WO2013033971A1 - Tetracyclic heterocycle compounds and methods of use thereof for the treatment of viral diseases - Google Patents

Tetracyclic heterocycle compounds and methods of use thereof for the treatment of viral diseases Download PDF

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WO2013033971A1
WO2013033971A1 PCT/CN2012/001117 CN2012001117W WO2013033971A1 WO 2013033971 A1 WO2013033971 A1 WO 2013033971A1 CN 2012001117 W CN2012001117 W CN 2012001117W WO 2013033971 A1 WO2013033971 A1 WO 2013033971A1
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mmol
compound
alkyl
mixture
mhz
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PCT/CN2012/001117
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French (fr)
Inventor
Casey Cameron Mccomas
Nigel J. Liverton
Joerg Habermann
Uwe Koch
Frank Narjes
Peng Li
Xuanjia Peng
Richard Soll
Hao Wu
Anandan Palani
Shuwen He
Xing DAI
Hong Liu
Zhong LAI
Clare London
Dong Xiao
Nicolas Zorn
Ravi Nargund
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Merck Sharp & Dohme Corp.
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Priority to KR1020147008867A priority Critical patent/KR20140059278A/en
Priority to CA2847019A priority patent/CA2847019A1/en
Priority to AU2012306944A priority patent/AU2012306944A1/en
Priority to BR112014005407A priority patent/BR112014005407A2/en
Priority to RU2014113539/15A priority patent/RU2014113539A/en
Priority to US14/343,450 priority patent/US9265773B2/en
Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Priority to MX2014002816A priority patent/MX2014002816A/en
Priority to CN201280050985.8A priority patent/CN103906512A/en
Priority to EP12830590.1A priority patent/EP2753325B1/en
Priority to JP2014528832A priority patent/JP2014526445A/en
Publication of WO2013033971A1 publication Critical patent/WO2013033971A1/en
Priority to IL231217A priority patent/IL231217A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • A61K31/535—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
    • A61K31/5365—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 heterocyclic 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
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to novel Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
  • HCV infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
  • Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.
  • RNA-dependent RNA polymerase RNA-dependent RNA polymerase
  • HCV NS5B polymerase is described, for example, in Behrens et al, EMBO J. 15(1) 12-22 (1996). Antagonists of NS5B activity are known to be inhibitors of HCV replication. See Carroll et al, J. Biol. Chem.. 278(14) 11979-84 (2003).
  • the resent invention provides Compounds of Formula (I)
  • A is phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered monocyclic cycloalkyl or 5 to 7-membered heterocycloalkyl, each of which can be optionally substituted with up to four R 5 groups;
  • V is N or -C(R 4 )-;
  • W is N or -CH-
  • X is -(CHR 8 ) N -0-, -C(0)-0-,
  • Y 1 is N or -C(R 5 )-;
  • Y 2 is N or -C(R 5 )-;
  • Z is N, -C(R 5 )- or -C(O)-, such that when Z is -C(O)-, then the endocyclic double bond depicted in formula (Q2) between Z and Y 1 is understood to be a single bond;
  • R 1 represents up to 4 optional ring substituents, which can be the same or different, and are independently selected from halo, C 1 -C5 alkyl, C 1 -C5 haloalkyl, phenyl, 3 to 7- membered monocyclic cycloalkyl, -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) and -CN;
  • R 2 is -C(0)N(R 6 )(R 7 ) or -C(0)0-(Ci-C 6 alkyl);
  • R 3 is H, 4- to 6-membered heterocycloalkyl, 5 or 6-membered heteroaryl, -N(R U ) 2 , halo, -CN, -N(R U ) 2 , -C(0)0-(Ci-C 6 alkyl) or -N(R 9 )-S(0) n -R 10 , wherein said 5 or 6- membered heterocycloalkyl can optionally have one of its ring carbon atoms replaced with a carbonyl group;
  • R 4 is selected from H, halo, C 1 -C5 alkyl, 3 to 7-membered monocyclic cycloalkyl, Ci-C 6 haloalkyl, -0-(Ci-C 6 alkyl), -C(OH)-C(0)OR u and -0-(Ci-C 6 haloalkyl);
