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WO2012003642A1 - Composés tricycliques condensés et leur utilisation pour le traitement de maladies virales - Google Patents

Composés tricycliques condensés et leur utilisation pour le traitement de maladies virales Download PDF

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Publication number
WO2012003642A1
WO2012003642A1 PCT/CN2010/075088 CN2010075088W WO2012003642A1 WO 2012003642 A1 WO2012003642 A1 WO 2012003642A1 CN 2010075088 W CN2010075088 W CN 2010075088W WO 2012003642 A1 WO2012003642 A1 WO 2012003642A1
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WIPO (PCT)
Prior art keywords
alkyl
group
independently
compound
inhibitor
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PCT/CN2010/075088
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English (en)
Inventor
Craig A. Coburn
Hao Wu
Bin Hu
Bin Zhong
Dahai Wang
Zaixu Xu
Fei Sun
Tao Ji
Zhigang Dan
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Merck Sharp & Dohme Corp.
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Priority to PCT/CN2010/075088 priority Critical patent/WO2012003642A1/fr
Publication of WO2012003642A1 publication Critical patent/WO2012003642A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel Fused Tricyclic Compounds
  • compositions comprising at least one Fused Tricyclic Compound, and methods of using the Fused Tricyclic Compounds for treating or preventing HCV infection in a patient.
  • HCV Hepatitis C virus
  • BB-NANBH blood-associated NANBH
  • NANBH is to be distinguished from other types of viral-induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biliar cirrhosis.
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HDV delta hepatitis virus
  • CMV cytomegalovirus
  • EBV Epstein-Barr virus
  • HCV replication inhibition is a viable strategy for the prevention of hepatocellular carcinoma.
  • Current therapies for HCV infection include a-interferon monotherapy and combination therapy comprising a-interferon and ribavirin. These therapies have been shown to be effective in some patients with chronic HCV infection, but suffer from poor efficacy and unfavorable side-effects and there are currently efforts directed to the discovery of HCV replication inhibitors that are useful for the treatment and prevention of HCV related disorders.
  • HCV HCV-resistant oligonucleotides
  • free bile acids such as ursodeoxycholic acid and chenodeoxycholic acid
  • conjugated bile acids such as tauroursodeoxycholic acid
  • Phosphonoformic acid esters have also been proposed as potentially useful for the treatment of various viral infections, including HCV.
  • Vaccine development has been hampered by the high degree of viral strain heterogeneity and immune evasion and the lack of protection against reinfection, even with the same inoculum.
  • HCV NS5A is a 447 amino acid phosphoprotein which lacks a defined enzymatic function. It runs as 56kd and 58kd bands on gels depending on
  • HCV NS5A resides in replication complex and may be responsible for the switch from replication of RNA to production of infectious virus (Huang, Y, et al, Virology 364: 1-9 (2007)).
  • the present invention provides Compounds of Formula (I)
  • X 1 , X 2 , X 3 , and X 4 are independently C(R 6 ) or N;
  • M 1 is -0-, -S-, -C(O)-, -C(F 2 )-, -C(Ci-C 6 alkyl) 2 -, -C(H)(Ci-C 6 alkyl)-, -C(CF 3 )(Ci-C 6 alkyl)-, -C(OH)(Ci-C 6 alkyl)-, -C(OCF 3 )(Ci-C 6 alkyl)-,
  • M 2 is -0-, -S-, -C(O)-, -C(F 2 )-, -C(Ci-C 6 alkyl) 2 -, -C(H)(Ci-C 6 alkyl)-,
  • each R 6 is independently H, C 1 -C 4 alkyl, halo, fluoroalkyl, OH, OCF 3 , C 3 -C 7 cycloalkyl, or a 3 - to 7-membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N;
  • each R 2 is independently H, halo, or Ci-C 3 alkyl
  • each of Y 1 and Y 2 is independently -QR 1 ⁇ -, -CH ⁇ R 1 ⁇ -, or -OQR 1 ⁇ -;
  • each R a is independently H, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 6- membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N;
  • each R b is independently C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 6-membered heterocycloalkyl containing one heteroatom selected from the group consisting of N and O;
  • each R 1 is independently H, Ci-C 3 alkyl, CN, F, flouroalkyl, OH, 0-(Ci-C 3 alkyl), OCF 3 , or optionally, two R 1 groups join to form a C 3 -C 6 cycloalkyl or 3- to 6- membered heterocycloalkyl ring containing one heteroatom selected from the group consisting of N and O.
  • the Compounds of Formula (I) (also referred to herein as the "Fused Tricyclic Compounds") and pharmaceutically acceptable salts thereof can be useful, for example, for inhibiting HCV viral replication or replicon activity, and for treating or preventing HCV infection in a patient. Without being bound by any specific theory, it is believed that the Fused Tricyclic Compounds inhibit HCV viral replication by inhibiting HCV NS5a.
  • the present invention provides methods for treating or preventing HCV infection in a patient, comprising administering to the patient an effective amount of at least one Fused Tricyclic Compound.
  • Other embodiments of the present invention include the following:
  • composition comprising an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a pharmaceutical combination that is (i) a Compound of Formula (I) and (ii) a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the Compound of Formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HCV replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of HCV protease inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • (k) A method of treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), or (c) or the combination of (d) or (e).
  • the present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) inhibiting HCV replication, or (b) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HCV antiviral agents, anti-infective agents, and immunomodulators.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, subclasses, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.
  • the present invention provides Fused Tricyclic Compounds, pharmaceutical compositions comprising at least one Fused Tricyclic Compound, and methods of using the Fused Tricyclic Compounds for treating or preventing HCV infection in a patient.
  • a "patient” is a human or non-human mammal. In one embodiment, a patient is a human. In another embodiment, a patient is a chimpanzee.
  • an effective amount refers to an amount of Fused Tricyclic Compound and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from HCV infection.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • preventing refers to reducing the likelihood of HCV infection.
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.
  • An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (Ci-C 6 alkyl) or from 1 to 4 carbon atoms (C 1 -C 4 alkyl) .
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl,
  • an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond.
  • An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , - NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -O-C(O)- cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • C 2 -C 6 alkenyl refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond.
  • An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms.
  • Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • An alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aiyl, -alkylene-O-alkyl, alkylthio, - H 2 , - H(alkyl), -N(alkyl) 2 , - H(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • C 2 -C 6 alkynyl refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • alkylene groups include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )- and -CH 2 CH(CH 3 )CH 2 -.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • an alkylene group is -CH 2 -.
  • the term "Ci-C 6 alkylene” refers to an alkylene group having from 1 to 6 carbon atoms. Unless otherwise indicated, an alkylene group is unsubstituted.
  • aryl refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non- limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.
  • arylene refers to a bivalent group derived from an aryl group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group.
  • An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6 to about 10 carbon atoms. In another
  • an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group.
  • An arylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • An arylene group is divalent and either available bond on an arylene group can connect to either group flanking the arylene group. For example, the group "A-arylene-B," wherein the arylene group is:
  • an arylene group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Unless otherwise indicated, an arylene group is unsubstituted. Non-limiting examples of arylene groups include phenylene and naphthalene. In another embodiment an arylene group is:
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms.
  • cycloalkyl also encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl.
  • a cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the term "3 to 7-membered cycloalkyl” refers to a cycloalkyl group having from 3 to 7 ring carbon atoms.
  • a cycloalkyl group is unsubstituted.
  • a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a cycloalkyl group includes, but is not limited to, cyclobutanoyl:
  • cycloalkenyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 4 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 4 to about 7 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.
  • monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-l,3-dienyl, and the like.
  • a cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • a cycloalkenyl group is cyclopentenyl.
  • a cycloalkenyl group is cyclohexenyl.
  • the term "4 to 7-membered cycloalkenyl” refers to a cycloalkenyl group having from 4 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkenyl group is unsubstituted.
  • halo means -F, -CI, -Br or -I. In one embodiment, a halo group is -F or -CI. In another embodiment, a halo group is -F.
  • haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non- limiting examples of haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 C1 and - CC1 3 .
  • Ci-C 6 haloalkyl refers to a haloalkyl group having from 1 to 6 carbon atoms.
  • hydroxyalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an -OH group. In one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include -CH 2 OH, - CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH and -CH 2 CH(OH)CH 3 .
  • hydroxyalkyl refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.
  • heteroaryl refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroaryl group has 5 to 10 ring atoms.
  • a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
  • a heteroaryl group is bicyclic.
  • a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • heteroaryl also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring.
  • Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • a heteroaryl group is a 5-membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
  • heteroarylene refers to a bivalent group derived from an heteroaryl group, as defined above, by removal of a hydrogen atom from a ring carbon or ring heteroatom of a heteroaryl group.
  • a heteroarylene group can be derived from a monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroarylene group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroarylene group is joined via a ring carbon atom or by a nitrogen atom with an open valence, and any nitrogen atom of a heteroarylene can be optionally oxidized to the corresponding N-oxide.
  • heteroarylene also encompasses a heteroarylene group, as defined above, which is fused to a benzene ring.
  • Non-limiting examples of heteroarylenes include pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinylene, pyridonylene (including those derived from N-substituted pyridonyls), isoxazolylene,
  • thiophenylene furazanylene, pyrrolylene, triazolylene, 1,2,4-thiadiazolylene, pyrazinylene, pyridazinylene, quinoxalinylene, phthalazinylene, oxindolylene, imidazo[l,2-a]pyridinylene, imidazo[2, l-b]thiazolylene, benzofurazanylene, indolylene, azaindolylene, benzimidazolylene, benzothienylene, quinolinylene, imidazolylene, benzimidazolylene, thienopyridylene, quinazolinylene,
  • heteroarylene also refers to partially saturated heteroarylene moieties such as, for example, tetrahydroisoquinolylene,
  • a heteroarylene group is divalent and either available bond on a heteroarylene ring can connect to either group flanking the heteroarylene group.
  • A-heteroarylene-B wherein the heteroarylene group is:
  • a heteroarylene group is a monocyclic heteroarylene group or a bicyclic heteroarylene group. In another embodiment, a heteroarylene group is a monocyclic heteroarylene group. In another embodiment, a heteroarylene group is a bicyclic heteroarylene group. In still another embodiment, a heteroarylene group has from about 5 to about 10 ring atoms. In another embodiment, a heteroarylene group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroarylene group is bicyclic and has 9 or 10 ring atoms. In another embodiment, a heteroarylene group is a 5-membered monocyclic heteroarylene. In another embodiment, a heteroarylene group is a 6-membered monocyclic heteroarylene. In another embodiment, a bicyclic heteroarylene group comprises a 5 or 6-membered
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 1 1 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms.
  • a heterocycloalkyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms.
  • a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms.
  • a heterocycloalkyl group is bicyclic and has from about 7 to about 1 1 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an - N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
  • heterocycloalkyl also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring.
  • a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, and the like, and all isomers thereof.
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is:
  • a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl.
  • the term "3 to 7-membered heterocycloalkyl” refers to a monocyclic heterocycloalkyl group having from 3 to 7 ring atoms.
  • the term "4 to 7-membered monocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms.
  • 7 to 11-membered bicyclic heterocycloalkyl refers to a bicyclic heterocycloalkyl group having from 7 to 11 ring atoms. Unless otherwise indicated, a heterocycloalkyl group is unsubstituted.
  • heterocycloalkenyl refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
  • a heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkenyl group has from 4 to 7 ring atoms.
  • a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group is bicyclic.
  • a heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocycloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6- tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2- imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluoro- substituted dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like and the like.
  • a ring carbon atom of a heterocycloalkenyl group may be functionalized as a carbonyl group.
  • a heterocycloalkenyl group is a 5-membered heterocycloalkenyl.
  • a heterocycloalkenyl group is a 6-membered heterocycloalkenyl.
  • the term "4 to 7-membered heterocycloalkenyl" refers to a heterocycloalkenyl group having from 4 to 7 ring atoms. Unless otherwise indicated, a heterocycloalkenyl group is unsubstituted.
  • Ring system substituent refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene- heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(0)-aryl, halo, -N0 2 , -CN, -SF 5 , -C(0)OH,
  • YiY 2 NS(0) 2 - wherein Yi and Y 2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene- aryl.
