悬浊液由白色变为粉色。之后反应液在65-75摄氏度搅拌3.5小时，此过程中悬浊液由粉色变为浅黄色。反应完成后，反应液冷却至室温，用饱和氯化氨溶液(10毫升)淬灭，乙酸乙酯(10毫升×3)萃取，有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥，过滤，减压旋干。粗品经薄层层析(石油醚/乙酸乙酯＝10/1)纯化，得到实施例26B化合物(30.0毫克，产率69％)。1H NMR(400MHz,CHLOROFORM-d)δ0.03-0.17(m,2H)0.20-0.30(m,2H)0.44-0.64(m,2H)0.68(s,3H)0.88(t,J＝7.40Hz,3H)0.92-0.97(m,6H)1.15-1.24(m,4H)1.28-1.55(m,11H)1.62-1.69(m,2H)1.71-1.87(m,4H)1.89-2.00(m,2H)2.22-2.29(m,1H)2.32-2.39(m,1H)3.68(s,3H)3.69-3.73(m,1H).
实施例80
Figure PCTCN2016080635-appb-000209
操作同实施例53，原料为化合物26B(30.0毫克，67.5微摩)，经薄层层析(石油醚/乙酸乙酯＝3/1)纯化得到标题化合物80(20.0毫克，产率65％)。1H NMR(400MHz,CHLOROFORM-d)δ0.03-0.16(m,2H)0.18-0.28(m,2H)0.43-0.62(m,2H)0.67(s,3H)0.84-0.89(m,3H)0.92-0.96(m,6H)1.12-1.23(m,4H)1.26-1.28(m,1H)1.28-1.38(m,4H)1.38-1.45(m,3H)1.45-1.54(m,3H)1.60-1.68(m,2H)1.72-1.77(m,1H)1.79-1.85(m,2H)1.87-1.93(m,1H)1.93-1.99(m,1H)2.20-2.33(m,2H)2.36-2.45(m,1H)3.65-3.73(m,1H).
路线27
Figure PCTCN2016080635-appb-000210
实施例81
Figure PCTCN2016080635-appb-000211
实施例27A
Figure PCTCN2016080635-appb-000212
氮气保护下，将干钯/碳(5.0毫克)加入到化合物26A(33.0毫克，69.8微摩)的甲醇(4毫升)溶液中，并用氢气球置换三次后，将反应液在1个大气压的氢气下20-28摄氏度搅拌18小时。之后反应液过滤，减压旋干溶剂得到实施例27A化合物(25.0毫克，产率75％)。1H NMR(400MHz,CHLOROFORM-d)δ5.01-5.16(m,1H)3.68(s,3H)2.30-2.44(m,1H)2.17-2.29(m,1H)2.07(s,3H)1.92-2.05(m,2H)1.68-1.89(m,5H)1.41-1.62(m,5H)1.30-1.41(m,5H)1.09-1.23(m,6H)0.97-1.05(m,2H)0.83-0.95(m,13H)0.66(s,3H).
实施例81
Figure PCTCN2016080635-appb-000213
操作同实施例53，以化合物27A(50.0毫克，105.3微摩尔)为原料，粗品经薄层层析(石油醚/乙酸乙酯＝1/1)纯化得到标题化合物81(30.0毫克，产率68％)。1H NMR(400MHz,CHLOROFORM-d)δ3.66-3.78(m,1H)2.36-2.47(m,1H)2.22-2.33(m,1H)1.91-2.00(m,2H)1.78-1.88(m,2H)1.61-1.71(m,2H)1.43-1.55(m,6H)1.21-1.43(m,9H)1.20(br.s.,3H)0.98-1.07(m,2H)0.88-0.97(m,12H)0.68(s,3H).
路线28
Figure PCTCN2016080635-appb-000214
实施例82A和82B
Figure PCTCN2016080635-appb-000215
实施例28A
Figure PCTCN2016080635-appb-000216
将硼烷四氢呋喃溶液(1M，58.0微摩)加入到实施例26A化合物(25.0毫克，58.0微摩)的四氢呋喃(1.5毫升)溶液中，25-30摄氏度搅拌4小时。反应完成后，将反应液冷却至0摄氏度，并依次加入水(0.1毫升)，5摩尔的氢氧化钠水溶液(0.2毫升)和双氧水(30％水溶液，6.9毫摩)。25-30摄氏度搅拌3小时。反应完成后，反应液用饱和亚硫酸钠溶液(2毫升)淬灭，乙酸乙酯(8毫升×2)萃取，有机相用饱和食盐水(10毫升×2)洗涤，用无水硫酸钠干燥，过滤，减压旋干。粗品经薄层层析(石油醚/乙酸乙酯＝3/1)纯化得到实施例28A1化合物(6.0毫克，产率14％，纯度60％)。1H NMR(400MHz,CHLOROFORM-d)δ3.70-3.75(m,1H),3.68(s,3H),3.57-3.67(m,2H),2.32-2.42(m,1H),2.19-2.29(m,1H),1.76-2.03(m,6H), 1.54-1.69(m,6H),1.33-1.50(m,10H),1.13-1.23(m,4H),0.88-0.97(m,9H),0.68(s,3H).和实施例28A1化合物(9.0毫克，产率28％，纯度80％)。1H NMR(400MHz,CHLOROFORM-d)δ3.69-3.74(m,1H),3.66(s,3H),3.41-3.51(m,2H),2.29-2.40(m,1H),2.16-2.27(m,1H),1.84-1.97(m,3H),1.67-1.82(m,3H),1.56-1.66(m,6H),1.39-1.51(m,8H),1.30(d,J＝3.01Hz,2H),1.06-1.22(m,4H),0.91(s,9H),0.66(s,3H).
实施例82A和82B
Figure PCTCN2016080635-appb-000217
操作同实施例53，化合物28A1(35.0毫克，78.0微摩)和28A2(25.0毫克，55.7微摩)为原料，粗品经薄层层析(石油醚/乙酸乙酯/醋酸＝20毫升/20毫升/1滴)纯化得到实施例82A化合物和实施例82B化合物。
实施例82A化合物(15.0毫克，产率44％)1H NMR(400MHz,CHLOROFORM-d)δ3.68-3.74(m,1H),3.54-3.68(m,2H),2.30-2.44(m,1H),2.17-2.30(m,1H),1.74-2.03(m,6H),1.28-1.70(m,15H),1.06-1.24(m,5H),0.81-0.98(m,9H),0.65(s,3H).
实施例82B化合物(10.0毫克，产率39％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d)δ3.66-3.77(m,1H),3.41-3.48(m,2H),2.33-2.44(m,1H),2.19-2.30(m,1H),1.80-1.94(m,3H),1.58-1.71(m,3H),1.42-1.54(m,7H),1.29-1.41(m,5H),1.23-1.25(m,3H),1.12-1.21(m,3H),0.98-1.09(m,2H),0.87-0.94(m,9H),0.65(s,3H).
路线29
Figure PCTCN2016080635-appb-000218
实施例83
Figure PCTCN2016080635-appb-000219
0摄氏度下，将钠氢(13.2毫克，552.2微摩尔)加入到化合物11A(40.0毫克，92.0微摩尔)的N,N-二甲基甲酰胺(1毫升)和四氢呋喃(2毫升)混合溶液中搅拌5分钟后，将碘甲烷(270.0毫克，1.9毫摩尔)加入到反应液中，25-30摄氏度搅拌18小时。薄层制备层析板监测显示反应完成后，反应液用乙酸乙酯(10毫升×2)萃取、有机相用饱和食盐水(15毫升×2)洗涤、无水硫酸钠干燥、过滤。滤液减压浓缩的粗品经薄层层析柱纯化(石油醚/乙酸乙酯＝7/3)得到实施例83化合物(20毫克，产率48％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d)δ0.68(s,3H)0.89-1.00(m,10H)1.11-1.21(m,3H)1.31-1.70(m,12H)1.71-2.02(m,9H)2.22-2.32(m,1H)2.37-2.48(m,1H)2.93-3.06(m,1H)3.36(s,3H)3.68-3.75(m,1H).
路线30
Figure PCTCN2016080635-appb-000220
实施例84
Figure PCTCN2016080635-appb-000221
实施例30A
Figure PCTCN2016080635-appb-000222
零下60摄氏度并在氮气保护下，将正丁基锂(0.1毫升，2.5摩每升的正己烷溶液)加入到甲氧甲基三苯基氯化磷(151.7毫克，442.4微摩尔)的乙醚(5.0毫升)溶液中后，反应液在25-30摄氏度搅拌半小时，期间血红色的膦叶立德生成。然后在冰浴下，将实施例24A化合物(70.0毫克，147.5微摩尔)的四氢呋喃(2.0毫升)溶液滴加到反应液中，25-30摄氏度搅拌3小时。反应液用饱和氯化氨溶液淬灭，之后用乙酸乙酯(10毫升×2)萃取。有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥、过滤，减压浓缩得到粗品。粗品经薄层层析制备板分离纯化得到实施例30A化合物(30.0毫克，产率38％，纯度95％)。1H NMR(400MHz,CHLOROFORM-d)δ0.55-0.72(m,3H)0.82-0.94(m,10H)1.03-1.20(m,5H)1.23-1.34(m,7H)1.44-1.54(m,2H)1.57-1.63(m,1H)1.69-1.88(m,7H)1.90-1.99(m,2H)2.05(d,J＝3.51Hz,3H)2.17-2.27(m,1H)2.31-2.38(m,1H)2.42-2.59(m,1H)3.44-3.58(m,3H)3.58-3.75(m,3H)4.96-5.15(m,1H)5.74(s,1H).
实施例30B
Figure PCTCN2016080635-appb-000223
将浓盐酸(12M，200.0微升)滴加到实施例30A化合物(30.0毫克，59.7微摩尔)的二氧六环(2.0毫升)溶液中，25-30摄氏度搅拌2小时。反应完成后，反应液用乙酸乙酯(10毫升×2)萃取，有机相用饱和食盐水(15毫升×2)洗涤，无水硫酸钠干燥、过滤，减压浓缩得到粗品。粗品经薄层层析制备板(石油醚/乙酸乙酯＝8/1)分离纯化得到实施例30B化合物(15.0毫克，42％产率，纯度85％)。1H NMR(400MHz,CHLOROFORM-d)δ0.64(s,3H)0.82-0.94(m,7H)0.94-1.03(m,3H)1.04-1.17(m,5H)1.31-1.39(m,3H)1.40-1.52(m,3H)1.55-1.62(m,1H)1.68(br.s.,6H)1.74-1.89(m,4H)1.92-1.99(m,2H)2.04(s,6H)2.15-2.25(m,1H)2.28-2.38(m,1H)3.66(d,J＝2.01Hz,1H)3.70(s,1H)5.04-5.13(m,1H)9.62-9.65(m,1H).
实施例30C
Figure PCTCN2016080635-appb-000224
将二乙胺基三氟化硫(82.5毫克，511.6微摩尔)滴加到实施例30B化合物(50.0毫克，102.3微摩尔)的二氯甲烷(2.0毫升)溶液中，并在25-30摄氏度搅拌36小时。反应完成后，反应液用冰水淬灭，乙酸乙酯(10毫升×3)萃取，有机相用饱和食盐水(15毫升×3)洗涤，无水硫酸钠干燥、过滤，减压浓缩得到粗品。粗品经薄层层析制备板(石油醚/乙酸乙酯＝8/1)分离纯化得到实施例30C化合物(40.0毫克，产率69％，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ0.66(s,3H)0.87-1.00(m,9H)1.02-1.21(m,6H)1.28(br.s.,6H)1.42-1.55(m,4H)1.55-1.72(m,5H)1.75-1.87(m,3H)1.91-2.02(m,2H)2.04-2.09(m,3H)2.17-2.29(m,1H)2.31-2.42(m,1H)3.68(s,3H)5.06-5.17(m,1H)5.40-5.75(m,1H).
实施例84
Figure PCTCN2016080635-appb-000225
以化合物30C(40.0毫克，78.33微摩尔)为原料，操作同实施例53，反应后处理所得粗品经薄层层析制备板(石油醚/乙酸乙酯＝3/1)分离纯化得到实施例84化合物(25.0毫克，产率67％，纯度95％)，为白色固体。1H NMR(400MHz,CHLOROFORM-d)δ0.66(s,3H)0.85-0.95(m,9H)0.95-1.04(m,1H)1.07-1.22(m,4H)1.24-1.25(m,1H)1.27-1.54(m,10H)1.54-2.00(m,10H)2.18-2.31(m,1H)2.33-2.45(m,1H)3.71(br.s.,1H)5.32-6.09(m,1H).
