WO2016127859A1 - Composés utilisés en tant qu'inhibiteurs du virus de l'hépatite c et leurs utilisations en médecine - Google Patents

Composés utilisés en tant qu'inhibiteurs du virus de l'hépatite c et leurs utilisations en médecine Download PDF

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WO2016127859A1
WO2016127859A1 PCT/CN2016/073156 CN2016073156W WO2016127859A1 WO 2016127859 A1 WO2016127859 A1 WO 2016127859A1 CN 2016073156 W CN2016073156 W CN 2016073156W WO 2016127859 A1 WO2016127859 A1 WO 2016127859A1
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compound
hcv
mixture
mmol
added
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PCT/CN2016/073156
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English (en)
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Yingjun Zhang
Huichao LUO
Qingyun REN
Zhimin Xiong
Yang Liu
Yibo LEI
Jinfeng XIONG
Jiancun Zhang
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Sunshine Lake Pharma Co., Ltd.
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Publication of WO2016127859A1 publication Critical patent/WO2016127859A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a field of medicine, and compounds and compositions thereof for treating Hepatitis C virus (HCV) infection, and use of the compounds and the compositions thereof, and methods thereof.
  • the compounds disclosed herein can be used for inhibiting NS3/4A protease.
  • the present invention relates to compounds and pharmaceutical compositions thereof which can be used for inhibiting a function of NS3/4A protein coded by the hepatitis C virus (HCV) , and a method of inhibiting NS3/4A protein function.
  • HCV is a major human pathogen, infecting an estimated 170 million persons worldwide roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.
  • HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5’untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame (ORF) .
  • ORF open reading frame
  • HCV infected cells viral RNA is translated into a polyprotein that is cleaved into ten individual proteins. At the amino terminus are structural proteins, follows E1 and E2. Additionally, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a function role in the HCV lifecycle (see, for example, Lindenbach et al., Nature, 2005, 436, 933-938) .
  • HCV human immunodeficiency virus
  • the first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease within the N-terminal region of NS3 (also referred herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
  • the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
  • NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
  • the compounds disclosed herein are used for treating HCV-infection in a patient, and which inhibit HCV viral replication selectively.
  • the present invention relates to a macrocyclic compound, which has an obvious advantage on inhibitory activity against HCV replicons compared with TMC-435 (Simeprevir) already on the market, the compound of the invention has a better inhibitory effect on various HCV genotype (such as GT1a, GT1b, CT2a, GT3a, GT4a, GT5a) , especially on GT2a.
  • the compounds or pharmaceutical composition thereof disclosed herein have a good inhibitory effect on HCV infection, especially on HCV NS3/4A protein.
  • R 1 is C 6-10 aryl or C 1-9 heteroaryl
  • each of R 2 and R 3 is independently H, F, Cl, Br, I, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl; and
  • R 4 is H, deuterium or C 1-6 alkyl
  • each the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl and amino is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl and C 1-9 heteroaryl.
  • provided herein is a compound having Formula (II) or a stereoisomer, a tautomer, an enantiomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof
  • R 1 of Formula (I) or (II) is phenyl or 5-6 membered heteroaryl; each of the phenyl and 5-6 membered heteroaryl is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C 3-10 cycloalkyl, C 2-10 heterocyclyl and C 6-10 aryl.
  • R 1 of Formula (I) or (II) is phenyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, quinolyl, indolyl or acridinyl, and wherein each R 1 is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, trifluoromethyl, difluoroethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, t-butyl,
  • each of R 2 and R 3 of Formula (I) or (II) is independently H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, trifluoromethyl, trifluoromethoxy, t-butyl, vinyl, propenyl, ethynyl, propinyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, methylamino and ethylamino.
  • R 4 of Formula (I) or (II) is H, deuterium, methyl, deuterated methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • composition comprising the compound disclosed herein.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition further comprises an anti-HCV agent, wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine5’-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, CIVACIR TM , boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir, EDP239, PPI-668, velpatasvir, s
  • the pharmaceutical composition further comprises at least one HCV inhibitor.
  • the HCV inhibitor inhibits HCV replication process and/or a function of an HCV viral protein, and wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral proteins comprise a metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) or inosine-5’-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IVS internal ribosome entry site
  • IMPDH inosine-5’-monophosphate dehydrogenase
  • HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral proteins comprise metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) and inosine-5’-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • IRS internal ribosome entry site
  • IMPDH inosine-5’-monophosphate dehydrogenase
  • provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder.