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moieties are methylenedioxy,
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • in substantially purified form refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof.
  • substantially purified form also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • any substituent or variable e.g., alkyl, R 6 , R a , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • prodrug means a compound (e.g., a drug precursor) that is transformed in vivo to provide a Fused
  • Tricyclic Compound or a pharmaceutically acceptable salt or solvate of the compound may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C8)alkyl, (C 2 - Ci 2 )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms
  • 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms
  • N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C i -C 2 )alkylamino(C 2 -C3)alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(Ci-C 2 )alkyl, N,N-di (Ci- C 2 )alkylcarbamoyl-(Ci-C 2 )alkyl and piperidino-, pyrrolidino- or morpholino(C 2 - C 3 )alkyl, and the like.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C 6 )alkanoyloxymethyl, l-((Ci- C 6 )alkanoyloxy)ethyl, 1 -methyl- 1 -((C i -C 6 )alkanoyloxy)ethyl, (C i - C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci- C 6 )alkanoyl, a-amino(Ci-C 4 )alkyl, a-amino(Ci-C 4 )alkylene-aryl, arylacyl and a- aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where each a-a-a group
  • L-amino acids independently selected from the naturally occurring L-amino acids, -P(0)(OH) 2 , -P(0)(0(Ci-Ce)alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, RR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, a natural a-aminoacyl,— C(OH)C(0)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl,
  • Y 2 is (Ci-C 4 ) alkyl and Y 3 is (Ci-C 6 )alkyl; carboxy (Ci-C 6 )alkyl; amino(Ci-C 4 )alkyl or mono- N- or di-N,N-(Ci-C 6 )alkylaminoalkyl; -C(Y 4 )Y 5 wherein Y 4 is H or methyl and Y 5 is mono-N- or di-N,N-(Ci-C 6 )alkylamino morpholino;
  • esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl ⁇ e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl ⁇ e.g., methoxymethyl), aralkyl ⁇ e.g., benzyl), aryloxyalkyl (for example,
  • aryl ⁇ e.g., phenyl optionally substituted with, for example, halogen, Ci- 4 alkyl, -0-(Ci -4 alkyl) or amino); (2) sulfonate esters, such as alkyl- or
  • aralkylsulfonyl for example, methanesulfonyl
  • amino acid esters ⁇ e.g., L-valyl or L-isoleucyl
  • phosphonate esters and (5) mono-, di- or triphosphate esters.
  • the phosphate esters may be further esterified by, for example, a C 1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6 -24 )acyl glycerol.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A “hydrate” is a solvate wherein the solvent molecule is water.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechours. , 5(1). article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the Fused Tricyclic Compounds can form salts which are also within the scope of this invention.
  • Reference to a Fused Tricyclic Compound herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)" denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Fused Tricyclic Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,
  • toluenesulfonates also known as tosylates
  • acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al,
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride), separating the diastereomers and converting (e.g., hydro lyzing) the individual diastereomers to the corresponding pure enantiomers.
  • Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques.
  • some of the Fused Tricyclic Compounds may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be directly separated using chiral chromatographic techniques.
  • Fused Tricyclic Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a Fused Tricyclic Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
  • the present invention provides Fused Tricyclic Compounds of Formula (I):
  • the 6-membered aromatic ring comprising the ring atoms X 1 an X 2 is referred to herein as ring Q
  • the 6-membered aromatic ring comprising the ring atoms X 3 an X 4 is referred to herein as ring T.
  • Compounds of Formula (IA) and Compounds of Formula (IB) are specific embodiments of the Compounds of Formula (I).
  • M 1 is -0-
  • X 1 and X 2 are independently C(R 6 ) or N, and
  • X 3 and X 4 are both C(R 6 ).
  • X 1 and X 2 are independently C(R 6 ) or N;
  • X 3 and X 4 are both C(R 6 );
  • M 1 is -0-
  • M 2 is -0-, -S-, -C(O)-, -C(F) 2 -, -C(Ci-C 6 alkyl) 2 -, -C(H)(d-C 6 alkyl)-, -C(OH)(Ci-C 6 alkyl)-, -C(OCF 3 )(Ci-C 6 alkyl)-, -C(0 Ci-C 6 alkyl)(Ci-C 6 alkyl)-, -N(Ci-C 6 alkyl)-, or -S(0) 2 -, or wherein two substituents bonded to M 2 , together with M 2 , form a C 3 -C 6 cycloalkyl ring or a 3 - to 7-membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N;
  • each R 6 is independently H, C 1 -C4 alkyl, halo, fluoroalkyl, OH, OCF 3 , C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N;
  • each R 2 is independently H or F
  • each of Y 1 and Y 2 is independently -C(R or -CH ⁇ R 1 ) ⁇ ;
  • each R a is independently H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 6- membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N; each R b is independently C 1 -C4 alkyl, C 3 -C7 cycloalkyl, or 4- to 6-membered heterocycloalkyl containing one heteroatom selected from the group consisting of N and O;
  • each R 1 is independently H, C 1 -C 3 alkyl, CN, fluoroalkyl, OH, 0-(Ci-C 3 alkyl), F, OCF 3 , or optionally, two R 1 groups, together with the carbon atom(s) to which they are attached, form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from the group consisting of N and O.
  • two R 1 groups together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from the group consisting of N and O, wherein the carbon atoms to which the two R 1 groups are either joined to the same carbon atom, or are joined to different, non- vicinal
  • two R 1 groups together with the carbon atoms to which they are attached, form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from the group consisting of N and O, wherein the carbon atoms to which the two R 1 groups
  • each R 6 is independently H, CH 3 , halo, or CF 3 ;
  • each R 2 is independently H or F
  • each R a is independently methyl, ethyl, isopropyl, t-butyl, cyclopropyl, or pyranyl;
  • each R b is independently methyl, ethyl, isopropyl, t-butyl, cyclopropyl, or pyranyl;
  • each R 1 is independently H, CH 3 , CF 3 , F, OCH 3 , OCF 3 , or two R 1 groups, together with the carbon atom(s) to which they are attached form a cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, or pyranyl ring.
  • each R 2 is independently H or F
  • each R a is independently isopropyl, t-butyl, or cyclopropyl;
  • each R b is independently isopropyl, t-butyl, or cyclopropyl;
  • each R 1 is independently H or F.