路线31
Figure PCTCN2016080635-appb-000226
实施例85
Figure PCTCN2016080635-appb-000227
实施例31A
Figure PCTCN2016080635-appb-000228
将化合物19B(20.0毫克，44.7毫摩尔)溶于二氯甲烷(3.0毫升)，依次加入N，N-二甲基-4-氨基吡啶(1.1毫克，9.0毫摩尔)和苯基磺酰氯(11.8毫克，67.0毫摩尔)的二氯甲烷溶液(1毫升)，20摄氏度搅拌12小时。浓缩除去溶剂，所得残留物经薄层层析色谱分离得到实施例31A化合物(12.0毫克，产率48％，近无色液体)。1H NMR(400MHz,CHLOROFORM-d)δ8.13(s,1H),7.87(d,J＝7.5Hz,2H),7.62-7.48(m,3H),5.17(br.s.,1H),3.52-3.47(m,2H),3.08-2.99(m,1H),2.97-2.88(m,1H),1.94-1.67(m,8H),1.51-1.24(m,10H),1.20-0.99(m,9H),0.93-0.81(m,9H),0.60(s,3H).
实施例85
Figure PCTCN2016080635-appb-000229
参考同实施例53的操作步骤，以化合物31A为原料(42.0毫克，75.0毫摩尔)，纯化得到实施例85化合物(15.0毫克，产率37.59％)。1H NMR(400MHz,CHLOROFORM-d)δ7.87(d,J＝7.3Hz,2H),7.62-7.56(m,1H),7.56-7.50(m,2H),4.31(t,J＝5.9Hz,1H),3.48-3.32(m,1H),3.10-2.86(m,2H),1.92(d,J＝12.0Hz,1H),1.86-1.71(m,5H),1.69-1.52(m，7H),1.50-1.25(m,11H),1.20-1.06(m,5H),0.89(s,4H),0.85(d,J＝6.5Hz,3H),0.66-0.55(m,3H).
实施例86和实施例87的制备参考实施例85的操作，通过路线31制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000230
路线32
Figure PCTCN2016080635-appb-000231
实施例88
Figure PCTCN2016080635-appb-000232
20摄氏度下，将碳酸钾(27.8毫克，27.8微摩尔)和硫酸二甲酯(25.3毫克，25.3微摩尔)加入实施例2化合物(40.0毫克，80.4微摩尔)的丙酮(1.0毫升)溶液中。混合搅拌12小时。薄层色谱(石油醚/乙酸乙酯＝1/2)检测反应完全。减压旋蒸出溶剂，并用薄层制备板(石油醚/乙酸乙酯＝1/2)分离纯化得实施例88化合物(23.0毫克，收率13％，白色固体)。1H NMR(400MHz,METHANOL-d4)δ3.68(br.s.,1H),3.29(s,6H),2.81-2.53(m,2H),2.02-1.29(m,20H),1.23-0.98(m,7H),0.96-0.87(m,6H),0.73(s,3H).
路线33
Figure PCTCN2016080635-appb-000233
实施例89
Figure PCTCN2016080635-appb-000234
实施例33A
Figure PCTCN2016080635-appb-000235
向实施例11A化合物(5.0克，11.5毫摩尔)的吡啶溶液(20毫升)中加醋酸酐(7.1克，69.1毫摩尔)和N,N二甲氨基吡啶(140.5毫克，1.2毫摩尔)，反应液在80摄氏度下搅拌12小时。旋干溶剂，体系用饱和碳酸氢钠水溶液(10毫升)洗，反应体系用乙酸乙酯(15毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发得到实施例33A化合物(5.0克，84％产率)。1H-NMR(CDCl3,400MHz)δ5.10(br.s.,1H),4.43(d,J＝5.0Hz,1H),3.67(s,3H),2.40-2.18(m,2H),2.08(s,3H),2.05(s,3H),1.90-1.67(m,9H),1.52-1.29(m,10H),1.17-0.99(m,6H),0.94-0.91(m,6H),0.91-0.87(m,3H),0.65(s,3H)。
实施例33B
Figure PCTCN2016080635-appb-000236
向实施例33A化合物(100.0毫克，193.0微摩尔)的甲醇溶液中加盐酸(12M，0.2毫升)混合物在20摄氏度下搅拌12小时。旋干溶剂，体系用饱和碳酸氢钠水溶液(10毫升)洗，反应体系用乙酸乙酯(15毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发得到实施例33B化合物(90.0毫克，98％产率)。1H-NMR(CDCl3,400MHz)δ5.10(br.s.,1H),3.67(s,3H),3.47(d,J＝5.0Hz,1H),2.40-2.18(m,2H),2.08(s,3H),1.90-1.67(m,9H),1.52-1.29(m,10H),1.17-0.99(m,6H),0.94-0.91(m,6H),0.91-0.87(m,3H),0.65(s,3H)。
实施例33C
Figure PCTCN2016080635-appb-000237
向实施例33B化合物(100.0毫克，209.0微摩尔)，三苯基磷(304.0毫克，1.2毫摩尔)和咪唑(83.0毫克，1.2微摩尔)的甲苯(8毫升)和乙腈溶液(2毫升)加碘(266.0毫克，1.1毫摩尔)。20摄氏度下反应1小时，饱和亚硫酸钠溶液(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，硫酸钠干燥，过滤并蒸发，残余物通过制备薄层板纯化(石油醚/乙酸乙酯＝10/1)得到实施例33C 化合物(100.0毫克，81％)。1H-NMR(CDCl3,400MHz)δ5.07(br.s.,1H),5.01(br.s.,1H),3.71-3.60(m,3H),2.39-2.29(m,1H),2.27-2.15(m,1H),2.04(s,3H),2.00-1.93(m,1H),1.88-1.74(m,6H),1.73-1.58(m,5H),1.55-1.38(m,4H),1.36-1.20(m,5H),1.17-1.06(m,4H),1.03(s,3H),0.93-0.87(m,6H),0.68-0.61(m,3H)。
实施例33D
Figure PCTCN2016080635-appb-000238
向实施例33C化合物(2.3克，3.9毫摩尔)，吡唑(534.0毫克，7.8毫摩尔)的DMF(30毫升)加碳酸钾(1.0克，7.8毫摩尔)。60摄氏度下反应12小时，水(50毫升)加入反应体系，水层用乙酸乙酯(30毫升×3)萃取，合并有机层，硫酸钠干燥，过滤并蒸发，残余物通过柱色谱纯化(石油醚/乙酸乙酯＝20/1)得到实施例33D化合物(1.4克，78％)。1H NMR(CDCl3,400MHz)δ5.70-5.44(m,2H),5.13(br.s.,1H),3.66(s,3H),2.57-2.47(m,1H),2.41-2.30(m,1H),2.25-2.16(m,2H),2.06(s,3H),1.96-1.64(m,9H),1.52-1.30(m,6H),1.25-1.05(m,6H),0.99(s,3H),0.93-0.88(m,6H),0.65(s,3H)。
实施例33E
Figure PCTCN2016080635-appb-000239
氮气保护，零度下向二碘甲烷(438.0毫克，1.6毫摩尔)的二氯甲烷溶液中滴加二乙基锌(1M，3.3毫升)，30分钟后，零度下滴加实施例33D化合物(150.0毫克，327.0微摩尔)的二氯甲烷(2毫升)溶液，20摄氏度下反应12小时。水(5毫升)加入反应体系，体系用盐酸溶液(1M)调至Ph＝6，水层用二氯甲烷(10毫升×3)萃取，合并有机层，硫酸钠干燥，过滤并蒸发得到实施例33E化合物(110.0毫克，71％)。1H NMR(CDCl3,400MHz)δ5.15-5.09(m,1H),3.68(s,3H),2.41-2.20(m,4H),2.13-2.08(m,3H),1.99(d,J＝12.0Hz,1H),1.90-1.70(m,5H),1.44-1.02(m,15H),0.95-0.87(m,6H),0.84(s,3H),0.82(d,J＝5.0Hz,1H),0.79-0.68(m,2H),0.67(s,3H),0.63(dd,J＝4.0,8.8Hz,1H)。
实施例89
Figure PCTCN2016080635-appb-000240
向实施例33E化合物(40.0毫克，84.3微摩尔)乙醇溶液(1毫升)加质量分数10％的氢氧化钾水溶液(1毫升)，混合物70摄氏度下反应12小时。体系用盐酸溶液(1M)调至Ph＝2，水层用乙酸乙酯(10毫升×3)萃取，合并有机层，硫酸钠干燥，过滤并蒸发。残余物通过制备薄层板纯化(石油醚/乙酸乙酯＝2/1)得到实施例89化合物(10.0毫克，28.36％)。1H NMR(CDCl3,400MHz)δ3.81-3.70(m,1H),2.58-2.43(m,1H),2.39(dd,J＝5.1,10.2Hz,1H),2.31-2.19(m,2H),1.98-1.76(m,5H),1.72-1.55(m,6H),1.46(dd,J＝5.5,10.5Hz,4H),1.23-1.02(m,6H),0.95-0.88(m,6H),0.82-0.78(m,3H),0.76-0.68(m,2H),0.68(s,3H),0.64(br.s.,1H),0.63-0.52(m,1H)。
路线34
Figure PCTCN2016080635-appb-000241
实施例34A
Figure PCTCN2016080635-appb-000242
向干燥的25毫升圆底烧瓶中加入干钯碳(50毫克，水<1％)和实施例33D化合物(600.0毫克，720.1微摩尔)，再加入无水甲醇(5.0毫升)和四氢呋喃(5.0毫升)，反应体系用氮气换气三次，然后再用氢气换气三次，反应液于氢气氛围中(15psi)，25摄氏度搅拌48小时。反应液用硅藻土过滤，二氯甲烷/甲醇洗涤(10/1，20毫升)，滤液浓缩得到实施例34A化合物(550.0毫克，91％产率)。1H NMR(400MHz,CHLOROFORM-d)δ5.13(br.s.,1H),3.68(s,3H),2.43-2.18(m,3H),2.06(s,3H),2.01-1.63(m,14H),1.55-1.15(m,25H),0.95(d,J＝6.5Hz,6H),0.91(s,6H),0.88(d,J＝2.3Hz,2H),0.70-0.66(m,3H).
实施例34B
Figure PCTCN2016080635-appb-000243
以实施例35A(550.0毫克，1.3毫摩尔)为原料，合成操作如同实施例53，得到实施例34B化合物(400.0毫克，75.3％产率)。1H NMR(400MHz,CHLOROFORM-d)δ3.72(br.s.,1H),2.48-2.35(m,1H),2.28(ddd,J＝6.4,9.5,15.7Hz,1H),2.02-1.87(m,3H),1.81(d,J＝13.3Hz,3H),1.77-1.60(m,5H),1.55-1.41(m,7H),1.39-1.26(m,7H),1.20-1.13(m,3H),1.08-1.02(m,1H),0.98-0.95(m,4H),0.92(s,3H),0.90-0.85(m,2H),0.70-0.67(m,3H).
实施例90
Figure PCTCN2016080635-appb-000244
操作同实施例2A，以实施例34B(100.0毫克，247.2微摩尔)为原料，进行酰化反应经纯化得到实施例90化合物(20.0毫克，16.8％产率)。1H NMR(400MHz,CHLOROFORM-d)δ3.72(br.s.,1H),3.32(s,3H),2.46-2.34(m,1H),2.30-2.18(m,1H),1.99-1.86(m,3H),1.85-1.77(m,3H),1.74-1.62(m,4H),1.56-1.40(m,8H),1.38-1.26(m,7H),1.22-1.16(m,3H),1.10-1.02(m,1H),0.97-0.93(m,4H),0.91(s,3H),0.90(d,J＝2.0Hz,1H),0.88(d,J＝3.0Hz,1H),0.71-0.66(m,3H).
路线35
Figure PCTCN2016080635-appb-000245
实施例91
Figure PCTCN2016080635-appb-000246
实施例35A
Figure PCTCN2016080635-appb-000247
