WO2016173524A1 - Dérivé d'acide chénodésoxycholique - Google Patents

Dérivé d'acide chénodésoxycholique Download PDF

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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
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group
pharmaceutically acceptable
tautomer
acceptable salt
compound
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PCT/CN2016/080635
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English (en)
Chinese (zh)
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贺海鹰
李鹏
肖华玲
陈正霞
张杨
陈曙辉
胡国平
黎健
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正大天晴药业集团股份有限公司
南京明德新药研发股份有限公司
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Priority to CN201680024495.9A priority Critical patent/CN107531743B/zh
Publication of WO2016173524A1 publication Critical patent/WO2016173524A1/fr

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    • 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
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    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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    • 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
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    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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.

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Abstract

La présente invention concerne les composés tels que représentés dans les formules I, II, III, IV ou V, des tautomères de ceux-ci, des stéréoisomères de ceux-ci ou des sels pharmaceutiquement acceptables de ceux-ci, et la présente invention concerne en outre l'utilisation de ceux-ci dans la préparation de médicaments pour le traitement de maladies liées à FXR.
PCT/CN2016/080635 2015-04-29 2016-04-29 Dérivé d'acide chénodésoxycholique WO2016173524A1 (fr)

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2018010651A1 (fr) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 Procédé de fabrication d'acide obéticholique et de ses intermédiaires
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EP3223822A4 (fr) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation
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EP3431486A1 (fr) * 2017-07-18 2019-01-23 Bionice, S.L.U. Procédé et intermédiaires de synthèse de l'acide obéticholique et leurs dérivés
US10246483B2 (en) 2015-02-11 2019-04-02 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
WO2019085963A1 (fr) 2017-11-02 2019-05-09 正大天晴药业集团股份有限公司 Procédé de préparation de composé d'acide cholique
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
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US10364267B2 (en) 2016-02-23 2019-07-30 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
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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 (fr) 2018-07-30 2020-02-06 NZP UK Limited Dérivés fluorés d'acide biliaire
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
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WO2021204142A1 (fr) * 2020-04-08 2021-10-14 西安奥立泰医药科技有限公司 Sel de dérivé d'acide biliaire, structure cristalline de celui-ci, son procédé de préparation et son utilisation
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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 (fr) * 2021-11-15 2023-05-19 Hepaitech (Beijing) Biopharma Technology Co., Ltd. Composés polycycliques et leurs procédés
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WO2023192221A1 (fr) * 2022-03-29 2023-10-05 Bilayer Therapeutics, Inc. Formes et compositions de chénodésoxycholate de sodium

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180148470A1 (en) * 2015-04-28 2018-05-31 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Cholic acid derivative, and preparation method and medical use thereof
ES2873088T3 (es) 2015-06-19 2021-11-03 Intercept Pharmaceuticals Inc Moduladores de TGR5 y métodos para su uso
TW201700447A (zh) * 2015-06-19 2017-01-01 英特賽普醫藥品公司 Tgr5調控劑及其用法
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082925A2 (fr) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Nouvel agoniste steroidien pour 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 (fr) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 Procédé de préparation d'acide obéticholique
WO2016086115A1 (fr) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Dérivés de tétrazole d'acides biliaires utilisés en tant qu'agonistes de fxr/tgr5 et leurs procédés d'utilisation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007095174A2 (fr) * 2006-02-14 2007-08-23 Intercept Pharmaceuticals, Inc. derives d'acides biliaires en tant que ligands de FXR pour la prevention ou le traitement de maladies ou d'etats induits par FXR

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005082925A2 (fr) * 2004-02-26 2005-09-09 Intercept Pharmaceuticals Inc. Nouvel agoniste steroidien pour 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 (fr) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 Procédé de préparation d'acide obéticholique
WO2016086115A1 (fr) * 2014-11-26 2016-06-02 Enanta Pharmaceuticals, Inc. Dérivés de tétrazole d'acides biliaires utilisés en tant qu'agonistes de fxr/tgr5 et leurs procédés d'utilisation
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 (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
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US10519191B2 (en) 2014-11-26 2019-12-31 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
EP3223822A4 (fr) * 2014-11-26 2018-07-11 Enanta Pharmaceuticals, Inc. Dérivés d'acide biliaire utilisés comme agonistes de fxr/tgr5 et leurs procédés d'utilisation
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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
US10323061B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US10323060B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
WO2018010651A1 (fr) * 2016-07-13 2018-01-18 江苏恒瑞医药股份有限公司 Procédé de fabrication d'acide obéticholique et de ses intermédiaires
EP3548038A4 (fr) * 2016-11-29 2020-07-01 Enanta Pharmaceuticals, Inc. Procédé de préparation de dérivés de type acide biliaire de la famille des sulfonylurées
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US10472386B2 (en) 2017-02-14 2019-11-12 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR agonists and methods of use thereof
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WO2019015914A1 (fr) * 2017-07-18 2019-01-24 Bionice, S.L.U. Procédés et intermédiaires pour la synthèse d'acide obéticholique et de dérivés de celui-ci
EP3431486A1 (fr) * 2017-07-18 2019-01-23 Bionice, S.L.U. Procédé et intermédiaires de synthèse de l'acide obéticholique et leurs dérivés
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
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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
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US11111265B2 (en) 2017-11-02 2021-09-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Method for preparing cholic acid compound
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