  • the moiety is bonded to the imidazole moiety at the 2-position of the imidazole moiety, and the Q or T ring is bonded to the same imidazole moiety at the 4- or 5- position.
  • the Compounds of Formula (I) can have
  • the moiety is bonded to the imidazole moiety at the 4 or 5-position of the imidazole moiety , and the Q or T ring is bonded to the same imidazole moiety at the 2-position.
  • the Q or T ring is bonded to the same imidazole moiety at the 2-position.
  • the invention provides Compounds of Formula (IA), and their pharmaceuticall acceptable salts:
  • X 1 , X 2 , X 3 , and X 4 are independently C(R 6 ) or N;
  • M 1 is -0-, -S-, -C(O)-, -C(Ci-C 6 alkyl) 2 -, -N(Ci-C 6 alkyl)-, or -S(0) 2 -;
  • M 2 is -0-, -S-, -C(O)-, -C(Ci-C 6 alkyl) 2 -, -N(d-C 6 alkyl)-, or -S(0) 2 -;
  • each R 2 is independently H or F
  • each R 6 is independently H, C 1 -C4 alkyl, CF 3 , OCF 3 , or halo;
  • each R a is independently H, Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 6- membered heterocycloalkyl containing one heteroatom selected from the group consisting of O and N;
  • each R b is independently Ci-C 4 alkyl, C 3 -C 7 cycloalkyl, or 4- to 6-membered heterocycloalkyl containing one heteroatom selected from the group consisting of N and O;
  • each R 1 is independently H, Ci-C 3 alkyl, 0-(Ci-C 3 alkyl), F, OCF 3 , or optionally, two R 1 groups join to form a C 3 -C 6 cycloalkyl or 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from the group consisting of N and O.
  • M 1 is -0-, -S-, -C(O)-, -C(CH 3 ) 2 -, -N(CH 3 )-, or -S(0) 2 -.
  • M 2 is -0-, -S-, -C(O)-, -C(CH 3 ) 2 -, -N(CH 3 )-, or -S(0) 2 -.
  • X 3 is C(R 6 ) or
  • each R 6 is independently H or halo.
  • each R 2 is H.
  • each R a is independently H, C1-C4 alkyl, or C3-C7 cycloalkyl.
  • each R b is independently C1-C4 alkyl.
  • each R 1 is independently H, C1-C3 alkyl, or F.
  • each of the two illustrated imidazole rings are joined to rings Q and T at a position that is either meta or para to the ring position where M 1 or M 2 join rings Q and T.
  • the Com ounds of Formula (IA) can have one of the following substructures:
  • the invention provides Compounds of Formula (IB), and their harmaceutically acceptable salts:
  • M 1 is -0-, -S-, -C(O)-, -C(CH 3 ) 2 -, -N(CH 3 )-, or -S(0) 2 -;
  • M 2 is -0-, -S-, -C(O)-, -C(CH 3 ) 2 -, -N(CH 3 )-, or -S(0) 2 -;
  • X 1 is C(R 6 ) or N;
  • each R 6 is independently H or halo
  • each R a is independently H, C1-C4 alkyl, or C 3 -C 7 cycloalkyl;
  • each R b is independently C1-C4 alkyl; each R 1 is independently H, C 1 -C3 alkyl, or F.
  • each of the two illustrated imidazole rings are joined to rings Q and T at a position that is either meta or para to the ring position where M 1 or M 2 join rings Q and T.
  • the Compounds of Formula (IA) can have one of the following substructures:
  • each R 6 is independently H or fluoro.
  • each R a is independently isopropyl, t-butyl, or cyclopropyl.
  • each R b is methyl.
  • each R 1 is H.
  • each R a is independently isopropyl, t-butyl, or cyclopropyl;
  • each R b is methyl
  • each R 1 is H.
  • each R a is independently isopropyl, t-butyl, or cyclopropyl;
  • each R b is methyl
  • each R 1 is H.
  • Compounds of Formula (I) are selected independently from each other.
  • a Compound of Formula (I) is in substantially purified form.
  • Non-limiting examples of the Compounds of Formula (I) include compounds 1-16, as listed in Table 1 in the Examples, and compounds 17-52, as listed
  • Compounds 1-16 were prepared using the methods, or procedures similar to those described in Example 1-6 in the Example section.
  • Compounds 17-52 can be prepared using procedures that are similar to those described in the Examples section.
  • the Compounds of Formula (I) include compounds 1-16 as listed above and pharmaceutically acceptable salts thereof.
  • the Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in the Examples below and generalized in Schemes 1-5 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. All stereoisomers and tautomeric forms of the compounds are contemplated.
  • Scheme 1 shows a method useful for making Compounds of Formula (I), wherein M 1 and M 2 are both -0-.
  • Schemes 2-5 show methods for making intermediate tricyclic halides useful for the synthesis of Compounds of Formula (I).
  • Scheme 2 shows a sequence useful for preparing Compounds of Formula (I) wherein M 1 is -O- and M 2 is -C(O)-.
  • Scheme 3 shows a sequence useful for preparing Compounds of Formula (I) wherein M 1 is -O- and M 2 is -N(Ci-C 6 alkyl)-.
  • Scheme 4 shows a method useful for making Compounds of Formula (I), wherein M 1 and M 2 are both -0-, and X 1 is N.
  • Scheme 5 shows a sequence useful for preparing Compounds of Formula (I) wherein M 1 is -O- and M 2 is -S-
  • the amino acids such as, but not limited to proline, 4,4-difluoroproline, (S)-2-piperidine carboxylic acid, valine, alanine, norvaline, etc.
  • Methods have been described in the general literature as well as in U.S. Patent Publication No. US20090068140.
  • the descriptions of the preparations of such amino acid-derived intermediates in U.S. Patent Publication No. US20090068140 are hereby incorporated by reference.
  • This example describes the preparation of Compounds of Formula (I) wherein M 1 and M 2 are each O. The preparation is specifically described for Compounds 1 and 2.
  • the mixture was purified by reverse phase HPLC (Syrergi, 30x 100mm, CH 3 CN-H 2 0- 0.1% TFA) to give the desired targets.