将氢氧化钠(79.6毫克，2.0毫摩)加入到实施例13A化合物(1.2克，2.0毫摩)的甲醇(15.0毫升)和水(1.5毫升)溶液中，并在25-30摄氏度搅拌18小时。反应完成后，溶剂浓缩至5毫升，并用乙酸乙酯稀释至12毫升后，用2M稀盐酸和柠檬酸酸化至pH＝5-6，分层之后，有机相用饱和食盐水洗涤(25毫升×3)，乙酸乙酯(20毫升×3)萃取，有机相用无水硫酸钠干燥，过滤浓缩得到实施例35A化合物(1.1克，纯度90％)。1H NMR(400MHz,CHLOROFORM-d)δ0.63(s,3H)0.81-0.97(m,10H)0.98-1.23(m,4H)1.28-1.49(m,9H)1.57-1.76(m,6H)1.76-1.98(m,9H)2.04(s,2H)2.09(s,2H)2.17-2.31(m,1H)2.34-2.47(m,1H)3.34-3.52(m,3H)3.54-3.64(m,1H)3.87-4.05(m,2H)4.44-4.58(m,1H)4.66-4.79(m,1H)
实施例35B
Figure PCTCN2016080635-appb-000248
将二环己基碳二亚胺(1.3克，6.4毫摩)加入到实施例35A化合物(1.4克，2.1毫摩)和N-羟基琥珀酰亚胺(734.0毫克，6.4毫摩)在四氢呋喃(15.0毫升)和乙腈(1.5毫升)溶液中，在20-28摄氏度搅拌18小时。反应完成后，将混合物过滤，滤液真空旋干。所得粗品溶于12毫升N，N-二甲基甲酰胺中，并向其中加入氨水(910.0毫克，7.3毫摩)。反应液在50-60摄氏度搅拌20分钟。反应完成后，反应液冷却至室温，并用饱和食盐水洗涤(35毫升×2)，乙酸乙酯(20毫升×2)萃取，有机相用无水硫酸钠干燥，过滤后低压旋干得到实施例35B化合物(1.8克，产率94.8％，纯度67％)。1H NMR(400MHz,CHLOROFORM-d)δ4.74(dd,J＝3.8,7.8Hz,1H),4.52(dd,J＝3.6,7.9Hz,1H),4.04-3.86(m,2H),3.70-3.58(m,1H),3.54-3.37(m,3H),3.26-3.16(m,2H),2.36-2.08(m,3H),2.02-1.73(m,19H),1.70-1.03(m,42H), 0.99-0.80(m,10H),0.65(s,3H)
实施例35C
Figure PCTCN2016080635-appb-000249
将实施例35B化合物(2.0克，3.4毫摩尔)溶于四氢呋喃(20.0毫升)，零摄氏度时，分批加入四氢铝锂(1.0克，27.2毫摩尔)，反应液于七十摄氏度搅拌十二小时。冷却至零摄氏度，向反应液中逐滴加入水(2毫升)，用二氯甲烷/甲醇(10/1，30毫升×3)萃取。有机层经水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩。残留物经硅胶柱层析(预先用三乙胺(1毫升)于石油醚/乙酸乙酯中(10:1，10毫升)洗涤)得到实施例35C化合物(1.3克，69.1％产率)。1H NMR(400MHz,CHLOROFORM-d)δ4.76-4.68(m,1H),4.52(td,J＝4.3,8.0Hz,1H),4.00-3.87(m,2H),3.60(d,J＝10.3Hz,1H),3.51-3.36(m,3H),2.73-2.56(m,2H),1.99-1.91(m,2H),1.83(d,J＝10.5Hz,4H),1.71-1.67(m,4H),1.52(d,J＝3.5Hz,6H),1.39-1.29(m,5H),1.14-1.00(m,4H),0.93-0.91(m,2H),0.89(s,3H),0.86(d,J＝5.8Hz,2H),0.63(s,3H).
实施例35D
Figure PCTCN2016080635-appb-000250
将实施例35C化合物(200.0毫克，348.5微摩尔)溶于二氯甲烷(4.0毫升)，依次加入三乙胺(70.5毫克，697.0微摩尔)和苯基磺酰氯(123.1毫克，697.0微摩尔)，反应液于二十摄氏度搅拌十二小时。浓缩除去溶剂，残留物经薄层色谱分离得到实施例35D化合物(180.0毫克，72.3％产率)。1H NMR(400MHz,CHLOROFORM-d)δ7.89(d,J＝7.3Hz,2H),7.62-7.52(m,3H),4.75(d,J＝3.3Hz,1H),4.53(d,J＝3.5Hz,1H),4.34(d,J＝4.3Hz,1H),3.95(br.s.,2H),3.66-3.58(m,1H),3.48(br.s.,3H),3.06-2.88(m,2H),1.91-1.84(m,3H),1.73(br.s.,3H),1.55(br.s.,7H),1.41-1.24(m,8H),1.17-0.98(m,6H),0.91(br.s.,3H),0.61(d,J＝2.3Hz,3H).
实施例91
Figure PCTCN2016080635-appb-000251
将实施例35D化合物(140.0毫克，196.06微摩尔)溶于甲醇(5.0毫升)，加入一水合对甲苯磺酸(37.3毫克，196.0微摩尔)，反应液于二十摄氏度搅拌十二小时。浓缩除去溶剂，残留物经薄层色谱分离得到实施例91化合物(92.0毫克，85.9％产率)。H NMR(400MHz,CHLOROFORM-d)δ7.89(d,J＝7.3Hz,2H),7.62-7.56(m,1H),7.56-7.49(m,2H),4.95(d,J＝5.5Hz,1H),3.70(br.s.,1H),3.47-3.34(m,1H),3.01-2.81(m,2H),1.93(d,J＝12.0Hz,1H),1.84-1.74(m,4H),1.68-1.57(m,3H),1.52-1.28(m,14H),1.20-1.06(m,5H),1.04-0.96(m,2H),0.92(br.s.,2H),0.89(br.s.,3H),0.85(d,J＝6.5Hz,4H),0.62(s,3H).
实施例92和实施例93的制备参考实施例91的操作，通过路线35制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000252
路线36
Figure PCTCN2016080635-appb-000253
实施例94
Figure PCTCN2016080635-appb-000254
实施例36A
Figure PCTCN2016080635-appb-000255
将三甲基硅基异氰酸酯(361.3毫克，3.1毫摩尔，415.35微升)加入至实施例35C(1.5g，2.61毫摩尔)的二氯甲烷(10.0毫升)溶液中。反应液在25摄氏度搅拌12小时。TLC(二氯甲烷/甲醇＝10/1)显示反应完成。向反应液中加水5毫升，并用二氯甲烷(5毫升×3)萃取，合并有机层用食盐水10毫升(5毫升×2)洗涤，无水硫酸钠干燥，过滤浓缩得到实施例36A(1.4g，产率86.9％)。1H NMR(400MHz,CHLOROFORM-d)δ4.77-4.69(m,1H),4.60-4.47(m,2H),4.39(br.s.,2H),4.00-3.87(m,2H),3.60(d,J＝10.3Hz,1H),3.52-3.38(m,3H),3.20-3.01(m,2H),2.10-1.75(m,9H),1.63-0.98(m,29H),0.96-0.82(m,11H),0.62(s,3H)
实施例94
Figure PCTCN2016080635-appb-000256
参考实施例65的操作步骤，以实施36A为原料，经纯化得到实施例94化合物(692.0毫克，产率67.8％)。1H NMR(400MHz,CHLOROFORM-d)δ4.66(br.s.,1H),4.44(br.s.,1H),3.72(br.s.,1H),3.49-3.36(m,1H),3.14(dt,J＝6.3,13.2Hz,2H),1.99(d,J＝12.0Hz,1H),1.94-0.98(m,33H),0.97-0.87(m,9H),0.67(s,3H)
路线37
Figure PCTCN2016080635-appb-000257
实施例95
Figure PCTCN2016080635-appb-000258
实施例37A
Figure PCTCN2016080635-appb-000259
将实施例35C化合物(200.0毫克，357.2微摩尔)溶于二氯甲烷(2毫升)，加入三乙胺(72.3毫克，714.5微摩尔，99.0微升)，于0摄氏度下，加入单草酰氯乙酯(97.6毫克，714.5微摩尔，79.9微升)，溶于二氯甲烷(1毫升)，反应液于30摄氏度搅拌十二小时。浓缩除去溶剂，向残留物中加入水(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。残留物经薄层层析色谱分离得到实施例37A化合物(130.0毫克，54.0％产率)。1H NMR(400MHz,CHLOROFORM-d)δ7.11(d,J＝4.8Hz,1H),4.77-4.64(m,1H),4.53-4.41(m,1H),4.37-4.25(m,4H),3.99-3.87(m,1H),3.63-3.54(m,1H),3.44(dd,J＝5.5,10.8Hz,1H),3.36-3.20(m,2H),2.33-2.19(m,1H),1.98-1.90(m,2H),1.86-1.73(m,5H),1.60(d,J＝8.0Hz,3H),1.51(d,J＝3.0Hz,3H),1.38(s,4H),1.25(d,J＝7.0Hz,3H),1.13-1.05(m,3H),0.92(s,3H),0.86(d,J＝5.3Hz,2H),0.62(s,3H).
实施例95
Figure PCTCN2016080635-appb-000260
操作例同实施例53以及实施例65化合物，以实施例37A(150.0毫克，222.6微摩尔)经两步合成，纯化得到了实施例95化合物(6.0毫克，9.1％产率)。1H NMR(400MHz,METHANOL-d4)δ3.67(br.s.,1H),3.34-3.34(m,1H),2.95-2.87(m,2H),2.03(d,J＝12.0Hz,1H),1.93-1.73(m,6H),1.63-1.48(m,9H),1.39(br.s.,4H),1.26-1.14(m,4H),1.02(d,J＝6.3Hz,3H),0.95-0.89(m,8H),0.74-0.68(m,3H).
路线38
Figure PCTCN2016080635-appb-000261
实施例38A
Figure PCTCN2016080635-appb-000262
向100毫升三颈烧瓶中加入二氯甲烷(10毫升)，碳酸氢钠水溶液(292.8毫克，3.5毫摩尔)，溶于水(5.0毫升)和实施例35C化合物(100.0毫克，174.2微摩尔)，零摄氏度下一次性加入三光气(103.4毫克，348.5微摩尔)，反应液于零摄氏度搅拌一小时。反应液倒入分液漏斗，分出有机层，水相用二氯甲烷萃取(20毫升×2)。有机层经水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩得到中间体A。零摄氏度下，(3S)-羟基吡咯(43.1毫克，348.5微摩尔)和三乙胺(35.2毫克，348.5微摩尔)加入到中间体A的二氯甲烷溶于中(5毫升)，两小时后除去冰浴，反应液于三十摄氏度搅拌两小时。浓缩除去溶剂，残留物经薄层层析色谱分离得到实施例38A化合物(76.0毫克，63.5％产率)。1H NMR(400MHz, CHLOROFORM-d)δ4.76-4.68(m,1H),4.54-4.46(m,2H),4.24-4.12(m,1H),4.00-3.87(m,2H),3.62-3.56(m,1H),3.52-3.37(m,7H),3.23(br.s.,1H),3.15(br.s.,1H),2.06-1.93(m,4H),1.83(d,J＝11.0Hz,4H),1.73-1.66(m,4H),1.48(br.s.,2H),1.44-1.36(m,5H),1.29-1.23(m,3H),1.13-1.03(m,3H),0.92(br.s.,2H),0.89(s,3H),0.88-0.85(m,3H),0.62(s,3H).
实施例96
Figure PCTCN2016080635-appb-000263
以实施例38A(76.0毫克，110.6微摩尔)为原料，参考实施例65的操作步骤，经薄层层析色谱分离得到实施例96化合物(40.0毫克，69.7％产率)。1H NMR(400MHz,METHANOL-d4)δ4.43-4.38(m,1H),3.67(br.s.,1H),3.49-3.41(m,3H),3.34-3.33(m,1H),3.30(br.s.,1H),3.20-3.06(m,2H),2.02(qd,J＝4.3,13.1Hz,2H),1.95-1.90(m,2H),1.86(br.s.,1H),1.80-1.72(m,3H),1.69-1.63(m,2H),1.59-1.53(m,4H),1.46-1.41(m,3H),1.37(d,J＝2.0Hz,2H),1.31-1.31(m,3H),1.21-1.17(m,3H),1.11-1.07(m,2H),0.99(s,3H),0.92(s,3H),0.90(br.s.,3H),0.88(s,3H),0.71(s,3H).