  • the compound or the pharmaceutical composition thereof disclosed herein for use in inhibiting HCV replication process and/or a function of an HCV viral protein, wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral protein comprises a metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) , or inosine-5’-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress
  • the HCV viral protein comprises a metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES)
  • provided herein is the compound or the pharmaceutical composition thereof for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder.
  • provided herein is a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering the patient a therapeutically effective amount of the compound or the pharmaceutical composition thereof disclosed herein.
  • provided herein is a method of preparing, separating or purifying the compound of Formula (I) or (II) .
  • grammatical articles “a” , “an” and “the” are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context.
  • the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article.
  • a component means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boling points, spectral properties or biological activities. Mixture of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • a specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50 %enantiomeric excess, at least 60 %enantiomeric excess, at least 70 %enantiomeric excess, at least 80 %enantiomeric excess, at least 90 %enantiomeric excess, at least 95 %enantiomeric excess, or at least 99 %enantiomeric excess in the (R) -or (S) -configuration.
  • the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.
  • Cis and trans isomers are diastereomer.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • the specific example of phenol-keto tautomerisms is pyridin-4-ol and pyridin-4 (3H) -one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • substituent When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • substituent When a substituent is defined by using “independently selected from... ” means that the substituent is independent from each other, each selection of subsituent can be identical or different.
  • substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. Unless otherwise stated, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms. In yet other embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl group examples include, methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , n-propyl (n-Pr, -CH 2 CH 2 CH 3 ) , isopropyl (i-Pr, -CH (CH 3 ) 2 ) , n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ) , isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ) , sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ) , tert-butyl (t-Bu, -C (CH 3 ) 3 ) , n-pentyl (-CH 2 CH 2 CH 2 CH 3 ) , 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ) , 3-pentyl (-CH (CH 2 CH 3 )
  • alkenyl refers to a linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be optionally substituted with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • the alkenyl contains 2 to 8 carbon atoms.
  • the alkenyl contains 2 to 6 carbon atoms.
  • the alkenyl contains 2 to 4 carbon atoms.
  • the alkenyl contains 2 to 3 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl contains 2 to 8 carbon atoms.
  • the alkynyl contains 2 to 6 carbon atoms.
  • the alkynyl contains 2 to 4 carbon atoms.
  • the alkynyl contains 2 to 3 carbon atoms. Examples of such groups include, but are not limited to, ethynyl (-C ⁇ CH) , propargyl (-CH 2 C ⁇ CH) , 1-propynyl (-C ⁇ C-CH 3 ) , and the like.
  • heterocyclyl and “heterocycle” as used interchangeably herein refer to a saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring containing 3-12 ring atoms of which at least one ring member is selected from nitrogen, sulfur and oxygen and at least one ring is nonaromatic.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl, 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl may be 4-7 membered heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl group containing 4-7 ring atoms examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thie
  • heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl, 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group containing 4-7 ring atoms may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl may be 4-membered heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl containing 4 ring atoms include azetidinyl, oxetanyl and thietanyl.
  • the heterocyclyl group containing 4 ring atoms may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl may be 5-membered heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl examples include, but are not limited to, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, and the like.
  • heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl.
  • the heterocyclyl group containing 5 ring atoms may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl may be 6-membered heterocyclyl, which refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl group containing 6 ring atoms examples include, but are not limited to, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl and thioxanyl.
  • heterocyclyl wherein the ring sulfur atom is oxidized is 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group containing 6 ring atoms may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclyl may be 7-12 membered heterocyclyl, which refers to a saturated or partially unsaturated spiro or fused bicyclyl ring containing 7-12 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur and oxygen.
  • the sulfur can be optionally oxygenized to S-oxide and the nitrogen can be optionally oxygenized to N-oxide.
  • heterocyclyl containing 7-12 ring atoms include indolinyl, 1, 2, 3, 4-tetrahrdroisoquinolyl, 1, 3-benzodioxoly, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl.
  • the heterocyclyl group containing 7-12 ring atoms may be optionally substituted with one or more substituents disclosed herein.
  • heterocyclylalkyl refers to an alkyl group substitued with heterocyclyl.
  • heterocyclylalkoxy refers to an alkoxy group substitued with heterocyclyl, attached to the rest of molecular through an oxygen atom.
  • heterocyclylalkylamino refers to an alkylamino group substitued with heterocyclyl, attached to the rest of molecular through a nitrogen atom.