  • the isomers were separated by preparative HPLC.
  • N-Bromo succinimide (838.4 mg, 4.71 mmol) was added in portions over 15 minutes to a cooled (ice/water) CH 2 C1 2 (20 mL) solution of imidazole Int-2c (1.06 g, 4.50 mmol). The reaction mixture was stirred for 75 minutes and concentrated in vacuo to an oil. The crude product was purified by silica-gel RPLC (Acetonitrile/ water/ 0.1% TFA) to separate the mono bromide from its dibromo analog (over bromination) and the starting material. The RPLC elute was neutralized with excess NH 3 /MeOH, and the volatile component was removed in vacuo.
  • This example describes the preparation of Compounds of the Formula (I) wherein M 1 is O and M 2 is N-Me .
  • the preparation is specifically described for Compound 13.
  • HCV replicon system Measurement of inhibition by compounds was performed using the HCV replicon system. Several different replicons encoding different HCV genotypes or mutations were used. In addition, potency measurements were made using different formats of the replicon assay, including different ways of measurements and different plating formats. See Jan M. Vrolijk et al., A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C, 110 J.
  • TaqMan®-Based Assay Protocol Compounds 1, 2, 4, and 8-14 were assayed for cell-based anti-HCV activity by the following protocol. Replicon cells were seeded at 5000 cells/well in 96-well collagen I-coated Nunc plates in the presence of the test compound. Various concentrations of test compound, typically in 10 serial 2-fold dilutions, were added to the assay mixture, with the starting concentration ranging from 250 ⁇ to 1 ⁇ . The final concentration of DMSO was 0.5%, fetal bovine serum was 5%, in the assay media. Cells were harvested on day 3 by the addition of lx cell lysis buffer (Ambion cat #8721).
  • the replicon RNA level was measured using real time PCR (TaqMan® assay).
  • the amplicon was located in 5B.
  • the PCR primers were: 5B.2F, ATGGACAGGCGCCCTGA (SEQ. ID NO. 1); 5B.2R,
  • TTGATGGGCAGCTTGGTTTC SEQ. ID NO. 2
  • the probe sequence was FAM- labeled CACGCCATGCGCTGCGG (SEQ. ID NO. 3).
  • GAPDH RNA was used as endogenous control and was amplified in the same reaction as NS5B (multiplex PCR) using primers and VIC-labeled probe recommended by the manufacturer (PE Applied Biosystem). The real-time RT-PCR reactions were run on ABI PRISM 7900HT Sequence Detection System using the following program: 48 C for 30 min, 95 C for 10 min, 40 cycles of 95 ° C for 15 sec, 60 ° C for 1 min.
  • ACT values were plotted against the concentration of test compound and fitted to the sigmoid dose-response model using XLfit4 (MDL).
  • a standard curve was established by including serially diluted T7 transcripts of replicon RNA in the Taqman assay. All TaqMan® reagents were from PE Applied Biosystems. Such an assay procedure was described in detail in e.g. Malcolm et al, Antimicrobial Agents and Chemotherapy 50: 1013-1020 (2006).
  • Luciferase-Based Replicon Assay Protocol Anti-HCV activities for compounds 3, 5, 6, 7, 15, and 16 were determined by a luciferase-based assay. In this assay, stable neomycin phosphotransferase encoding replicon-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. In some cases, the cell lines encoded a luciferase: Neor fusion and could be assayed either directly by determination of RNA copy number, or indirectly through measurement of the luciferase activity.
  • replicon cells were plated in the presence of a dilution series of test compound in the absence of G418. Typically, the assays were performed in a 96-well plate format for manual operation, or a 384-well plate in an automated assay. Replicon cells and compound were incubated for 24 to 72 hours. At the end of the assay, cells are washed free of media and compound and then lysed. Luciferase activity was measured using a conventional luciferase assay. EC 50 determinations were calculated as a percent of a DMSO control by fitting the data to a four parameter fit function
  • HCV replicon assay data was calculated for genotypes lb, 2a and la for representative compounds of the present invention using this method and is provided in the table below.
  • 16* 0.0694 0.1083 0.0440 indicates that data for this compound was obtained by the luciferase-based assay.
  • the Fused Tricyclic Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient.
  • the Fused Tricyclic Compounds can be inhibitors of viral replication.
  • the Fused Tricyclic Compounds can be inhibitors of HCV replication. Accordingly, the Fused Tricyclic Compounds are useful for treating viral infections, such as HCV.
  • the Fused Tricyclic Compounds can be
  • the invention provides methods for treating a viral infection in a patient comprising administering to the patient an effective amount of at least one Fused Tricyclic Compound or a pharmaceutically acceptable salt thereof. Treatment or Prevention of a Flaviviridae Virus
  • the Fused Tricyclic Compounds can be useful for treating or preventing a viral infection caused by the Flaviviridae family of viruses.
  • Flaviviridae infections that can be treated or prevented using the present methods include but are not limited to, dengue fever, Japanese encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis encephalitis, Tick- borne encephalitis, West Nile encephalitis, yellow fever and Hepatitis C Virus (HCV) infection.
  • dengue fever Japanese encephalitis
  • Kyasanur Forest disease Murray Valley encephalitis
  • St. Louis encephalitis St. Louis encephalitis
  • Tick- borne encephalitis West Nile encephalitis
  • West Nile encephalitis yellow fever
  • HCV Hepatitis C Virus
  • the Flaviviridae infection being treated is hepatitis C virus infection.
  • the Fused Tricyclic Compounds are useful in the inhibition of HCV (e.g., HCV replication), the treatment of HCV infection and/or reduction of the likelihood or severity of symptoms of HCV infection and the inhibition of HCV viral replication and/or HCV viral production in a cell-based system.
  • HCV e.g., HCV replication
  • Tricyclic Compounds are useful in treating infection by HCV after suspected past exposure to HCV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures.
  • the hepatitis C infection is acute hepatitis C. In another embodiment, the hepatitis C infection is chronic hepatitis C.
  • the invention provides methods for treating HCV infection in a patient, the methods comprising administering to the patient an effective amount of at least one Fused Tricyclic Compound or a pharmaceutically acceptable salt thereof.
  • the amount administered is effective to treat or prevent infection by HCV in the patient.