  • each occurrence of R 5 is independently selected from H, halo, C 1 -C5 alkyl, C 1 -C5 haloalkyl, -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) and -CN, wherein said C 1 -C5 alkyl group can be optionally substituted with -OH or -N(R U ) 2 ;
  • R 6 and R 7 are each independently selected from hydrogen, -C(0)R n , -C(0)OR u , -C(0)C(0)OR u , Ci-C 6 alkyl, C 1 -C5 hydroxyalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;
  • each occurrence of R 8 is independently selected from H, halo, -OH, C 1 -C5 alkyl, Ci-C 6 hydroxyalkyl, phenyl, 5 or 6-membered monocyclic heteroaryl, -N(R U ) 2 , C 1 -C5 haloalkyl, -(C 1 -C 3 alkylene) p -(3 to 7-membered monocyclic cycloalkyl), -(C 1 -C 3 alkylene) p -0-(Ci-C 6 alkyl), -(C1-C3 alkylene)p-N(R n ) 2 , -(C1-C3 alkylene)- HC(0)-(Ci-C 6 alkyl), -(C1-C3 alkylene)- OC(0)(Ci-C 6 alkyl) HC(0)0-(Ci-C 6 alkyl), -(C1-C3 alkylene)-OC(0)(Ci
  • heterocycloalkyl - R u -(Ci-C 6 hydroxyalkyl) and -CN, or two R 8 groups and the common carbon atom to which they are attached, can join to form a spirocyclic ring selected from 3 to 7- membered monocyclic cycloalkyl and 3 to 7-membered monocyclic heterocycloalkyl;
  • R 9 is selected from H, C 1 -C5 alkyl, C 1 -C5 haloalkyl, C 1 -C5 hydroxyalkyl, benzyl, -
  • R 10 is selected from H, C 1 -C5 alkyl, C 1 -C5 haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl, wherein said C 1 -C5 alkyl group can be optionally substituted with a group selected from -N(R U ) 2 , -OR 11 , -COOH, -C(0)N(R n ) 2 , and -S(0) 2 N(R n ) 2 ;
  • each occurrence of R 11 is independently selected from H, C 1 -C5 alkyl, and 3 to 7- membered monocyclic cycloalkyl;
  • n 1, 2 or 3;
  • each occurrence of p is 0 or 1.
  • Heterocycle 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 Tetracyclic Heterocycle Compounds inhibit HCV viral replication by inhibiting HCV NS5B.
  • 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 Tetracyclic Heterocycle Compound.
  • the present invention relates to novel Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle 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.
  • the term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount” for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount” for reduction of the severity or likelihood of one or more symptoms of the disease or condition.
  • the effective amount is a "therapeutically effective amount" for inhibition of HCV viral replication and/or HCV viral production.
  • the term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount”).
  • an “inhibition effective amount” When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.
  • 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 (C 1 -C5 alkyl) or from about 1 to about 3 carbon atoms (C 1 -C3 alkyl).
  • Non- limiting examples of 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, -O-aiyl, -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.
  • an alkyl group is linear.
  • 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, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl.
  • C 2 -C6 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-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -O-C(O)- 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.
  • 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.
  • 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 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.
  • aryl e.g., benzene
  • heteroaryl ring e.g., benzene
  • 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.
  • a cycloalkyl group is unsubstituted.
  • the term "3 to 7-membered cycloalkyl” refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, 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 (also referred to herein as a "cycloalkanoyl” 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.
  • 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 .
  • Ci-C 6 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 and has 9 or 10 ring atoms.
  • 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.