  • Some non-limiting examples of such groups include pyrrol-2-yl-methyl, morpholin-4-yl-ethyl, morpholin-4-yl-ethoxy, piperazin-4-yl-ethoxy, piperazin-4-yl-ethylamino and the like.
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6 membered heterocycloalkyl
  • 1, 2, 3, 4-tetrahydro-naphthalene is an example of a 10 membered cycloalkyl group.
  • unsaturated refers to a moiety having one or more units of unsaturation.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus and silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) .
  • halogen refers to fluorine (F) , chlorine (Cl) , bromine (Br) or iodine (I) .
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, or 6 to 12 ring members, or 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • aryl and “aromatic ring” can be used interchangeably herein. Examples of aryl ring may include phenyl, naphthyl and anthracene. The aryl group may be optionally and independently substituted with one or more substituents disclosed herein.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems having 1 to 9 carbon atoms, wherein at least one ring in the system is aromatic, and at least one ring system contains one or more heteroatoms selected from O, S and N, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • heteroaryl and “heteroaromatic ring” or “heteroaromatic compound” can be used interchangeably herein.
  • the heteroaryl group is optionally substituted with one or more substituents disclosed herein.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 12 ring members, wherein at least one ring in the system is aromatic, and at least one ring system contains one or more heteroatoms selected from O, S and N, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • heteroaryl refers to monocyclic and bicyclic ring systems having a total of 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring system contains one or more heteroatoms selected from O, S and N, and wherein each ring in the system contains 5 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule.
  • heteroaryl refers to monocyclic aromatic ring system having a total of 5 to 6 ring members and containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, and that has a single point or multipoint of attachment to the rest of the molecule.
  • heteroaryl group examples include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl) , triazolyl (e.g., 1, 2, 3-triazolyl and 1, 2, 4-triazolyl) , 2-thieny
  • Carboxy or “carboxyl” , whether used alone or with other terms, such as “carboxyalkyl” , refer to -CO 2 H.
  • alkylamino refers to “N-alkylamino” and “N, N-dialkylamino” wherein amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively.
  • the alkylamino group is lower alkylamino group having one or two alkyl groups of 1 to 6 carbon atoms attached to nitrogen atom.
  • the alkylamino group is lower alkylamino group having 1 to 3 carbon atoms.
  • suitable alkylamino radical include mono or dialkylamino. Some examples include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino and N, N-diethylamino, and the like.
  • arylamino refers to an amino group substituted with one or two aryl groups. Some non-limiting examples of such group included N-phenylamino. In some embodiments, the aryl group of the arylamino may be further substituted.
  • aminoalkyl refers to a C 1-10 linear or branched-chain alkyl group substituted with one or more amino groups.
  • the aminoalkyl is a C 1-6 lower aminoalkyl derived from C 1-6 lower alkyl substituted with one or more amino groups.
  • Some non-limiting examples of the aminoalkyl group include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In other embodiment, the alkoxy group contains 1-4 carbon atoms. In still other embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents disclosed herein.
  • alkoxy group examples include, but are not limited to, methoxy (MeO, -OCH 3 ) , ethoxy (EtO, -OCH 2 CH 3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) , 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3 ) 2 ) , 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ) , 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ) , 2-butoxy (s-BuO, s-butoxy, -OCH (CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3 ) 3 ) , 1-pentoxy (n-pentoxy,
  • alkylthio refers to a group derived from an alkoxy group, the oxygen atom of which is replaced by a sulphur atom.
  • haloalkyl refers to alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl refers to alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl refers to alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl include trifluoromethyl, difluoroethyl (CHF 2 CH 2 -) , trifluoromethoxy, and the like.
  • hydroxyalkyl “hydroxy-substituted alkyl” refer to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl is as defined herein. Some non-limiting examples include hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, and the like.
  • amino refers to -NH 2 .
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • protecting groups and their use see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley &Sons, New York, 1991; and P.J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • prodrug refers to a compound that is transformed in vivo into a compound of Formula (I) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • phosphates such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound.
  • a thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.
  • a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.
  • a “pharmaceutically acceptable salts” refers to organic or inorganic salts of a compound disclosed herein.
  • Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of pharmaceutically acceptable and nontoxic salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate or aryl sulfonate.
  • solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • hydrate refers to the complex where the solvent molecule is water.