  • the amount administered is effective to inhibit HCV viral replication and/or viral production in the patient.
  • the Fused Tricyclic Compounds are also useful in the preparation and execution of screening assays for antiviral compounds.
  • the Fused Tricyclic Compounds are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5 A, which are excellent screening tools for more powerful antiviral compounds.
  • the Fused Tricyclic Compounds are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
  • compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any HCV genotype.
  • HCV types and subtypes may differ in their antigenicity, level of viremia, severity of disease produced, and response to interferon therapy as described in Holland et al, Pathology, 30(2): 192-195 (1998).
  • the nomenclature set forth in Simmonds et al., J Gen Virol, 74(Ptl l):2391-2399 (1993) is widely used and classifies isolates into six major genotypes, 1 through 6, with two or more related subtypes, e.g., la and lb.
  • genotypes 7-10 and 11 have been proposed, however the phylogenetic basis on which this classification is based has been questioned, and thus types 7, 8, 9 and 11 isolates have been reassigned as type 6, and type 10 isolates as type 3 (see Lamballerie et al, J Gen Virol, 78(Ptl):45-51 (1997)).
  • the major genotypes have been defined as having sequence similarities of between 55 and 72% (mean 64.5%), and subtypes within types as having 75%-86% similarity (mean 80%) when
  • the present methods for treating or preventing HCV infection can further comprise the administration of one or more additional
  • the additional therapeutic agent is an antiviral agent.
  • the additional therapeutic agent is an
  • immunomodulatory agent such as an immunosuppressive agent.
  • the present invention provides methods for treating a viral infection in a patient, the method comprising administering to the patient: (i) at least one Fused Tricyclic Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Fused Tricyclic Compound, wherein the amounts administered are together effective to treat or prevent a viral infection.
  • therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • a Fused Tricyclic Compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
  • the at least one Fused Tricyclic Compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-oxide
  • the at least one Fused Tricyclic Compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one Fused Tricyclic Compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one Fused Tricyclic Compound and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.
  • the at least one Fused Tricyclic Compound and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • this composition is suitable for subcutaneous administration.
  • this composition is suitable for parenteral administration.
  • Viral infections and virus-related disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.
  • the viral infection is HCV infection.
  • the at least one Fused Tricyclic Compound and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
  • Compound and the additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents.
  • Non-limiting examples of additional therapeutic agents useful in the present compositions and methods include an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-dependent polymerase-related disorder.
  • the additional therapeutic agent is a viral protease inhibitor.
  • the additional therapeutic agent is a viral replication inhibitor.
  • the additional therapeutic agent is an HCV NS3 protease inhibitor.
  • the additional therapeutic agent is an HCV NS5B polymerase inhibitor.
  • the additional therapeutic agent is a nucleoside inhibitor.
  • the additional therapeutic agent is an interferon.
  • the additional therapeutic agent is an HCV replicase inhibitor.
  • the additional therapeutic agent is an antisense agent. In another embodiment, the additional therapeutic agent is a therapeutic vaccine.
  • the additional therapeutic agent is a virion
  • the additional therapeutic agent is an antibody therapy.
  • the additional therapeutic agent is an HCV NS2 inhibitor. In still another embodiment, the additional therapeutic agent is an HCV NS4A inhibitor.
  • the additional therapeutic agent is an HCV NS4B inhibitor.
  • the additional therapeutic agent is an HCV NS5A inhibitor.
  • the additional therapeutic agent is an HCV NS3 helicase inhibitor.
  • the additional therapeutic agent is an HCV IRES inhibitor.
  • the additional therapeutic agent is an HCV p7 inhibitor.
  • the additional therapeutic agent is an HCV entry inhibitor.
  • the additional therapeutic agent is an HCV assembly inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor and a viral polymerase inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor and an immunomodulatory agent.
  • the additional therapeutic agents comprise a polymerase inhibitor and an immunomodulatory agent.
  • the additional therapeutic agents comprise a viral protease inhibitor and a nucleoside.
  • the additional therapeutic agents comprise an immunomodulatory agent and a nucleoside.
  • the additional therapeutic agents comprise an HCV protease inhibitor and an HCV polymerase inhibitor.
  • the additional therapeutic agents comprise a nucleoside and an HCV NS5 A inhibitor.
  • the additional therapeutic agents comprise a viral protease inhibitor, an immunomodulatory agent and a nucleoside.
  • the additional therapeutic agents comprise a viral protease inhibitor, a viral polymerase inhibitor and an immunomodulatory agent.
  • the additional therapeutic agent is ribavirin.
  • HCV polymerase inhibitors useful in the present compositions and methods include, but are not limited to, VP- 19744 (Wyeth/ViroPharma), PSI-7851
  • HCV polymerase inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in International Publication Nos. WO 08/082484, WO 08/082488, WO 08/083351, WO 08/136815, WO
  • Interferons useful in the present compositions and methods include, but are not limited to, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1 and PEG- interferon alpha conjugates.
  • PEG-interferon alpha conjugates are interferon alpha molecules covalently attached to a PEG molecule.
  • Illustrative PEG-interferon alpha conjugates include interferon alpha-2a (RoferonTM, Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alpha-2a ⁇ e.g., as sold under the trade name PegasysTM), interferon alpha-2b (IntronTM, from Merck Corporation) in the form of pegylated interferon alpha-2b ⁇ e.g., as sold under the trade name PEG-IntronTMfrom Merck Corporation), interferon alpha-2b-XL ⁇ e.g., as sold under the trade name PEG- IntronTM), interferon alpha-2c (Berofor AlphaTM, Boehringer Ingelheim, Ingelheim, Germany), PEG-interferon lambda (Bristol-Myers Squibb and ZymoGenetics), interferon alfa-2b alpha fusion polypeptides, interferon fused with the human blood protein albumin (Albufer
  • Protease inhibitors useful in the present compositions and methods include, but are not limited to, SCH503034 (Boceprevir, Merck), SCH900518 (Merck), VX- 950 (Telaprevir, Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335 (Boehringer Ingelheim), TMC-435 (Medivir/Tibotec), ABT-450 (Abbott), MK-7009 (Merck), TMC-435350 (Medivir), ITMN-191/R7227 (InterMune/Roche), EA-058 (Abbott/Enanta), EA-063 (Abbott/Enanta), GS-9132 (Gilead/Achillion), ACH-1095 (Gilead/Achillon), IDX-136 (Idenix), IDX-316 (Idenix), ITMN-8356 (InterMune), ITMN-8347 (InterMune
  • HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in Landro et al, Biochemistry, 36(31):9340-9348 (1997); Ingallinella et al, Biochemistry,
  • compositions and methods include, but are not limited to, the following compounds:
  • Viral replication inhibitors useful in the present compositions and methods include, but are not limited to, HCV replicase inhibitors, IRES inhibitors, NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors, NS5B inhibitors, ribavirin, AZD- 2836 (Astra Zeneca), BMS-790052 (Bristol-Myers Squibb), PPI-461 (Presidio Pharmaceuticals, Inc.), PPI-1301 (Presidio Pharmaceuticals, Inc.), viramidine, A-831 (Arrow Therapeutics); an antisense agent or a therapeutic vaccine.