路线39
Figure PCTCN2016080635-appb-000264
实施例97
Figure PCTCN2016080635-appb-000265
实施例39A
Figure PCTCN2016080635-appb-000266
将实施例35C(1.3克，2.3毫摩尔)溶于四氢呋喃(12毫升)，加入三乙胺(458.4毫克，4.5毫摩尔)，再滴加氯乙基异氰酸酯(478.1毫克，4.5毫摩尔)，溶于四氢呋喃(3毫升)，反应液于三十摄氏度搅拌十二小时。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。粗产物经薄层层析色谱分离得到实施例39A化合物(1.2克，77.8％产率)。1H NMR(400MHz,CHLOROFORM-d)δ5.03(br.s.,1H),4.79(br.s.,1H),4.72(d,J＝4.3Hz,1H),4.51(dd,J＝3.8,13.3Hz,1H),4.42(br.s.,1H),3.93(d,J＝5.8Hz,2H),3.63(s,2H),3.58-3.53(m,4H),3.47(d,J＝3.0Hz,2H),3.19-3.03(m,2H),1.83(d,J＝10.3Hz,4H),1.52(br.s.,7H),1.44-1.36(m,5H),1.30-1.23(m,5H),1.10-1.03(m,2H),0.92(d,J＝4.0Hz,2H),0.89(s,3H),0.71(s,3H).
实施例39B
Figure PCTCN2016080635-appb-000267
将钠氢(63.6毫克，2.6毫摩尔)(65％于矿物油中)悬浮于四氢呋喃(25毫升)，零摄氏度氮气保护下，逐滴加入实施例39A化合物(600.0毫克，883.1微摩尔)，溶于四氢呋喃(5毫升)。一小时后除去冰浴，于三十摄氏度继续搅拌十一小时。加入水(5毫升)，用一摩尔盐酸酸化(pH＝5-6)，乙酸乙酯萃取(20毫升×3)。有机层经水洗(10毫升)，无水硫酸钠干燥，过滤和浓缩。粗产物经薄层层析色谱分离得到实施例39B化合物(360.0毫克，63.4％产率)。1H NMR(400MHz,CHLOROFORM-d)δ8.95(s,1H),4.72(d,J＝4.3Hz,1H),4.51(dd,J＝3.8,7.8Hz,1H),3.99-3.89(m,2H),3.83-3.77(m,1H),3.67-3.56(m,2H),3.53-3.39(m,4H),3.28(t,J＝7.0Hz,1H),1.83(d,J＝11.5Hz,4H),1.69(d,J＝10.5Hz,5H),1.52(br.s.,6H),1.52-1.51(m,2H),1.42-1.36(m,4H),1.14-1.03(m,5H),0.89(br.s.,3H),0.87(d,J＝3.3Hz,4H),0.63(s,3H)。
实施例97
Figure PCTCN2016080635-appb-000268
以实施例39B化合物(360.0毫克，559.9微摩尔)为原料，合成操作例同实施例65，纯化得到实施例97化合物(200.0毫克，75.2％产率)。1H NMR(400MHz,METHANOL-d4)δ4.62(br.s.,1H),3.67(br.s.,1H),3.51-3.44(m,2H),3.43-3.37(m,2H),3.32-3.29(m,1H),3.13(t,J＝7.0Hz,2H),2.03(d,J＝12.3Hz,1H),1.97-1.72(m,6H),1.68-1.42(m,11H),1.32(d,J＝12.3Hz,6H),1.23-1.07(m,4H),0.99(d,J＝6.5Hz,3H),0.93(s,3H),0.90(d,J＝3.3Hz,2H),0.72(s,3H).
路线40
Figure PCTCN2016080635-appb-000269
实施例98
Figure PCTCN2016080635-appb-000270
实施例40A
Figure PCTCN2016080635-appb-000271
将实施例19B化合物(100.0毫克，223.4微摩尔)溶于二氯甲烷(2.0毫升)，在0摄氏度时，加入 三乙胺(33.9毫克，335.1微摩尔)，再加入氯代草酸单乙酯(61.0毫克，446.7微摩尔)，反应液于20摄氏度搅拌16小时。浓缩除去溶剂，残留物经薄层层析色谱分离得到实施例40A化合物(50.0毫克，91.29微摩尔，40.7％产率)。1H NMR(400MHz,CHLOROFORM-d)δ8.17(s,1H),8.09-8.04(m,1H),7.04(br.s.,1H),5.21(br.s.,1H),4.78-4.65(m,1H),4.37(q,J＝7.2Hz,2H),3.52-3.36(m,1H),3.35-3.23(m,1H),2.05-1.87(m,3H),1.83-1.71(m,4H),1.59(s,3H),1.54-1.47(m,3H),1.41(t,J＝7.2Hz,4H),1.34-1.27(m,4H),1.23-1.12(m,5H),1.00(d,J＝6.5Hz,3H),0.98(s,3H),0.92(t,J＝7.3Hz,3H),0.71-0.64(m,3H).
实施例98
Figure PCTCN2016080635-appb-000272
将实施例40A化合物(50.0毫克，91.2微摩尔)溶于四氢呋喃(1.0毫升)，甲醇(1.0毫升)和水(1.0毫升)，加入一水合氢氧化锂(76.6毫克，1.8毫摩尔)，反应液于25摄氏度搅拌十二小时。反应液用二氯甲烷/甲醇萃取(10/1，10毫升×3)，有机层经水洗(10毫升)，无水硫酸钠干燥和浓缩得到实施例98化合物(38.0毫克，89.7％产率)。1H NMR(400MHz,CHLOROFORM-d)δ7.32(br.s.,1H),3.71(br.s.,1H),3.42(d,J＝3.8Hz,2H),3.37-3.23(m,1H),1.96(d,J＝11.8Hz,1H),1.92-1.76(m,5H),1.73-1.56(m,5H),1.54-1.38(m,6H),1.37-1.25(m,7H),1.24-1.12(m,4H),0.99(d,J＝6.5Hz,4H),0.92(br.s.,1H),0.90(s,3H),0.88(br.s.,1H),0.66(s,3H)。
实施例99的制备参考实施例98的操作，通过路线40制备得到，所得结果如下：
Figure PCTCN2016080635-appb-000273
Figure PCTCN2016080635-appb-000274
路线41
Figure PCTCN2016080635-appb-000275
实施例100
Figure PCTCN2016080635-appb-000276
实施例41A
Figure PCTCN2016080635-appb-000277
向实施例2A化合物(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25摄氏度下反应2小时。体系冷却至摄氏度，硼氢化钠(210.0毫克，5.5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。0.2M的稀盐酸淬灭反应，水层用乙酸乙酯(10毫升×3)萃取，合并有机层，硫酸钠干燥，过滤并蒸发，残余物通过柱色谱(石油醚/乙酸乙酯＝4/1，二氯甲烷/乙酸乙酯＝1/1)纯 化得到实施例41A化合物(600.0毫克，粗品)。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41B
Figure PCTCN2016080635-appb-000278
零度下向实施例41A化合物(280.0毫克，605.0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)溶液中加入碘(461.0毫克，1.8毫摩尔)，反应体系25℃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，硫酸钠干燥，过滤并蒸发，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41B化合物(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41C
Figure PCTCN2016080635-appb-000279
向实施例41B化合物(400.0毫克，699微摩尔)的N,N-二甲基甲酰胺(5毫升)溶液中加入氰化钠(171.0毫克，3.5毫摩尔)，反应体系100摄氏度下反应2小时。水(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，硫酸钠干燥，过滤并蒸发得到标题化合物41C化合物(225.0毫克，68％)，1H NMR(400MHz,CHLOROFORM-d)δ8.15(d,J＝3.0Hz,1H),8.04(s,1H),5.19(br.s.,1H),4.77-4.66(m,1H),3.46(d,J＝4.5Hz,1H),2.37-2.25(m,2H),2.01-1.66(m,10H),1.39-1.03(m,12H),0.98-0.87(m,9H),0.66(d,J＝1.5Hz,3H)及3位脱甲酰基的产物(75毫克，24％)，1H NMR(400MHz,CHLOROFORM-d)δ＝8.14(s,1H),5.19(br.s.,1H),3.46(br.s.,1H),2.30(dt,J＝3.8,6.9Hz,2H),2.02-1.66(m,11H),1.43-1.03(m,17H),0.94-0.86(m,9H),0.66(s,3H)。
实施例41D
Figure PCTCN2016080635-appb-000280
实施例41C化合物(100.0毫克，212微摩尔)的30％氢氧化钾的甲醇：水(体积比1:1)(10毫升)溶液90摄氏度下反应16小时。水(10毫升)和乙酸乙酯(10毫升)加入反应体系，有机层用饱和氢氧化钾溶液(20毫升)洗涤，合并水层，水层用4M盐酸调至Ph＝4，水层用乙酸乙酯(20毫升×3)萃取，合并有机层，硫酸钠干燥，过滤并蒸发得到标题化合物41D化合物(85.0毫克，92％)，1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s.,1H),3.52-3.32(m,1H),2.33(qt,J＝7.9,16.0Hz,2H),2.00-1.33(m,22H),1.22-1.00(m,5H),0.96-0.83(m,8H),0.66(s,3H)。
实施例100
Figure PCTCN2016080635-appb-000281
25摄氏度下向实施例41D化合物(50.0毫克，115.0微摩尔)的二氯甲烷(1毫升)溶液中加环己基羰二酰亚胺(36.0毫克，172微摩尔)，N,N-二甲基吡啶(14.0毫克，115微摩尔)和甲基磺酰胺(16.0毫克，172微摩尔)，反应体系25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＝2，乙酸乙酯(10毫升×3)萃取，有机层经无水硫酸钠干燥，过滤，浓缩。残余物通过制备薄层板纯化(二氯甲烷/甲醇＝20/1)得实施例100化合物(15.0毫克，25％产率)。1H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.47-3.36(m,1H),3.28(s,3H),2.36-2.23(m,2H),1.95-1.40(m,20H),1.26-1.05(m,7H),0.95-0.88(m,9H),0.65(s,3H)。
路线42
Figure PCTCN2016080635-appb-000282
实施例101
Figure PCTCN2016080635-appb-000283
实施例42A
Figure PCTCN2016080635-appb-000284
氮气保护下，向参考例1A化合物(35.0克，89.6毫摩尔)的二氧六环(550毫升)溶液中加入一水对甲苯磺酸(1.5克，8.9毫摩尔)和二氢吡喃(11.3克，134.4毫摩尔)。TLC检测反应完毕，在50摄氏度下氢化2小时(50psi)。将溶剂部分蒸发，加水(50毫升)，用乙酸乙酯(50毫升×3)萃取。合并的有机层用盐水(50毫升)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标题化合物42A化合物(33.0克，77.5％产率)。1H NMR(400MHz,CHLOROFORM-d)δ4.67-4.76(m,1H),3.81-3.94(m,1H),3.39-3.65(m,2H),2.76-2.90(m,1H),2.18-2.43(m,4H),1.62-2.01(m,12H),1.29-1.59(m,12H),1.07-1.14(m,2H),0.92(d,J＝6.27Hz,3H),0.64(s,3H).
实施例42B
Figure PCTCN2016080635-appb-000285