  • N-oxide refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chloro
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like) , or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • the compounds disclosed herein, including their salts can also be obtained in the form of their hydrates, or include other solvents such as ethanol, DMSO, and the like, used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds. Any formula given herein is also intended to represent isotopically unenriched forms as well as isotopically enriched forms of the compounds.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H (deuterium, D) , 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I, respectively.
  • the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically enriched compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F-enriched compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-enriched compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, acetone-d 6 , DMSO-d
  • provided herein is a compound for preparing the compound of Formula (I) .
  • provided herein is a method of preparing, separating or purifying the compound of Formula (I) .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds disclosed herein and pharmaceutically acceptable carrier, excipient, diluent, adjuvant, solvent and a combination thereof.
  • the pharmaceutical composition can be liquid, solid, semisolid, gel or spray.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g. synergistic effect.
  • co-administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of the invention and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of the invention and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • inhibiting HCV viral protein should be broadly understood, which comprises inhibiting the expression level of HCV viral protein, inhibiting activity level of HCV viral protein, viral assembly and egress level.
  • the expression level of HCV protein includes, but are not limited to translation level of the viral protein, posttranslational modification level of the viral protein, replication level of genetic material in offsprings and so on.
  • the present invention relates to a macrocyclic compound and a pharmaceutic preparation thereof, which can inhibit HCV infection effectively, especially HCV NS3/4A protein activity.
  • ring A is C 6-10 phenyl or C 1-9 heteroaryl; and ring A is optionally substituted with 1, 2, 3 or 4 independent R 2 ;
  • R 1 is C 6-10 aryl or C 1-9 heteroaryl
  • each of R 2 and R 3 is independently H, F, Cl, Br, I, amino, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl;
  • R 4 is H, deuterium or C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • each the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl and amino is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-10 cycloalkyl, C 2-10 heterocyclyl, C 6-10 aryl and C 1-9 heteroaryl.
  • ring A is phenyl or 5-6 membered heteroaryl; and wherein each of the phenyl and 5-6 membered heteroaryl is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C 3-10 cycloalkyl, C 2-10 heterocyclyl and C 6-10 aryl.
  • substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C
  • ring A is phenyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, quinolyl, indolyl or acridinyl.
  • a compound having Formula (I) or a stereoisomer, a tautomer, an enantiomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof
  • R 1 of Formula (I') , (I) or (II) is phenyl or 5-6 membered heteroaryl; and wherein each of the phenyl and 5-6 membered heteroaryl is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylamino, C 3-10 cycloalkyl, C 2-10 heterocyclyl and C 6-10 aryl.
  • R 1 of Formula (I') , (I) or (II) is phenyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, quinolyl, indolyl or acridinyl, and wherein each R 1 is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, trifluoromethyl, difluoroethyl, trifluoromethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl,
  • each R 2 and R 3 of Formula (I') , (I) or (II) is independently H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, trifluoromethyl, trifluoromethoxy, t-butyl, vinyl, propenyl, ethynyl, propinyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, methylamino or ethylamino.
  • R 4 of Formula (I') , (I) or (II) is H, deuterium, methyl, deuterated methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • R 1 of Formula (I') , (I) or (II) is 5-6 membered heteroaryl; and wherein the 5-6 membered heteroaryl is independently and optionally substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, hydroxy, amino, F, Cl, Br, I, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 alkylamino; R 2 of Formula (I') , (I) or (II) is C 1-6 alkyl; R 3 of Formula (I') , (I) or (II) is C 1-3 alkyl; and R 4 of Formula (I') , (I) or (II) is H or C 1-3 alkyl.
  • the compound of the invention (comprising a compound having Formula (I') , (I) or (II) , or a stereoisomer, a geometric isomer, a tautomer, an enantiomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof) can be used in the manufacture of a medicine for treatment of acute or chronic HCV infection including that described herein. Further more, the compound of the invention can be used in the manufacture of an anti-HCV drug.
  • the compound disclosed herein also can be used in the manufacture of a medicine for lessening,preventing, managing or treating diseases mediated by HCV, especially HCV NS3/4A protein.
  • the compound of the invention can act as an active ingredient of a pharmaceutical composition
  • the pharmaceutical composition may comprises the compound of Formula (I') , (I) or (II) and may further comprise at least one pharmaceutically acceptable carrier, adjuvant or diluent.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the skills in the art could choose “pharmaceutically acceptable” substance or composition base on the other ingredients and the objects for treatment such as human.