  • HCV NS4A inhibitors useful in the useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Nos. 7,476,686 and 7,273,885; U.S. Patent Publication No. US20090022688; and International Publication Nos. WO 2006/019831 and WO 2006/019832.
  • Additional HCV NS4A inhibitors useful in the useful in the present compositions and methods include, but are not limited to, ACH-806 (Achillon Pharmaceuticals, New Haven, CT).
  • HCV NS5A inhibitors useful in the useful in the present compositions and methods include, but are not limited to, AZD-2836 (Astra Zeneca), AZD-7295 (Astra Zeneca), BMS-790052 (Bristol-Myers Squibb), PPI-461 (Presidio Pharmaceuticals, Inc.), and PPI-1301 (Presidio Pharmaceuticals, Inc.).
  • HCV replicase inhibitors useful in the useful in the present compositions and methods include, but are not limited to, those disclosed in U.S. Patent Publication No. US20090081636.
  • Therapeutic vaccines useful in the present compositions and methods include, but are not limited to, IC41 (Intercell Novartis), CSL123 (Chiron/CSL), GI 5005 (Glo situmune), TG-4040 (Transgene), GNI-103 (GENimmune), Hepavaxx C (ViRex Medical), ChronVac-C (Inovio/Tripep), PeviPROTM (Pevion Biotect), HCV/MF59 (Chiron/Novartis) and Civacir (NABI).
  • TT033 Benitec/Tacere Bio/Pfizer
  • Sirna-034 Sirna Therapeutics
  • GNI-104 GNI-104
  • IDX-102 Idenix
  • LevovirinTM ICN Pharmaceuticals, Costa Mesa, California
  • Humax Genemab
  • ITX-2155 Ithrex/Novartis
  • PRO 206 Progenies
  • HepaCide-I NemoVirocides
  • MX3235 Migenix
  • SCY-635 Scynexis
  • KPE02003002 Kemin Pharma
  • Lenocta VasoQuest Pharmaceuticals
  • IET - Interferon Enhancing Therapy Transition Therapeutics
  • Zadaxin SciClone Pharma
  • VP 50406TM Viropharma, Incorporated, Exton, Pennsylvania
  • Taribavirin Valeant Pharmaceuticals
  • Nitazoxanide Romark
  • Debio 025 Debiopharm
  • GS-9450 Gilead
  • PF-4878691 Pfizer
  • ANA773 Acadys
  • SCV-07 SciClone
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of HCV infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Fused Tricyclic Compound(s) and the other agent(s) can be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially.
  • kits comprising the separate dosage forms is therefore advantageous.
  • a total daily dosage of the at least one Fused Tricyclic Compound(s) alone, or when administered as combination therapy can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
  • the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the additional therapeutic agent is INTRON-A interferon alpha 2b (commercially available from Merck)
  • this agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW for 24 weeks or 48 weeks for first time treatment.
  • the additional therapeutic agent when the additional therapeutic agent is PEG- INTRON interferon alpha 2b pegylated (commercially available from Merck Corp.), this agent is administered by subcutaneous injection at 1.5 mcg/kg/week, within a range of 40 to 150 meg/week, for at least 24 weeks.
  • the additional therapeutic agent when the additional therapeutic agent is ROFERON A interferon alpha 2a (commercially available from Hoffmann-La Roche), this agent is administered by subcutaneous or intramuscular injection at 3MIU(11.1
  • mcg/mL mcg/mL/TIW for at least 48 to 52 weeks, or alternatively 6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks.
  • PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La Roche), this agent is administered by subcutaneous injection at 180 mcg/lmL or 180 mcg/0.5mL, once a week for at least 24 weeks.
  • INFERGEN interferon alphacon-1 (commercially available from Amgen), this agent is administered by subcutaneous injection at 9 mcg/TIW is 24 weeks for first time treatment and up to 15 mcg/TIW for 24 weeks for non-responsive or relapse treatment.
  • the additional therapeutic agent is Ribavirin (commercially available as REBETOL ribavirin from Merck or COPEGUS ribavirin from Hoffmann-La Roche)
  • this agent is administered at a daily dosage of from about 600 to about 1400 mg/day for at least 24 weeks.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating an RNA- dependent polymerase-related disorder.
  • additional therapeutic agents selected from: an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • the combination therapies can include any combination of these additional therapeutic agents.
  • one or more compounds of the present invention are administered with one additional therapeutic agent selected from an HCV protease inhibitor, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with two additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with an HCV protease inhibitor and ribavirin. In another specific embodiment, one or more compounds of the present invention are administered with a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with three additional therapeutic agents selected from an HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
  • one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor. In another embodiment, one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor. In another embodiment, one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and ribavirin.
  • one or more compounds of the present invention are administered with one additional therapeutic agent selected from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral replication inhibitor. In another embodiment, one or more compounds of the present invention are
  • one or more compounds of the present invention are administered with two additional therapeutic agents selected from an HCV
  • polymerase inhibitor a viral protease inhibitor, an interferon, and a viral replication inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent. In another embodiment, one or more compounds of the present invention are administered with ribavirin, interferon and another therapeutic agent, wherein the additional therapeutic agent is selected from an HCV polymerase inhibitor, a viral protease inhibitor, and a viral replication inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and a viral protease inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and an HCV protease inhibitor.