零下78摄氏度氮气保护下，向四氢呋喃(100.0毫升)滴加二异丙基胺基锂(2摩尔每升，6.74毫升)，六甲基磷酸三胺(2.4克，13.4毫摩尔，2.4毫升)滴加到上述溶液中，滴加完后保持零下78摄氏度搅拌30分钟，然后化合物42A化合物(2.0克，4.2毫摩尔)的四氢呋喃溶液滴加到上述溶液中并保持零下78摄氏度搅拌30分钟，最后碘甲烷(4.9克，34.5毫摩尔)的四氢呋喃(8毫升)溶液缓慢加入反应器中，之后升到室温搅拌过夜。加饱和氯化铵(10毫升)摧灭，用10％柠檬酸调pH到4，加入水，20毫升，用乙酸乙酯萃取(200毫升×3)，将合并的有机层用饱和食盐水(100毫升)洗一次，有机相用无水硫酸钠干燥，过滤并蒸发得到标题化合物42B化合物(2.1克，粗品)，直接用于下一步反应。
实施例42C
Figure PCTCN2016080635-appb-000286
向实施例42B化合物(2.1克，4.2毫摩尔)的甲醇溶液加对甲苯磺酸(73.1毫克，424.0微摩尔)。反应加热到80摄氏度搅拌2小时，旋蒸蒸出主要溶剂(50摄氏度)加入水2毫升，用乙酸乙酯萃取(5毫升×3)，将合并的有机层用饱和碳酸氢钠(2毫升)饱和食盐水(5毫升)洗，有机相用无水硫酸钠干燥，过滤并蒸发，剩余物过柱纯化(石油醚/乙酸乙酯＝10/1到3/1)得到标题化合物42C化合物(350.0毫克，17.7％产率)。1HNMR(400MHz,CHLOROFORM-d)δ0.61-0.73(m,3H)0.93(d,J＝6.53Hz,3H)1.01(dd,J＝12.05,6.53Hz,1H)1.09-1.24(m,7H)1.26-1.38(m,6H)1.40-1.52(m,5H)1.62-1.87(m,6H)1.89-2.04(m,2H)2.06-2.15(m,1H)2.16-2.27(m,2H)2.31-2.40(m,1H)2.57(t,J＝11.29Hz,1H)3.59(br.s.,1H)3.67(s,3H)。
实施例42D
Figure PCTCN2016080635-appb-000287
向实施例42C化合物(340.0毫克，812.21微摩尔)加入氢氧化钠(105.5毫克，2.6毫摩尔)的水(60.0毫升)溶液，加热到80摄氏度，硼氢化钠(184.3毫克，4.8毫摩尔)分批加入，反应升温到100摄氏度搅拌8小时，冷却到15摄氏度，加饱和氯化铵(100毫升)摧灭，用1摩尔每升的稀盐酸调pH到2～3，用乙酸乙酯萃取(100毫升×3)，将合并的有机层用饱和食盐水(100毫升)洗，有机相用无水硫酸钠干燥，过滤并蒸发，剩余物过柱纯化(石油醚/乙酸乙酯＝2/1→1/2、加少量乙酸)得到标题化合物42D化合物(230.0毫克，62.6％产率)。1HNMR(400MHz,CHLOROFORM-d)δppm0.66(s,3H)0.86-1.05(m,11H)1.08-1.29(m,6H)1.30-1.54(m,7H)1.59-2.00(m,11H)2.26(ddd,J＝15.94,9.41,6.27Hz,1H)2.35-2.47(m,1H)3.36-3.47(m,1H)3.60(br.s.,1H)
实施例101
Figure PCTCN2016080635-appb-000288
20℃氮气保护下，混合物甲烷磺酰胺(16.4毫克，172.1微摩尔)、实施例42D化合物(70.0毫克，172.1微摩尔)、二环己基碳二亚胺(71.0毫克，344.3微摩尔)和二异丙基乙胺(22.2毫克，172.1微摩尔)在二氯甲烷(2毫升)中搅拌10小时，加入水10毫升，用乙酸乙酯萃取(15毫升×3)，将合并的有机层用饱和食盐水(10毫升)洗一次，有机相浓缩得到实施例101化合物(15.0毫克，16.2％产率)。1HNMR(400MHz,CHLOROFORM-d)δppm0.66(s,3H)0.88-1.03(m,10H)1.07-1.19(m,7H)1.29-1.42(m,7H)1.45-1.74(m,11H)1.77-2.03(m,14H)2.25(ddd,J＝15.75,9.72,6.15Hz,1H)2.34-2.47(m,1H)3.29(s,3H)3.43(dd,J＝10.04,5.02Hz,2H)3.59(br.s.,1H)4.40(br.s.,1H)。
路线43
Figure PCTCN2016080635-appb-000289
实施例102
Figure PCTCN2016080635-appb-000290
实施例43A
Figure PCTCN2016080635-appb-000291
零下30摄氏度氮气保护下向实施例17A化合物(240.0毫克，534.9微摩尔)的无水四氢呋喃(15毫升)溶液中加入四氯磷酸酯(200毫克，803.6微摩尔)，并搅拌2.5小时。溶剂旋干后加水(10毫升)，过滤，滤饼溶于甲醇并减压旋干得到粗品实施例43A化合物(240.0毫克，80.6％收率)。1H NMR(400MHz, METHANOL-d4)δ8.21(s,1H),5.18(br.s.,1H),4.03(td,J＝7.7,14.8Hz,2H),3.46(br.s.,2H),2.05(d,J＝12.5Hz,1H),1.93-1.80(m,6H),1.75-1.60(m,7H),1.54(br.s.,3H),1.43-1.06(m,15H),1.01(d,J＝6.5Hz,3H),0.99(s,3H),0.93(t,J＝7.3Hz,3H),0.73(s,3H)
实施例102
Figure PCTCN2016080635-appb-000292
参考实施例2的操作步骤，以实施例43A化合物为原料(240.0毫克，479.4微摩尔)纯化得到实施例102化合物(200.0毫克，79.4％收率)。1H NMR(400MHz,METHANOL-d4)δ4.03(td,J＝7.7,15.8Hz,2H),3.68(br.s.,1H),3.47(br.s.,1H),2.04(d,J＝11.8Hz,1H),1.98-1.71(m,8H),1.67-1.48(m,9H),1.34(br.s.,7H),1.26-1.09(m,4H),1.02(d,J＝6.5Hz,3H),0.99(br.s.,1H),0.96-0.90(m,6H),0.73(s,3H).
路线44
Figure PCTCN2016080635-appb-000293
实施例103
Figure PCTCN2016080635-appb-000294
实施例44A
Figure PCTCN2016080635-appb-000295
将实施例21A化合物(2.0克，4.6毫摩尔)溶于甲酸(24.4克，530.1毫摩尔，再加入高氯酸(4.6毫克，46.2微摩尔)，反应液于25摄氏度搅拌十二小时。浓缩除去溶剂，残留物经柱层析硅胶得到实施例44A化合物(700.0毫克，32.9％产率)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),5.32-5.21(m,1H),3.68(s,3H),2.87-2.74(m,1H),2.47-2.34(m,2H),2.29-2.19(m,3H),2.11-2.01(m,3H),1.94-1.76(m,6H),1.72-1.66(m,1H),1.58-1.40(m,6H),1.36-1.12(m,9H),1.07(s,3H),0.98-0.89(m,7H),0.72(br.s.,3H).
实施例44B
Figure PCTCN2016080635-appb-000296
将实施例44A化合物(80.0毫克，173.6微摩尔)溶于二氯甲烷(3.0毫升)，在25摄氏度，氮气保护下，加入三溴化吡啶盐(55.5毫克，173.6微摩尔)，反应液于40摄氏度搅拌四小时。向反应液中加入二氯甲烷(25毫升)，有机层经水洗(10毫升)，无水硫酸钠干燥和浓缩。残留物经薄层色谱柱层析分离得到实施例44B化合物(40.0毫克，42.69％产率)。1H NMR(400MHz,CHLOROFORM-d)δ8.13(s,1H),5.34-5.21(m,1H),4.79(dd,J＝5.1,14.2Hz,1H),3.71-3.59(m,3H),3.05-2.93(m,1H),2.69(dd,J＝5.3,13.8Hz,1H),2.53(dd,J＝4.5,14.8Hz,1H),2.43-2.14(m,3H),2.00-1.79(m,5H),1.71-1.62(m,2H),1.53-1.21(m,9H),1.17-1.13(m,2H),1.08(s,2H),0.95-0.80(m,7H),0.74-0.66(m,3H).
实施例44C
Figure PCTCN2016080635-appb-000297
将实施例44B化合物(100.0毫克，185.3微摩尔)和硫代尿(28.2毫克，370.6微摩尔)溶于吡啶中(2.0毫升)，反应液于90摄氏度搅拌十二小时。除去溶剂，向残留物中加入水(5毫升)，用乙酸乙酯萃取(10毫升×3)。所得有机层经水洗(10毫升)，无水硫酸钠干燥和浓缩。残留物经薄层色谱柱层析分离得到实施例44C化合物(45.0毫克，47.0％产率)。1H NMR(400MHz,CHLOROFORM-d)δ8.15(br.s.,1H),6.95(br.s.,1H),5.35-5.20(m,1H),3.67(s,3H),3.10(br.s.,1H),2.92-2.73(m,1H),2.54-2.16(m,4H),2.05-1.61(m,9H),1.47-1.27(m,9H),1.08(d,J＝9.8Hz,4H),0.91(d,J＝6.5Hz,4H),0.69-0.62(m,3H).
实施例103
Figure PCTCN2016080635-appb-000298
参考实施例2的操作步骤，以实施例44C化合物为原料(45.0毫克，87.1微摩尔)纯化得到实施例103化合物(19.0毫克，45.9％产率，黄色固体)。1H NMR(400MHz,METHANOL-d4)δ3.76(br.s.,1H),3.48(dd,J＝10.9,15.2Hz,1H),2.77(d,J＝16.6Hz,1H),2.44-2.30(m,2H),2.25-2.18(m,2H),2.01-1.96(m,1H),1.95-1.88(m,1H),1.84-1.74(m,3H),1.67-1.61(m,2H),1.55-1.47(m,3H),1.40-1.29(m,5H),1.20-1.15(m,3H),1.12(s,3H),1.01-0.95(m,6H),0.94-0.86(m,5H),0.73(s,3H).
实验例1：体外研究
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40μL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7.5ul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7.5ul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Prism5.0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 PCTCN2016080635-appb-000299
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200μL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40μL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Prism5.0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)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 PCTCN2016080635-appb-000300
Figure PCTCN2016080635-appb-000301
Figure PCTCN2016080635-appb-000302
Figure PCTCN2016080635-appb-000303
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、(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 PCTCN2016080635-appb-000304
ah,L/kg,mL/min/kg,nM.h；bnM,h,nM.h,％
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(pH7.4)＝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 PCTCN2016080635-appb-000305
结论：如表3中所示，口服给予相同剂量列表中本发明化合物，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，肝/血浓度比也高于对照化合物，表现出显著的效果。