  • the compounds disclosed herein also include salts of the compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I') , (I) or (II) and/or for separating enantiomers of compounds of Formula (I') , (I) or (II) .
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid or organic acid, wherein the inorganic acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • organic acid examples include acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; a pyranosidyl acid, such as glucuronic acid and galacturonic acid; an alpha-hydroxy acid, such as citric acid and tartaric acid; an amino acid, such as aspartic acid and glutamic acid; an aromatic acid, such as benzoic acid and cinnamic acid; a sulfonic acid, such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary) , an alkali metal hydroxide, or alkaline earth metal hydroxide, and the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine; ammonia, such as primary, secondary and tertiary amine and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium, and the like.
  • the pharmaceutical composition disclosed herein comprises any one of the compounds.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially which has a good inhibitory effect on NS3/4A protein.
  • the pharmaceutical composition disclosed herein further comprises anti-HCV agents.
  • the anti-HCV agent may be any other known anti-HCV agent except the compound described herein.
  • the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine5’-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, CIVACIR TM , boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF-961, GS-9256, narlap
  • the interferon is interferon ⁇ -2b, pegylated interferon ⁇ , interferon ⁇ -2a, pegylated interferon ⁇ -2a, consensus interferon- ⁇ , interferon ⁇ or a combination thereof.
  • the pharmaceutical composition futher comprise an HCV inhibitor, wherein the HCV inhibitor inhibits HCV replication process and/or a function of an HCV viral protein, and wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral proteins comprise metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) and inosine-5’-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • HCV inhibitor inhibits HCV replication process and/or a function of an HCV viral protein
  • therapeutically effective amounts of the compound of formula (I) of the invention may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition.
  • the invention further provides pharmaceutical compositions, which comprise therapeutically effective amounts of compounds of Formula (I) or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carrier, diluent or excipient.
  • therapeutically effective amount, ” as used herein refers to the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., a reduction in viral load) . When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof are as described above.
  • the carrier (s) , diluent (s) , or excipient (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of Formula (I) , or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram ( “mg/kg” ) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a mono therapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • mg/kg milligram per kilogram
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.
  • compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80%of the dosage normally administered in a monotherapy regimen.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual) , rectal, nasal, topical (including buccal, sublingual, or transdermal) , vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier (s) or excipient (s) . Oral administration and administration by injection are preferred.
  • compositions adapted for oral administration may be presented as discrete units such as capsules of tablets; powders or granules; solution or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
  • Capsules are maded by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluents or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt and/or
  • absorption agent such as betonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solution of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solution of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac,
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating of embedding particulate material in polymers, wax, or the like.
  • the compounds of Formula (I) can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carrier to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxy ethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly ( ⁇ -caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.
  • compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting HCV replication process and/or a function of an HCV viral protein, and wherein the HCV replication process is a whole viral cycle consisting of HCV entry, uncoating, translation, replication, assembly and egress; and wherein the HCV viral proteins comprise metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site (IRES) and inosine-5’-monophosphate dehydrogenase (IMPDH) required in HCV viral replication.
  • the pharmaceutical composition can be used for treating HCV infection or a HCV disorder, especially which has a good inhibitory effect on HCV NS3/4A protein.
  • the present invention also disclosed a therapeutic method comprising administering the compound or pharmaceutical composition disclosed herein, further comprising administering an other than anti-HCV agent, therefore, the method can comprise administering both the compound and the other than anti-HCV agent in a combination, wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, imiquimod, an inosine 5’-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, bavituximab, CIVACIR TM , boceprevir, telaprevir, erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir, danoprevir, sovaprevir, grazoprevir, vedroprevir, BZF
  • the treatment method that includes administering a compound or composition disclosed herein can further include administering to the patient an additional anti-HCV agent, wherein the additional anti-HCV drug is administered together with a compound or composition disclosed herein as a single dosage form or separately from the compound or composition as part of a multiple dosage form.
  • the additional anti-HCV agent may be administered at the same time as a compound disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
  • an “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders.
  • the compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like.
  • a compound or composition can also be administered with one or more other therapeutic agents as discussed above.
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, hexane, DMAC and DMF were treated with anhydrous Na 2 SO 4 prior to use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315B DAD detector were applied in the analysis, and an ESI source was used in the LC-MS spectrometer.
  • MS data were determined by an Agilent 6120 Series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column was operated at 30 °C) .
  • G1329A autosampler and G1315D DAD detector were applied in the analysis, and an ESI source was used on the LC-MS spectrometer.