  • heteroaryl also encompasses any fused polycyclic ring system containing at least one ring heteroatom selected from N, O and S, wherein at least one ring of the fused polycyclic ring system is aromatic.
  • the term "9 to 10-membered bicyclic heteroaryl” encompasses a non-aromatic 5 membered heterocyclic ring that is fused to a benzene or pyridyl ring.
  • heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2, l-b]thiazoly
  • 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.
  • 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, ring silicon atom 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 monocyclic has from about 5 to about 7 ring atoms. In another embodiment, 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.
  • heterocycloalkyl 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.
  • monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone, silacyclopentane, silapyrrolidine and the like, and all isomers thereof.
  • silyl- containing heterocycloalkyl group include:
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • heterocycloalkyl groups include:
  • a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered
  • monocyclic heterocycloalkyl refers to a monocyclic heterocycloalkyl group having from 3 to 7 ring atoms.
  • 4 to 7-membered monocyclic cycloalkyl refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms.
  • 5 to 7-membered monocyclic cycloalkyl refers to a monocyclic
  • heterocycloalkyl group having from 5 to 7 ring atoms.
  • the term "7 to 11-membered bicyclic heterocycloalkyl” refers to a bicyclic heterocycloalkyl group having from 7 to 11 ring atoms. Unless otherwise indicated, an 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. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, 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,
  • 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 moiety are methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • silylalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a -Si(R x ) 3 group, wherein each occurrence of R x is independently Ci-C 6 alkyl, phenyl or a 3- to 6- membered cycloalkyl group.
  • a silylalkyl group has from 1 to 6 carbon atoms.
  • a silyl alkyl group contains a -Si(CH 3 ) 3 moiety.
  • Non-limiting examples of silylalkyl groups include -CH 2 -Si(CH 3 ) 3 and -CH 2 CH 2 -Si(CH 3 ) 3 .
  • 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.
  • 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.
  • the term “in 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. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
  • 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.
  • 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.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and
  • prodrug means a compound ⁇ e.g., a drug precursor) that is transformed in vivo to provide a Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt or solvate of the compound.
  • the transformation 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-C 8 )alkyl, (C 2 -Ci2)alkanoyloxymethyl, 1- (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, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,
  • 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-(C i - C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci-Ce)alkanoyl, a-amino(Ci-C 4 )alkyl, a-amino(Ci- C 4 )alkylene-aryl, arylacyl and a-aminoacyl, or ⁇ -aminoacyl-a-aminoacyl, where
  • 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-, NRR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, a natural a-aminoacyl,
  • Y 1 is H, (Ci-C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein 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; piperidin-l-yl or pyrrolidin-l-yl, and the like.
  • 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, phenoxymethyl), 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, methanes),
  • 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 room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention.
  • Reference to a Tetracyclic Heterocycle Compound herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, 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 Tetracyclic Heterocycle 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 ("mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.
  • a compound of formula (I) is present as its dihydrochloride salt. In another embodiment, a compound of formula (I) is present as its dimesylate salt.
  • 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, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,
  • 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.
  • 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., dec
  • 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., hydrolyzing) 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 Tetracyclic Heterocycle 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.
  • Tetracyclic Heterocycle Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • 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 Tetracyclic Heterocycle 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 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
  • 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.
  • Tetracyclic Heterocycle Compounds Polymorphic forms of the Tetracyclic Heterocycle Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Tetracyclic Heterocycle Compounds, are intended to be included in the present invention.