Claims (52)

  1. 式Ⅰ所示的化合物，其互变异构体、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2016080635-appb-100001
    其中，
    R7、R8和R9分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基，任选地，R8和R9可连接在一起形成一个3～6元环；或者，R9选自H，R7和R8与所连碳原子形成任选被1、2、3、4或5个R取代的5～6元杂芳环或C3-6环烷基；
    上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的C1-3烷基、C1-3杂烷基；
    上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
    条件是，R7、R8和R9不同时为H，并且，当R8为OH时，R7和R9不同时选自H，并且，R8或R9不选自
    Figure PCTCN2016080635-appb-100002
  2. 根据权利要求1所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R7选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
    Figure PCTCN2016080635-appb-100003
  3. 根据权利要求2所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R7选自H或
    Figure PCTCN2016080635-appb-100004
  4. 根据权利要求1所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R8和R9分别独立地选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
    Figure PCTCN2016080635-appb-100005
    Figure PCTCN2016080635-appb-100006
    或者，R8和R9连接在一起形成C3-6环烷基。
  5. 根据权利要求4所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于， 所述R8和R9分别独立地选自H、F、OH、Me、Et、
    Figure PCTCN2016080635-appb-100007
    或者，R8和R9连接在一起形成环丙基，且R8和R9不同时为H。
  6. 根据权利要求1所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R9选自H，R7和R8与所连碳原子形成任选被1或2个R取代的咪唑基、吡唑基、吡咯基、噻吩基、恶唑基、噻唑基、呋喃基或环丙基。
  7. 根据权利要求6所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R9选自H，R7和R8与所连碳原子形成任选被甲基或氨基取代的
    Figure PCTCN2016080635-appb-100008
    Figure PCTCN2016080635-appb-100009
  8. 根据权利要求7所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述R9选自H，R7和R8与所连碳原子形成
    Figure PCTCN2016080635-appb-100010
    Figure PCTCN2016080635-appb-100011
  9. 式Ⅱ、式Ⅲ或式Ⅳ所示化合物、其互变异构体或其药学上可接受的盐：
    Figure PCTCN2016080635-appb-100012
    其中，
    R1、R2、R3、R5分别独立地选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
    当R2为OH时，R1和R3不同时选自H；
    任选地，R2、R3可连接在一起形成一个3～6元环；
    Figure PCTCN2016080635-appb-100013
    代表单键或双键；
    环A选自任选被1、2、3、4或5个R取代的5～6元杂芳环；
    L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(ORL)O-或-S(＝O)2N(RL)-；
    RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基；
    R4选自H、或选自任选被1、2、3、4、或5个R取代的：C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
    R分别独立地选自卤素、CN、OH、NH2、SH、或任选被1、2、3、4或5个R’取代的：C1-3烷基、C1-3杂烷基；和/或
    任选地，任何一个RL可与R4连接在一起形成一个任选被1、2、3、4或5个R取代的4～6元环；
    R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
    “杂”代表杂原子或杂原子团，选自-NH-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-和/或-S(＝O)2-；
    每个上述含“杂”的基团上所述“杂”的数目为1、2、3、4或5个。
  10. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R选自卤素、CN、OH、NH2、SH、或任选被1、2、3、4或5个R’取代的：C1-3烷基、C1-3烷氧基、C1-3烷氨基。
  11. 根据权利要求10所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R选自F、Cl、Br、I、OH、CN、NH2、SH、Me、Et、
    Figure PCTCN2016080635-appb-100014
    或CF3。
  12. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R1、R2、R3、R5分别独立地选自H、卤素、OH、NH2、SH、CN、Me、Et、
    Figure PCTCN2016080635-appb-100015
  13. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R2、R3连接在一起形成一个环丙基。
  14. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，环A选自任选被1或2个R取代的咪唑基、吡唑基、吡咯基、噻吩基、恶唑基、噻唑基或呋喃基。
  15. 根据权利要求14所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，环A选自被甲 基取代的
    Figure PCTCN2016080635-appb-100016
  16. 根据权利要求15所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，环A选自
    Figure PCTCN2016080635-appb-100017
    Figure PCTCN2016080635-appb-100018
  17. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R4选自H，或任选被1、2、3、4、或5个R取代的Me、Et、
    Figure PCTCN2016080635-appb-100019
    Figure PCTCN2016080635-appb-100020
  18. 根据权利要求17所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R4选自H，或选自任选被1、2、3、4、或5个R取代的Me、Et、
    Figure PCTCN2016080635-appb-100021
    Figure PCTCN2016080635-appb-100022
  19. 根据权利要求18所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述R4选自：H、 Me、Et、
    Figure PCTCN2016080635-appb-100023
    Figure PCTCN2016080635-appb-100024
  20. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2(CH2)0-2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)N(RL)(CH2)0-2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(ORL)O-或-S(＝O)2NH-。
  21. 根据权利要求20所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，所述L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2-、-C(＝O)NHS(＝O)2CH2-、-C(＝O)NHS(＝O)2(CH2)2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)O-、-NHC(＝O)OCH2-、-NHC(＝O)O(CH2)2-、-NHC(＝O)NH-、-NHC(＝O)NHCH2-、-NHC(＝O)NH(CH2)2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-或-S(＝O)2NH-。
  22. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，RL和R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环时，结构单元-L-R4选自任选被1或2个R取代的
    Figure PCTCN2016080635-appb-100025
  23. 根据权利要求22所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，RL和R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环时，结构单元-L-R4选自
    Figure PCTCN2016080635-appb-100026
    Figure PCTCN2016080635-appb-100027
  24. 根据权利要求9所述的化合物、其互变异构体或其药学上可接受的盐，其特征在于，其中-L-R4选自：
    Figure PCTCN2016080635-appb-100028
  25. 式Ⅴ所示化合物、其互变异构体、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2016080635-appb-100029
    其中，
    R4选自H、或选自任选被1、2、3、4或5个R取代的C1-3烷基、C3-10环烷基、3～6元杂环烷基、5～6元芳基或5～6元杂芳基；
    R5选自H、卤素、OH、NH2、SH、CN，或选自任选被1、2、3、4或5个R取代的C1-3烷基或C1-3烷氧基；
    R6选自H或OH；
    n选自0、1或2；
    L选自：单键、-C(＝O)-、-C(＝O)S-、-C(＝O)N(RL)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(ORL)O-；
    上述RL选自H，或选自任选被1、2、或3个R取代的C1-3烷基，优选RL选自H或C1-3烷基；
    上述R分别独立地选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的：C1-3烷基、C1-3杂烷基和/或
    任选地，任何一个RL与R4连接在一起形成一个任选被1、2、3、4、或5个R取代的4～6元环；
    上述R’选自卤素、CN、OH、NH2、SH、Me或三氟甲基；
    条件是，当R4选自C1-3烷基时，R不选自OH和NH2。
  26. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，所述式Ⅴ所示化合物的立体异构体如下式Ⅴ’所示：
    Figure PCTCN2016080635-appb-100030
  27. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R选自卤素、CN、OH、NH2、SH，或任选被1、2、3、4或5个R’取代的C1-3烷基、C1-3烷氧基或C1-3烷氨基。
  28. 根据权利要求27所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R选自F、Cl、Br、I、OH、CN、NH2、SH、Me、Et、
    Figure PCTCN2016080635-appb-100031
    或CF3。
  29. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于， R5选自H、F、Cl、Br、I、OH、NH2、SH、CN、Me、Et、
    Figure PCTCN2016080635-appb-100032
  30. 根据权利要求29所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R5选自H、Me或Et。
  31. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R4选自H，或任选被1、2、3、4或5个R取代的Me、Et、
    Figure PCTCN2016080635-appb-100033
    Figure PCTCN2016080635-appb-100034
  32. 根据权利要求31所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R4选自H，或选自任选被1、2、3、4或5个R取代的Me、Et
    Figure PCTCN2016080635-appb-100035
    Figure PCTCN2016080635-appb-100036
  33. 根据权利要求32所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，R4选自H、Me、Et、
    Figure PCTCN2016080635-appb-100037
    Figure PCTCN2016080635-appb-100038
    Figure PCTCN2016080635-appb-100039
  34. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，L选自单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2(CH2)0-2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O(CH2)0-2-、-NHC(＝O)N(RL)(CH2)0-2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2NH-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(ORL)O-。
  35. 根据权利要求34所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，L选自单键、-C(＝O)-、-C(＝O)S-、-C(＝O)NHS(＝O)2-、-C(＝O)NHS(＝O)2CH2-、-C(＝O)NHS(＝O)2(CH2)2-、-C(＝O)N(CH3)S(＝O)2-、-NHC(＝O)O-、-NHC(＝O)OCH2-、-NHC(＝O)O(CH2)2-、-NHC(＝O)NH-、-NHC(＝O)NHCH2-、-NHC(＝O)NH(CH2)2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2NH、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(CH3)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-、-NHC(＝O)C(＝O)O-或-OP(＝O)(OMe)O-。
  36. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，RL和R4连接在一起形成一个任选被1、2、3、4或5个R取代的4～6元环时，结构单元-L-R4选自任选被1或2个R取代的
    Figure PCTCN2016080635-appb-100040
    Figure PCTCN2016080635-appb-100041
  37. 根据权利要求36所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，RL和R4连接在一起形成一个任选被1、2、3、4或5个R取代的4～6元环时，结构单元-L-R4选自
    Figure PCTCN2016080635-appb-100042
    Figure PCTCN2016080635-appb-100043
  38. 根据权利要求25所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，其特征在于，-L-R4选自：
    Figure PCTCN2016080635-appb-100044
    Figure PCTCN2016080635-appb-100045
  39. 根据权利要求1-38任一项权利要求所述的化合物，其选自：
    Figure PCTCN2016080635-appb-100046
    Figure PCTCN2016080635-appb-100047
    Figure PCTCN2016080635-appb-100048
    Figure PCTCN2016080635-appb-100049
    Figure PCTCN2016080635-appb-100050
    Figure PCTCN2016080635-appb-100051
    Figure PCTCN2016080635-appb-100052
  40. 药物组合物，其包含治疗有效量的权利要求1-39中任一项权利要求所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体或赋形剂。
  41. 权利要求1-39任一项权利要求所述的化合物，其互变异构体、其立体异构体或其药学上可接受的盐或权利要求40所述的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。
  42. 根据权利要求41所述的用途，其特征在于，所述受益于FXR激动的疾病选自心血管疾病、肝/胆系统疾病、肥胖症、糖尿病、下尿路症状(附近地区)与良性前列腺增生或输尿管结石。
  43. 根据权利要求42所述的用途，其特征在于，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。
  44. 根据权利要求42所述的用途，其特征在于，所述心血管疾病包括动脉粥样硬化、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。
  45. 根据权利要求42所述的用途，其特征在于，所述肝/胆系统疾病包括胆汁淤积性肝疾病、及高HDL胆固醇疾病、高甘油三酯疾病或纤维变性疾病。
  46. 根据权利要求42所述的用途，其特征在于，所述肝/胆系统疾病包括非酒精性脂肪性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、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、肝纤维变性。
  47. 用于治疗或预防受益于FXR激动的疾病的方法，包括将权利要求1-39任一项权利要求所述的化合物、其互变异构体、其立体异构体或其药学上可接受的盐或权利要求40所述的药物组合物向有需要的个体给药。
  48. 根据权利要求47所述的方法，其特征在于，所述受益于FXR激动的疾病选自心血管疾病、肝/胆系统疾病、肥胖症、糖尿病、下尿路症状(附近地区)与良性前列腺增生或输尿管结石。
  49. 根据权利要求48所述的方法，其特征在于，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。
  50. 根据权利要求48所述的方法，其特征在于，所述心血管疾病包括动脉粥样硬化、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。
  51. 根据权利要求48所述的方法，其特征在于，所述肝/胆系统疾病包括胆汁淤积性肝疾病、及高HDL胆固醇疾病、高甘油三酯疾病或纤维变性疾病。
  52. 根据权利要求48所述的方法，其特征在于，所述肝/胆系统疾病包括非酒精性脂肪性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、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、肝纤维变性。
PCT/CN2016/080635 2015-04-29 2016-04-29 鹅去氧胆酸衍生物 Ceased WO2016173524A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202010345654.3A CN111574577B (zh) 2015-04-29 2016-04-29 鹅去氧胆酸衍生物
CN201680024495.9A CN107531743B (zh) 2015-04-29 2016-04-29 鹅去氧胆酸衍生物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510214260.3 2015-04-29
CN201510214260 2015-04-29