  • one or more compounds of the present invention are administered with ribavirin, interferon and boceprevir or telaprevir.
  • one or more compounds of the present invention are administered with ribavirin, interferon and an HCV polymerase inhibitor.
  • the Fused Tricyclic Compounds are useful in veterinary and human medicine. As described above, the Fused Tricyclic Compounds are useful for treating or preventing HCV infection in a patient in need thereof.
  • the Fused Tricyclic Compounds When administered to a patient, the Fused Tricyclic Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • the present invention provides pharmaceutical compositions comprising an effective amount of at least one Fused Tricyclic
  • the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.
  • suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.
  • Liquid form preparations may also include solutions for intranasal
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • a pharmaceutically acceptable carrier such as an inert compressed gas.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral
  • Such liquid forms include solutions, suspensions and emulsions.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the one or more Fused Tricyclic Compounds are administered orally. In another embodiment, the one or more Fused Tricyclic Compounds are administered intravenously.
  • the one or more Fused Tricyclic Compounds are administered topically.
  • the one or more Fused Tricyclic Compounds are administered sublingually.
  • a pharmaceutical preparation comprising at least one Fused Tricyclic Compound is in unit dosage form.
  • the preparation is subdivided into unit doses containing effective amounts of the active components.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Fused Tricyclic Compound(s) by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Fused Tricyclic Compound(s) by weight or volume.
  • the quantity of Fused Tricyclic Compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 2500 mg. In various embodiment, the quantity is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 100 mg.
  • the total daily dosage may be divided and administered in portions during the day if desired.
  • the daily dosage is
  • the total daily dosage is administered in one portion.
  • the total daily dosage is administered in two divided doses over a 24 hour period.
  • the total daily dosage is administered in three divided doses over a 24 hour period.
  • the total daily dosage is administered in four divided doses over a 24 hour period.
  • a total daily dosage of the Fused Tricyclic Compounds range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 100 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses.
  • compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Fused Tricyclic Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Fused Tricyclic Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat HCV infection.
  • the present invention provides a kit comprising a therapeutically effective amount of at least one Fused Tricyclic Compound, or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present invention provides a kit comprising an amount of at least one Fused Tricyclic Compound, or a pharmaceutically acceptable salt of said compound and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect.
  • the one or more Fused Tricyclic Compounds and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more Fused Tricyclic Compounds and the one or more additional therapeutic agents are provided in separate containers.

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Abstract

L'invention porte sur des composés tricycliques condensés de formule (I) et sur des sels pharmaceutiquement acceptables de ceux-ci, dans laquelle formule X1, X2, X3, X4, Y1, Y2, M1, M2, Ra, Rb, R1, R2 et R6 sont tels que définis dans la description. L'invention porte également sur des compositions comprenant au moins un composé tricyclique condensé et sur des procédés d'utilisation des composés tricycliques condensés pour le traitement ou la prévention d'une infection à VHC chez un patient.
PCT/CN2010/075088 2010-07-09 2010-07-09 Composés tricycliques condensés et leur utilisation pour le traitement de maladies virales WO2012003642A1 (fr)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140199264A1 (en) * 2011-03-17 2014-07-17 Craig A. Coburn Tetracyclic xanthene derivatives and methods of use thereof for the treatment of viral diseases
US8859595B2 (en) 2010-08-26 2014-10-14 Rfs Pharma, Llc Potent and selective inhibitors of hepatitis C virus
US9303061B2 (en) 2011-07-09 2016-04-05 Sunshine Luke Pharma Co., Ltd. Spiro compounds as Hepatitis C virus inhibitors
US9309231B2 (en) 2012-08-03 2016-04-12 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as hepatitis C virus (HCV) inhibitors and pharmaceutical applications thereof
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9340520B2 (en) 2011-02-07 2016-05-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9416139B2 (en) 2012-11-29 2016-08-16 Sunshine Lake Pharma Co., Ltd. Spiro ring compound as hepatitis C virus (HCV) inhibitor and uses thereof
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9738629B2 (en) 2014-01-23 2017-08-22 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
WO2017184476A1 (fr) * 2016-04-21 2017-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du virus de l'hépatite c
US9802949B2 (en) 2012-11-29 2017-10-31 Sunshine Lake Pharma Co., Ltd. Fused ring compounds as hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10101591A (ja) * 1996-09-27 1998-04-21 Eisai Co Ltd ウイルス感染症の予防・治療剤
CN101336248A (zh) * 2005-12-16 2008-12-31 国家健康医学研究所 与pea-15相互作用的新型化合物
WO2010111534A1 (fr) * 2009-03-27 2010-09-30 Presidio Pharmaceuticals, Inc. Inhibiteurs à noyaux fusionnés de l'hépatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10101591A (ja) * 1996-09-27 1998-04-21 Eisai Co Ltd ウイルス感染症の予防・治療剤
CN101336248A (zh) * 2005-12-16 2008-12-31 国家健康医学研究所 与pea-15相互作用的新型化合物
WO2010111534A1 (fr) * 2009-03-27 2010-09-30 Presidio Pharmaceuticals, Inc. Inhibiteurs à noyaux fusionnés de l'hépatite c

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BETH WILSON ET AL.: "Tunable DNAPhotocleavage by an Acridine-Imidazole Conjugate", INORGANIC CHEMISTRY, vol. 44, no. 18, 2005, pages 6159 - 6173 *

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US20140199264A1 (en) * 2011-03-17 2014-07-17 Craig A. Coburn Tetracyclic xanthene derivatives and methods of use thereof for the treatment of viral diseases
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US9802949B2 (en) 2012-11-29 2017-10-31 Sunshine Lake Pharma Co., Ltd. Fused ring compounds as hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
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US9738629B2 (en) 2014-01-23 2017-08-22 Sunshine Lake Pharma Co., Ltd. Bridged ring compounds as Hepatitis C virus inhibitors, pharmaceutical compositions and uses thereof
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2017184476A1 (fr) * 2016-04-21 2017-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du virus de l'hépatite c
US10787441B2 (en) 2016-04-21 2020-09-29 Merck Sharp & Dohme Corp. Hepatitis C virus inhibitors

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