  • Ac is acyl
  • BOC or Boc is tert-butyloxycarbonyl
  • (BPin) 2 is bis (pinacolato)diboron
  • CDI is N,N- carbonyl diimidazole
  • dba is dibenzylideneacetone
  • DMF is N,N-dimethylformamide
  • dppf is diphenylphosphinoferrocene
  • EtOAc is ethyl acetate
  • HPLC high performance liquid chromatography
  • HRMS is high resolution mass spectrometry
  • KOAc is potassium acetate
  • LCMS is liquid chromatography/mass spectrometry; MeOH is methanol; Ms is mesyl (-S0 2 CH 3 ); NCS is N-chlorosuccinimide; Pd/C is palladium on carbon; PdCl 2 (dppf) 2 is [ ⁇ , - bis(diphenylphosphino)ferrocene] dichloro palladium(II); petroleum ether is petroleum ether; PPA is polyphosphoric acid; PTSA is p-toluenesulfonic acid; TLC is thin-layer chromatography; and XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
  • the present invention provides Tetracyclic Heterocycle Compounds of Formula
  • each occurrence of R 1 is halo.
  • R 1 represents a single halo substituent.
  • R 1 represents a single F substituent.
  • R 2 is -C(0) H-(Ci-C 6 alkyl).
  • R 2 is -C(0) H-CH 3 .
  • R 3 is -N(R 9 )-S(0) n -R 10 wherein R 9 and R 10 are each independently C 1 -C5 alkyl.
  • Q is Ql and A is phenyl.
  • Q is Ql and A is pyridyl.
  • Q is Ql and V is -CH-.
  • Q is Ql and V is N.
  • Q is Ql and W is N.
  • Q is Ql and X is -CHR 8 -0-.
  • Q is Ql
  • X is -CHR 8 -0- and R 8 is H, methyl or cyclopropyl.
  • Q is Ql and X is -CH 2 -0-.
  • Q is Ql and X is -CH 2 CH 2 -0-
  • Q is Ql and X is -C(0)0-. In one embodiment, Q is Ql and Y 1 is -CH-.
  • Q is Ql and Y 1 is -N-.
  • Q is Ql and Y 2 is -CH-.
  • Q is Ql and Y 2 is -N-.
  • Q is Ql
  • Y 1 is -CH- and Y 2 is -N-.
  • Q is Ql
  • Y 1 is -N- and Y 2 is -CH-.
  • Q is Ql and Z is -CH-.
  • Q is Ql and Z is N.
  • Q is Ql and Y 1 , Y 2 and Z are each -CH-.
  • Q is Ql
  • A is phenyl
  • W is N.
  • Q is Ql
  • A is phenyl
  • W is N
  • Y 1 is CH
  • Y 2 is CH.
  • Q is Ql
  • A is phenyl
  • W is N
  • Y 1 is N
  • Y 2 is CH.
  • Q is Ql
  • A is phenyl
  • W is N
  • Y 1 is CH
  • Y 2 is N.
  • Q is Ql
  • A is pyridyl
  • W is N.
  • Q is Ql
  • A is pyridyl
  • W is N
  • Y 1 is CH
  • Y 2 is CH.
  • Q is Ql
  • A is pyridyl
  • W is N
  • Y 1 is N
  • Y 2 is CH.
  • Q is Ql
  • A is pyridyl
  • W is N
  • Y 1 is CH
  • Y 2 is N.
  • Q is Q2 and and A is phenyl.
  • Q is Q2 and and A is pyridyl.
  • Q is Q2 and X is -CHR 8 -0-.
  • Q is Q2
  • X is -CHR 8 -0- and R 8 is H, methyl or cyclopropyl.
  • Q is Q2 and X is -CH 2 -0-.
  • Q is Q2 and X is -CH 2 CH 2 -0-.
  • Q is Q2 and X is -C(0)0-.
  • Q is Q2 and Y 1 is -CH-.
  • Q is Q2 and Y 1 is -N-.
  • Q is Q2 and Y 2 is -CH-.
  • Q is Q2 and Y 2 is -N-.
  • Q is Q2
  • Y 1 is -CH- and Y 2 is -N-.
  • Q is Q2
  • Y 1 is -N- and Y 2 is -CH-.
  • Q is Q2 and Z is -CH-. In another embodiment, Q is Q2 and Z is N.
  • Q is Q2 and Y 1 , Y 2 and Z are each -CH-.