Publications (1)

Publication Number Publication Date
WO2016173524A1 true WO2016173524A1 (zh) 2016-11-03

Family

ID=57198167

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/080635 Ceased WO2016173524A1 (zh) 2015-04-29 2016-04-29 鹅去氧胆酸衍生物

Country Status (3)

Country Link
CN (2) CN107531743B (zh)
TW (1) TW201704251A (zh)
WO (1) WO2016173524A1 (zh)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106749472A (zh) * 2016-12-30 2017-05-31 江苏开元医药化工有限公司 一种3α‑羟基‑6α‑乙基‑7‑酮‑5β‑胆烷‑24‑酸的制备方法
CN106986910A (zh) * 2017-04-19 2017-07-28 成都百特万合医药科技有限公司 奥贝胆酸中间体的制备方法
JP2017533923A (ja) * 2014-11-06 2017-11-16 エナンタ ファーマシューティカルズ インコーポレイテッド Ｆｘｒ／ｔｇｒ５アゴニストとしての胆汁酸類似体およびその使用方法
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
WO2018010651A1 (zh) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 一种奥贝胆酸及其中间体的制备方法
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
CN108218945A (zh) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 去氧胆酸衍生物、其制备方法、药物组合物及用途
EP3223822A4 (en) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
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
EP3431486A1 (en) * 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
US10246483B2 (en) 2015-02-11 2019-04-02 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
WO2019085963A1 (zh) 2017-11-02 2019-05-09 正大天晴药业集团股份有限公司 一种胆酸类化合物的制备方法
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
CN109929005A (zh) * 2017-12-19 2019-06-25 西安奥立泰医药科技有限公司 用于代谢性疾病治疗的化合物及其制备方法和应用
US10364267B2 (en) 2016-02-23 2019-07-30 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
CN110121347A (zh) * 2016-11-29 2019-08-13 英安塔制药有限公司 制备磺酰脲胆汁酸衍生物的方法
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
WO2020025942A1 (en) 2018-07-30 2020-02-06 NZP UK Limited Fluorinated bile acid derivatives
US10676500B2 (en) 2017-04-07 2020-06-09 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
US20200231622A1 (en) * 2017-07-26 2020-07-23 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing steroid derivative fxr agonist
CN112824425A (zh) * 2019-11-21 2021-05-21 成都西岭源药业有限公司 一种6-位烯基取代胆酸化合物及其制备方法和应用
CN112898368A (zh) * 2019-12-03 2021-06-04 中国科学院成都有机化学有限公司 一种奥贝胆酸中间体的制备方法
WO2021204142A1 (zh) * 2020-04-08 2021-10-14 西安奥立泰医药科技有限公司 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用
CN114641280A (zh) * 2019-05-10 2022-06-17 哈佛大学的校长及成员们 肠道细菌胆汁酸代谢的小分子调节剂
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
WO2023083343A1 (en) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Polycyclic compounds and methods thereof
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
WO2023192221A1 (en) * 2022-03-29 2023-10-05 Bilayer Therapeutics, Inc. Forms and compositions of sodium chenodeoxycholate

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111116699B (zh) * 2015-04-28 2023-02-28 江苏豪森药业集团有限公司 胆酸衍生物及其制备方法和医药用途
TW201704251A (zh) * 2015-04-29 2017-02-01 正大天晴藥業集團股份有限公司 鵝去氧膽酸衍生物
EP3310801B1 (en) * 2015-06-19 2021-04-07 Intercept Pharmaceuticals, Inc. Tgr5 modulators and methods of use thereof
US10800807B2 (en) 2015-06-19 2020-10-13 Intercept Pharmaceuticals, Inc. TGR5 modulators and methods of use thereof
CN106478756A (zh) * 2015-09-02 2017-03-08 中美华世通生物医药科技（武汉）有限公司 Oca-e单晶及其制备方法和用途
CN109762043B (zh) * 2019-03-06 2020-07-24 华南理工大学 鹅去氧胆酸及其制备方法
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
CN118620018B (zh) * 2024-05-31 2025-03-28 华南理工大学 一种侧链含噁二唑结构的甾体类fxr激动剂及其制备方法和应用
CN120271652B (zh) * 2025-05-27 2025-10-03 华南理工大学 噁二唑-甾体化合物、药物组合物和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082925A2 (en) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
JP2013206716A (ja) * 2012-03-28 2013-10-07 Fujifilm Corp 光電変換素子及び色素増感太陽電池
CN104672290A (zh) * 2015-01-05 2015-06-03 北京普禄德医药科技有限公司 一种用于预防或治疗fxr-介导的疾病的药物及其制备方法和用途
WO2016045480A1 (zh) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 一种奥贝胆酸的制备方法
WO2016086115A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as fxr/tgr5 agonists and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010517931A (ja) * 2006-02-14 2010-05-27 インターセプト ファーマシューティカルズ， インコーポレイテッド Ｆｘｒ媒介性の疾患または状態の予防または治療用のｆｘｒリガンドとしての胆汁酸誘導体
TW201704251A (zh) * 2015-04-29 2017-02-01 正大天晴藥業集團股份有限公司 鵝去氧膽酸衍生物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082925A2 (en) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Novel steroid agonist for fxr
JP2013206716A (ja) * 2012-03-28 2013-10-07 Fujifilm Corp 光電変換素子及び色素増感太陽電池
WO2016045480A1 (zh) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 一种奥贝胆酸的制备方法
WO2016086115A1 (en) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as fxr/tgr5 agonists and methods of use thereof
CN104672290A (zh) * 2015-01-05 2015-06-03 北京普禄德医药科技有限公司 一种用于预防或治疗fxr-介导的疾病的药物及其制备方法和用途