  • Compound 8 can be prepared by the process illustrated in Scheme 1, wherein R 2 and R 3 are as defined herein. Cyclization of compound 1 and compound 2 can afford compound 3; compound 3 can be hydrolyzed under a base (such as lithium hydroxide, sodium hydroxide, and the like) , the hydrolysis product can react with acyl chloride (such as oxalyl chloride, thionyl chloride, and the like) to afford compound 5.
  • Compound 5 can react with compound 6 to afford compound 7; compound 7 can be cyclized under a base (such as potassium tert-butoxide, sodium tert-butoxide, and the like) to afford compound 8.
  • Compound 13 can be prepared by the process illustrated in Scheme 2, wherein R 4 is as defined herein; the condensation agent used herein is CDI, EDCI, HATU and so on, the acid used herein is hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and so on.
  • Compound 10 can be condensed with compound 11 in the present of a condensating agent to afford compound 12; and then a protecting group of compound 12 can be removed under an acid condition to afford compound 13.
  • Compound 20 disclosed herein can be prepared by the process illustrated in scheme 3, Compound 14 can react with compound 15 under a base (such as lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and so on) to afford compound 16; compound 16 can be hydrolyzed under a base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like) , the hydrolysis product can be decarboxylated in the present of an acid (such as citric acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and the like) to afford compound 18.
  • a base such as lithium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and so on
  • compound 16 can be hydrolyzed under a base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like) , the hydrolysis product can be decarboxylated in the present of an acid (such as citric acid, hydroch
  • Compound 28 can be prepared by the process illustrated in Scheme 4, wherein R 1 , R 2 , R 3 and R 4 are as defined herein.
  • the protecting group PG is Boc, Fmoc, Cbz, Bn, PMB, and so on;
  • the base used herein is sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide and so on;
  • X is halogen or hydroxy;
  • the condensation agent used herein is CDI, EDCI, HATU and so on;
  • the catalyst used for cyclization is Grubb's Catalyst 2nd generation, ZHAN Catalyst-1B, ZHAN Catalyst-1C and so on.
  • Compund 8 can react with compound 21 by Mitsunobu reaction to afford compound 22; compound 22 can be hydrolyzed under a base, the hydrolysis product can be condensed with compound 13 in the present of a condensation agent to afford compound 23.
  • the protecting group of compound 23 can be removed to afford compound 24; compound 24 can react with compound 20 in the present of a condensation agent to afford compound 25.
  • Compound 25 can convert to compound 26 catalyzed by a catalyst used for cyclization; the protecting group of compound 26 can be removed to afford compound 27; compound 27 can react with compound 38 in the present of a condensation agent to afford compound 28.
  • Compound 28 can be prepared by the process illustrated in Scheme 5, wherein R 1 , R 2 , R 3 and R 4 are as defined herein.
  • the protecting group PG is Boc, Fmoc, Cbz, Bn, PMB, and so on;
  • the base used herein is sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide and so on;
  • X is halogen or hydroxy;
  • the catalyst used for cyclization is Grubb's Catalyst 2nd generation, ZHAN Catalyst-1B, ZHAN Catalyst-1C and so on.
  • Compound 29 can react with compound 30 in the present of a condensation agent to afford compound 31; the amino protecting group of compound 31 can be removed to afford compound 32; compound 32 can react with compound 20 in the present of a condensation agent to afford compound 33.
  • Compound 33 can react with compound 8 by Mitsunobu reaction to afford compound 34; compound 34 can convert to compound 35 catalyzed by a catalyst used for cyclization; compound 35 can be hydrolysed under a base to afford compound 36.
  • Compound 36 can react with compound 11 in the present of a condensation agent to afford compound 26.
  • the amino protecting group of compound 26 can be removed to afford compound 27.
  • Compound 27 can react with compound 38 in the present of a condensation agent to afford compound 28.
  • Compound 28 can be prepared by the process illustrated in Scheme 6, wherein R 1 , R 2 , R 3 and R 4 are as defined herein.
  • the protecting group PG is Boc, Fmoc, Bn, Cbz, and so on.
  • Compound 39 can be protected with an amino protecting group to afford compound 40.
  • Mitsunobu reaction of compound 40 can afford lactonic compound 41; the protecting group of compound 41 can be removed to afford compound 42.
  • Condensation reaction of compound 42 with compound 20 can afford compound 43, the condendation agent used herein is CDI, EDCI, HATU, and so on.