  • Q is Q2
  • A is phenyl
  • Z is CH
  • Y 1 is CH
  • Y 2 is CH.
  • Q is Q2
  • A is phenyl
  • Z is CH
  • Y 1 is N
  • Y 2 is CH.
  • Q is Q2
  • A is phenyl
  • Z is CH
  • Y 1 is CH
  • Y 2 is N.
  • Q is Q2
  • A is phenyl
  • Y 1 , Y 2 and Z are each CH.
  • the compounds of formula (I) have the formula (la):
  • L is N or -CH-
  • V is N or -C(R 4 )-;
  • X is -(CHR 8 ) n -0- or -C(0)-0-;
  • R 1 is H, halo or Ci-C 6 alkyl
  • R 4 is H or halo
  • R 5 represents a single and optional halo substituent
  • R 8 is H, Ci-C 6 alkyl or 3 to 7-membered cycloalkyl
  • R 9 and R 10 are each C 1 -C5 alkyl
  • n 1 or 2.
  • V is -CH-.
  • V is N.
  • W is N.
  • X is -CHR 8 -0-.
  • X is -CHR 8 -0- and R 8 is H, methyl or cyclopropyl.
  • X is -CH 2 -0-. In still another embodiment, for the compounds of formula (la), X is -CH 2 CH 2 -0-. In another embodiment, for the compounds of formula (la), X is -C(0)0-.
  • L and V are each -CH- and X is -CH 2 -0-.
  • V is N or -C(R 4 )-;
  • R 1 is F
  • R 4 is H or CI
  • R 5 represents a single and optional F substituent
  • R 8 is H, methyl or cyclopropyl
  • R 9 and R 10 are each methyl.
  • the compounds of formula (I) have the formula (lb):
  • V is N or -CH-
  • Y 1 is N or -C(R 5 )-;
  • Y 2 is N or -CH-
  • R la is H or F
  • R 3 is -N(CH 3 )S(0) 2 CH 3 or
  • R 5 is H or -0-(Ci-C 6 alkyl);
  • R 5a and R 5b are each independently H or F; and each occurrence of R is H, or both R groups, together with the common carbon which they are attached, join to form a 4- to 6-membered monocyclic heterocycloalkyl
  • V is CH.
  • V is N.
  • Y 1 is CH and Y 2 is CH.
  • Y 1 is CH and Y 2 is N.
  • Y 1 is N and Y 2 is CH.
  • V is N.
  • R la is H.
  • R 3 is - N(CH 3 )S(0) 2 CH 3 .
  • R la is H and R 3 is - N(CH 3 )S(0) 2 CH 3.
  • each occurrence of R 8 is H.
  • R 5a is H and R 5b is F. In another embodiment, for the compounds of formula (lb), R 5a is F and R 5b is H. In one embodiment, for the compounds of formula (lb), V is CH; R la is H; R 3 is - N(CH 3 )S(0) 2 CH 3; and each occurrence of R 8 is H.
  • the compound of formula (lb) is:
  • variables Q, R 1 , R 2 and R 3 are selected independently of each other.
  • the Compounds of Formula (I) are in substantially purified form.
  • the compound of the invention is one of compounds 1-211, as depicted in the Examples below, or a pharmaceutically acceptable salt thereof.
  • compositions comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • 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 NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
  • HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV viral replication and/or HCV viral production in a cell-based system which comprises administering to the subject an effective amount of a compound of formula (I) in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,
  • HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
  • a method of inhibiting HCV NS5B activity 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 NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine.
  • 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.
  • each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
  • Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the compounds described above.
  • the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate.
  • 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.
  • Scheme 1 shows methods useful for making the compounds of formula F, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is -CH-; W is N; X is - CH 2 ) n -0-; Y and Z are each -CH-.
  • Ms is mesyl (-SO 2 CH 3 ).
  • This scheme describes the preparation of compounds with the general structure of F.