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BABU, P. ET AL.: "Micellar Aggregates and Hydrogels from Phosphonobile Salts", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 3, no. 20, 8 September 2005 (2005-09-08), pages 3695 - 3700, XP055230783 *
PELLICCIARI, R. ET AL.: "Back Door Modulation of the Farnesoid X Receptor: Design, Synthesis, and Biological Evaluation of a Series of Side Chain Modified Chenodeoxycholic Acid Derivatives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 14, 15 June 2006 (2006-06-15), pages 4208 - 4215, XP008092111 *
PELLICCIARI, R. ET AL.: "Bile Acid Derivatives as Ligands of the Farnesoid X Receptor. Synthesis, Evaluation, and Structure-Activity Relationship of a Series of Body and Side Chain Modified Analogues of Chenodeoxycholic Acid", JOURNAL OF MEDICINAL CHEMISTRY, vol. 47, no. 18, 23 July 2004 (2004-07-23), pages 4559 - 4569, XP002370634 *

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3215179A4 (en) * 2014-11-06 2018-07-25 Enanta Pharmaceuticals, Inc. Bile acid analogs an 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
JP2017533923A (ja) * 2014-11-06 2017-11-16 エナンタ ファーマシューティカルズ インコーポレイテッド Ｆｘｒ／ｔｇｒ５アゴニストとしての胆汁酸類似体およびその使用方法
US11718641B2 (en) 2014-11-26 2023-08-08 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
US12281140B2 (en) 2014-11-26 2025-04-22 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
EP3223822A4 (en) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Bile acid derivatives 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
US10208081B2 (en) 2014-11-26 2019-02-19 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
AU2015353372B2 (en) * 2014-11-26 2020-07-23 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
US11040998B2 (en) 2015-03-31 2021-06-22 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
US10457703B2 (en) 2015-03-31 2019-10-29 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
WO2018010651A1 (zh) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 一种奥贝胆酸及其中间体的制备方法
EP3548038A4 (en) * 2016-11-29 2020-07-01 Enanta Pharmaceuticals, Inc. METHOD FOR THE PRODUCTION OF SULFONYL UREA GALLENIC ACID DERIVATIVES
US10584145B2 (en) 2016-11-29 2020-03-10 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
CN110121347A (zh) * 2016-11-29 2019-08-13 英安塔制药有限公司 制备磺酰脲胆汁酸衍生物的方法
US10947264B2 (en) * 2016-11-29 2021-03-16 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
US20200247839A1 (en) * 2016-11-29 2020-08-06 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
CN108218945A (zh) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 去氧胆酸衍生物、其制备方法、药物组合物及用途
CN108218945B (zh) * 2016-12-15 2021-05-28 宁波百纳西药业有限公司 去氧胆酸衍生物、其制备方法、药物组合物及用途
CN106749472B (zh) * 2016-12-30 2019-02-22 江苏开元医药化工有限公司 一种3α-羟基-6α-乙基-7-酮-5β-胆烷-24-酸的制备方法
CN106749472A (zh) * 2016-12-30 2017-05-31 江苏开元医药化工有限公司 一种3α‑羟基‑6α‑乙基‑7‑酮‑5β‑胆烷‑24‑酸的制备方法
US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
US10676500B2 (en) 2017-04-07 2020-06-09 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
US10961272B2 (en) 2017-04-07 2021-03-30 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
CN106986910A (zh) * 2017-04-19 2017-07-28 成都百特万合医药科技有限公司 奥贝胆酸中间体的制备方法
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
EP3431486A1 (en) * 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
JP2020527148A (ja) * 2017-07-18 2020-09-03 バイオニス、ソシエダッド、リミターダ、ウニペルソナルＢｉｏｎｉｃｅ，Ｓ．Ｌ．Ｕ オベチコール酸およびその誘導体の合成法、並びにその中間体
WO2019015914A1 (en) * 2017-07-18 2019-01-24 Bionice, S.L.U. METHODS AND INTERMEDIATES FOR THE SYNTHESIS OF OBETICHOLIC ACID AND DERIVATIVES THEREOF
JP7286615B2 (ja) 2017-07-18 2023-06-05 クリスタル ファルマ、エセ、ア、ウ オベチコール酸およびその誘導体の合成法、並びにその中間体
US11104702B2 (en) 2017-07-18 2021-08-31 Crystal Pharma, S.A.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
US11059854B2 (en) * 2017-07-26 2021-07-13 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing steroid derivative FXR agonist
US20200231622A1 (en) * 2017-07-26 2020-07-23 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing steroid derivative fxr agonist
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
CN111247160A (zh) * 2017-11-02 2020-06-05 正大天晴药业集团股份有限公司 一种胆酸类化合物的制备方法
CN111247160B (zh) * 2017-11-02 2021-09-28 正大天晴药业集团股份有限公司 一种胆酸类化合物的制备方法
WO2019085963A1 (zh) 2017-11-02 2019-05-09 正大天晴药业集团股份有限公司 一种胆酸类化合物的制备方法
US11111265B2 (en) 2017-11-02 2021-09-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing cholic acid compound
CN109929005B (zh) * 2017-12-19 2020-10-30 西安奥立泰医药科技有限公司 用于代谢性疾病治疗的化合物及其制备方法和应用
WO2019119832A1 (zh) * 2017-12-19 2019-06-27 西安奥立泰医药科技有限公司 用于代谢性疾病治疗的化合物及其制备方法和应用
CN109929005A (zh) * 2017-12-19 2019-06-25 西安奥立泰医药科技有限公司 用于代谢性疾病治疗的化合物及其制备方法和应用
US11028111B2 (en) 2017-12-19 2021-06-08 Xi' An Biocare Pharma Ltd. Compound for treating metabolic diseases and preparation method and use thereof
JP2020536119A (ja) * 2017-12-19 2020-12-10 西安奥立泰医薬科技有限公司Ｘｉ’Ａｎ Ｂｉｏｃａｒｅ Ｐｈａｒｍａ Ｌｔｄ． 代謝性疾患治療用化合物及びその製造方法、並びに応用
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
WO2020025942A1 (en) 2018-07-30 2020-02-06 NZP UK Limited Fluorinated bile acid derivatives
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
CN116178473B (zh) * 2018-12-10 2025-03-04 江西科睿药业有限公司 一种奥贝胆酸的制备方法
CN114641280A (zh) * 2019-05-10 2022-06-17 哈佛大学的校长及成员们 肠道细菌胆汁酸代谢的小分子调节剂
CN112824425A (zh) * 2019-11-21 2021-05-21 成都西岭源药业有限公司 一种6-位烯基取代胆酸化合物及其制备方法和应用
CN112824425B (zh) * 2019-11-21 2023-10-03 成都西岭源药业有限公司 一种6-位烯基取代胆酸化合物及其制备方法和应用
CN112898368A (zh) * 2019-12-03 2021-06-04 中国科学院成都有机化学有限公司 一种奥贝胆酸中间体的制备方法
CN112898368B (zh) * 2019-12-03 2023-08-18 中国科学院成都有机化学有限公司 一种奥贝胆酸中间体的制备方法
WO2021204142A1 (zh) * 2020-04-08 2021-10-14 西安奥立泰医药科技有限公司 胆汁酸衍生物盐、其晶型结构及它们的制备方法和应用
JP2023504015A (ja) * 2020-04-08 2023-02-01 西安奥立泰医薬科技有限公司 胆汁酸誘導体塩、その結晶形構造及びそれらの製造方法と使用
US12331071B2 (en) 2020-04-08 2025-06-17 Xi'an Biocare Pharma Ltd. Bile acid derivative salt, crystal structure thereof, preparation method therefor and use thereof
WO2023083343A1 (en) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Polycyclic compounds and methods thereof
WO2023192221A1 (en) * 2022-03-29 2023-10-05 Bilayer Therapeutics, Inc. Forms and compositions of sodium chenodeoxycholate

Also Published As

Publication number Publication date
CN111574577A (zh) 2020-08-25
CN107531743A (zh) 2018-01-02
TW201704251A (zh) 2017-02-01
CN111574577B (zh) 2025-02-25
CN107531743B (zh) 2020-05-05

Similar Documents

Publication Publication Date Title
CN107531743B (zh) 鹅去氧胆酸衍生物
AU2021202018B2 (en) Steroid derivative fxr agonist
TW201700447A (zh) Tgr5調控劑及其用法
CN110662743A (zh) 作为fxr受体激动剂的内酰胺类化合物
AU2017368069B2 (en) Process for preparation of sulfonylurea bile acid derivatives
JP2018519246A (ja) コール酸誘導体、及びその製造方法及び医薬用途
US10273263B2 (en) Pro-drug forming compounds
CN101296914B (zh) 具有ppar激动活性的衍生物
CA3121952A1 (en) Macrocyclic compound and use thereof
JP2025528193A (ja) シクロヘキシル基を含む化合物
WO2021100730A1 (ja) ピロリジン化合物の製造方法
EA038580B1 (ru) Агонист fxr, представляющий собой производное стероидов
WO1997031892A1 (fr) Derives d&#39;acide hydroxamique
HK1259152B (zh) 甾体类衍生物fxr激动剂
HK1259152A1 (zh) 甾体类衍生物fxr激动剂
CN118525011A (zh) 一种吗啉基喹唑啉类化合物、其制备方法及应用
CN116789636A (zh) 双功能化合物及其制备方法、药物组合物和用途
BR112018015474B1 (pt) Compostos agonistas de fxr derivados de esteroide, composição farmacêutica que compreende os mesmos e usos terapêuticos dos ditos compostos
HK40017900B (zh) 作为fxr受体激动剂的内酰胺类化合物
HK40017900A (zh) 作为fxr受体激动剂的内酰胺类化合物

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: 16785952

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16785952

Country of ref document: EP

Kind code of ref document: A1