  • Compound 43 can react with compound 30 under a base (such as sodium iso-octoate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and so on) to afford compound 44.
  • a base such as sodium iso-octoate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and so on
  • Compound 44 can reacted with sulfonyl chloride (such as methylsufonyl chloride, p-toluensulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, and so on) to afford an intermediate having a better leaving group.
  • sulfonyl chloride such as methylsufonyl chloride, p-toluensulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulf
  • the intermediate can react with compound 8 under a base (such as cesium carbonate, potassium carbonate, sodium carbonate and so on) to afford compound 45; the amide group of compound 45 can be protected to afford compound 46.
  • a base such as cesium carbonate, potassium carbonate, sodium carbonate and so on
  • Olefin metathesis of compound 46 in the present of a catalyst such as ZHAN Catalyst-1B, ZHAN Catalyst-1C, Grubb's Catalyst 2nd generation, and so on
  • Deprotection reaction of compound 47 can afford compound 48.
  • Condendation reaction of compound 48 with compound 38 can afford compound 49; compound 49 can be hydrolyzed under a base (such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like) to afford compound 50.
  • Compound 50 can react with compound 11 to afford compound 28.
  • the mixture was warmed to 39 °C, and 50%aqueous sodium hydroxide solution was added to adjusted pH 8.0.
  • a solution of compound 2-4 (10.58 g, 42.5 mmol) in DMSO (100 mL) was added over 20 min.
  • the mixture was warmed to 40 °C and stirred for 24 hours.
  • Aqueous sodium hydroxide solution (50%) was added frequently to keep pH about 8.0 during the reaction process.
  • the mixture was cooled to 30 °Cand further stirred for 48 hours.
  • High throughput screening of HCV NS3/4A protease inhibitors was performed by using 520 HCV protease detection kit (Anaspec) based on Fluorescence Resonance Energy Transfer (FRET) technology.
  • the fluorescence of 5-FAM was quenched with QXL TM 520 in 5-FAM/QXL TM 520 FRET substrate peptide.
  • the inhibitory effect of compound on HCV NS3/4A protease was evaluated by detecting the fluorescence signal intensity of 5-FAM.
  • the processes were summarized as follows: the compound was dissloved in DMSO, the solution was mixed thoroughly to prepare 10 mM mother solution, which was diluted with Assay buffer containing DTT. The initial concentration tested of the compound was 1 ⁇ M, the compound was diluted by 3-fold serially for a total of 10 concentrations, 3 ⁇ L of the gradient diluted compound was added into a 384 well plate, the final concentration of DMSO in each well was 1%.
  • HCV NS3/4A recombination protease genotypes 1a (Anaspec) or HCV NS3/4Ab recombination protease genotypes1b (Anaspec) was added into the 384 well plate, the final concentration of protease in each well was 0.25 ng/ ⁇ L. Positive compound control group, negative control group and substrate control group were set up.
  • the 384 well plate was placed in an incubator at 25 °C for 15 min, and the substrate solution was incubated at same temperature. After 15 min of incubation, 50-fold diluted FRET peptide substrate was added to each well, and the plate was shocked mildly for 1 min to mix well.
  • Detection of activity of GT1a, GT1b and GT2a replicons HCV GT 1a H77 replicon, GT1b Con1b replicon and GT2a JFH1 replicon containing G418 resistance gene NEO and luciferase reporter gene were transfected respectively and immediately to Huh-7 cell by using an electric shock method. After the addition of G418, the cells were screened for 3 to 4 weeks, stable and transfected cell line was established. Cell line Huh7-H77 and Huh7-JFH1 was diluted to 5 ⁇ 10 4 /mL, 200 ⁇ L of which was seeded to a 96 well plate.
  • Cell line Huh7-Con1b was diluted to 1 ⁇ 10 5 /mL, 50 ⁇ L of which was seeded to a 384 well plate. 16-24 h later, the compound was diluted by 3-fold serially for a total of 11 concentrations to a suitable concentration, the diluted compound was added into the 96 well plate with POD TM 810 plate assembler, the final concentration of DMSO in each well was 0.5%.
  • the plate was incubated in a constant temperature incubator at 37 °C under 5%CO 2 for 72 h, and then to each well was added 40 ⁇ L of luciferase assay reagent (Promega Bright-Glo) , 5 min later, the plate was detected by chemiluminescence detection system (Envision) .
  • the results were processed by using GraphPad Prism software, EC50 of the compound against HCV relipcon was calculated.