  • compound A which coupling with aromatic halides can afford compounds B.
  • Compounds C are generated by deprotecting of methyl with BBr 3 , and then the hydroxyl groups and the nitrogen of the left (aza-)indole in compounds C are cyclized with X(CH 2 ) n X (X can be CI, Br or I) or CDI to furnish compounds D.
  • Transition metal mediated coupling of compounds D with compound E (made as described below in Scheme 4) provides the target compounds of general structure F.
  • compounds D can be converted to corresponding boronic esters G in the presence of transition metal catalyst, and coupling of compounds G with compound H (described in previous patent) also can provides the target compounds of general structure F.
  • Scheme 2 show a method useful for making the compounds of formula M, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is -CH-; W is N; X is - CH(cyclopropyl)-0-; Y and Z are each -CH-.
  • This scheme describes the preparation of compounds L and M.
  • compound H can be prepared using method for compounds C), which reacting with NCS can afford compound I.
  • Compounds J is generated by cyclization with cyclopropanecarbaldehyde in the presence of PTSA.
  • Compounds J can be converted to corresponding boronic esters K in the presence of transition metal catalyst, and coupling of compounds K with compound H provides the target compound L.
  • Compounds L can be transferred to compound M by reduction of chlorine through catalytic hydrogenation.
  • Scheme 3 shows a method useful for making the compounds of formula Q, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is N; W is N; X is - (CH 2 ) n -0-; Y and Z are each -CH-.
  • Scheme 4 shows a method useful for making compound E, which is a
  • Intermediate boronic acid compound E can be made by reacting bromo-substitued benzofuran compound H with bis(pinacolato)diboron in the presence of an appropriate palladium catalyst.
  • Scheme 5 shows a method useful for making certain compounds of Formula (I). The cyclization was accomplished through an indoline intermediate.
  • the starting materials used and the intermediates prepared using the methods set forth above in Schemes 1-5 may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.
  • Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI). 1H MR spectra were recorded at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures.
  • BBr 3 (0.4 mL, 0.39 mmol) was added to the solution of 2-(6-chloro-3- methoxypyridin-2-yl)-lH-indole (50 mg, 0.19 mmol) in CH 2 C1 2 (0.5 mL) at -78 °C under N 2 . The mixture was allowed to stir at room temperature for 3 hours. The mixture was then quenched with CH 3 OH (10 mL) at -78 °C.
  • Step 5 Synthesis of 2-chloro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indole with / withou 2- chloro-6, 11-dihydropyridof 2 ', 3 ':5, 6]pyrano[ 4, 3-b ] indole
  • Step 6 Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyrido [2' ' : 5, 6] [ 1 , 3] oxazino [3,4-a]indol-2-yl)benzofuran-3-carboxamide (Compound 1)
  • Step 6 Synthesis of 5-(l l-fluoro-6H-benzo[5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl) -N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 43)
  • Step 6 Synthesis of 2-(4-fluorophenyl)-5-(10-methoxy-6H-pyrido[2,3- e Jpyridof 2 ', 3 ': 4, 5 ]pyrrolo[ 1, 2-c ][ 1, 3 ]oxazin-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 45)
  • Step 1 Synthesis of 2-(3-( enzyloxy)-6-chloropyridin-2-yl)-4-fluoro-lH-pyrrolo[2,3-cJpyridme
  • Step 2 Synthesis of 5-(5-(benzyloxy)-6-(4-fluoro-lH-pyrrolo[2, 3-c]pyridin-2-yl)pyridin-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 3 Synthesis of 5-(6-(4-fluoro-lH-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 4 Synthesis of 5-( 1 l-fluoro-6H-pyridof 2, 3-e Jpyridof 4 ', 3 ': 4, 5 Jpyrrolof 1, 2-c ][ 1, 3 ]oxazin-2- yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-m
  • Step 1 Synthesis of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,S-b]pyridine
  • 6-chloro-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-3-ol (320 mg, 1.10 mmol) was added to HC1 / 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and stirred for 10 hours. Then the mixture was concentrated in vacuo, diluted with EtOAc, washed with brine, dried over Na 2 S0 4 and concentrated to provde the crude product of compound 5 (200 mg, yield: 74%), which was used for the next step without further purification.