  • HCVGT1b/GT3a-NS3, HCVGT1b/GT4a-NS3 and HCVGT1b/GT5a-NS3 chimeric replicon RNA were transfected to Huh7 cell by using an electric shock method, and then the cells were seeded to a 96 well plate containing the compound with a corresponding concentration at a density of 10000 cells per well.
  • the compound in DMSO mother solution was diluted, and the diluted solution was added to the 96 well plate; the final concentration of DMSO was 0.5%.
  • the cells were incubated under 5%CO 2 at 37 °C for 72 hours.
  • Example 4 0.58 1.74 - - - - Example 7 3.33 0.33 1.33 - 0.18 0.35
  • Example 8 1.35 0.37 2.37 - - - Example 9 2.61 0.95 - - - - Example 10 8.43 4.04 - - - - Example 11 4.50 2.74 - - - - Example 13 27.2 13.8 - - - - Example 14 6.75 2.17 - - - - Example 15 5.24 1.15 - - - - Example 16 15.24 4.59 - - - - Example 17 2.37 0.78 - - - - Example 18 13.9 10.3 - - - - Example 20 - 0.51 4.57 - 0.08 0.53
  • IC 50 of the compound against HCV NS3/4A protease and EC 50 of the compound against HCV relipcon indicates that the compounds of the invention have a better inhibitory effect on GT1a, GT1b, GT2a, GT3a, GT4a and GT5a especially on GT2a, therefore, the compounds of the invention can inhibit HCV NS3/4A protease specifically, and have a good antiviral effect.
  • a drug solution (1.5 ⁇ M, 30 ⁇ L) was added into an EP tube (1.5 mL) , and 150 mL of ACN with internal standard was added immediately, and then 15 ⁇ L of NADPH solution (6 mM) was added. After mixing well, the resulting solution was placed in refrigerator at 4°C as a 0 point sample; each drug was prepared in duplicate. 30 ⁇ L of 1.5 ⁇ M drug solution was added into a 96 well plate, the different time points were marked on the wells, each drug was prepared in duplicate, the plate was preheated at 37 °C for 10 min. An NADPH solution (6 mM, 15 ⁇ L) was added into the 60 min point well, the reaction was started and the timer was started.
  • 250-300 g male SD rats were grouped to two groups, each group had 3 rats.
  • the two groups were administered with test compound by intravenous injection and gavage respectively.
  • Blood samples were collected at 8 to 9 time points within 24 hours, and the standard curve was established based on the concentrations of the samples in a suitable range; the concentration of test compound in plasma samples was detected by using AB SCIEX API4000 or Agilent 6430 LC-MS/MS in a MRM mode, and performing quantitative analysis.
  • Pharmacokinetic parameters were calculated according to drug concentration -time curve using a noncompartmental method by WinNonLin 6.3 software.

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Abstract

La présente invention concerne des composés utilisés en tant qu'inhibiteurs du virus de l'hépatite C et des utilisations de ceux-ci en médecine. L'invention concerne spécifiquement un composé de formule (I) ou un stéréoisomère, un tautomère, un énantiomère, un N-oxyde, un hydrate, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament correspondant, qui peuvent être utilisés pour le traitement d'une infection par le virus de l'hépatite C (VHC) ou de l'hépatite C. L'invention concerne également une composition pharmaceutiquement acceptable contenant un tel composé et un procédé de traitement d'une infection par le VHC ou de maladies liées à l'hépatite C comprenant l'administration du composé ou de la composition pharmaceutique correspondante selon l'invention.
PCT/CN2016/073156 2015-02-13 2016-02-02 Composés utilisés en tant qu'inhibiteurs du virus de l'hépatite c et leurs utilisations en médecine WO2016127859A1 (fr)

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WO2018222172A1 (fr) * 2017-05-30 2018-12-06 Taigen Biotechnology Co., Ltd. Formulation de dispersion de solide

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TW201805289A (zh) * 2016-08-11 2018-02-16 廣東東陽光藥業有限公司 作為丙型肝炎病毒抑制劑的鹽
CN108689909A (zh) * 2017-04-12 2018-10-23 浙江九洲药物科技有限公司 一种光学活性n-叔丁氧羰基-2-氨基-8-壬烯酸二环己胺盐的合成方法
CN110123810A (zh) * 2018-02-02 2019-08-16 歌礼生物科技（杭州）有限公司 用于治疗丙型病毒性肝炎的药物组合物
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