  • Step 6 Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyrido[ 2, 3-e Jpyridof 3 ', 2 ': 4, 5 ]pyrrolo[ l,2-c][l,3 ]oxazin-2-yl) benzofuran-3-carboxamide (Compound 48)
  • Step 2 Synthesis of 5-(ll-fluoro-6-phenyl-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofura ⁇
  • Step 1 Synthesis of 2-chloro-l l-((2-(trimethylsilyl)ethoxy)methyl)-6, l 1- dihydropyridof 2 ', 3 ':5, 6]pyrano[ 4, 3-b ]- 7-aza-indole
  • Step 2 Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(l l-((2- (trimethylsilyl)ethoxy)methyl)-6, l 1 -dihydropyrido f 2', 3': 5, 6Jpyranof 4, 3-bJ-7-aza-indol-2- yl) benzofuran-3-carboxamide
  • Step 2 Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6- benzo -a Jindol-2-yl) benzofuran-3-carboxamide ( ompound 53 )
  • Step 2 Synthesis of 5-(5-(benzyloxy)-6-(4fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 3 Synthesis of 5-(6-(4-fluoro-lH-indol-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N- methyl-6- N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 4 Synthesis of 5-(l l-fluoro-6-oxo-6H-pyrido [2' , 3' : 5, 6] ' [l,3]oxazino[3,4-a]indol-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 3 Synthesis of 5-(12-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 55)
  • Step 1 Synthesis of 5-(12-bromo-6H-pyridof2',3':5,6Jfl,3Joxazinof3,4-aJmdol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • NBS 33 mg, 0.19 mmol
  • compound 1 100 mg, 0.17 mmol, described in Example 1
  • THF 1 mL
  • Step 2 Synthesis of 5-(12-cyano-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benz (Compound 60)
  • Step 2 Synthesis of 6,6-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,l 1- dihydrochromen -b ] indole
  • Step 3 Synthesis of 5-(6, 6-dimethyl-6, l l-dihydrochromeno[4,3-b]indol-2-yl)-2-(4- ⁇ uorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 61)
  • Step 2 Synthesis of 2-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH- indole
  • Step 3 Synthesis of 5-(3-(lH-indol-2-yl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 4 Synthesis of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(lH-indol-2-yl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 1 Synthesis of 2-chloro-7-fluoro-6-(thiophen-2-yl)-6, 11- dihydropyridof 2 ', 3 ':5 6]pyrano[ 4, 3-b ] indole
  • Step 2 Synthesis of 5-(7-fluoro-6-(thiophen-2-yl)-6, l l-dihydropyrido[2 ',3 ':5, 6]pyrano[4,3- b]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfo
  • Step 2 Synthesis of 2-(4-fluorophenyl)-5-(l l-formyl-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 3 Synthesis of 2-(4-fluorophenyl)-5-(l l-(hydroxymethyl)-6H-pyrido[2',3':5, 6][l,3] oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benz
  • Step 1 Synthesis of methyl 2-chloro-6H-pyrido[2',3':5, 6] ' [1,3] oxazino [3, 4-a] indole- 11- carboxylate
  • Step 2 Synthesis of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido [2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole- 11- carboxylate
  • MeOH 20 : 1) to provide 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l- carboxylic acid (120 mg, yield: 76%).
  • Step 2 Synthesis of 5-(7-fluoro-7,8-dihydro-6H-benzo[2,3] [l,5]oxazocino[5,4-a]indol-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
  • Step 2 Synthesis of 2-(4-fluorophenyl)-5-(7-hydroxy-7-(trifluoromethyl)-7,8-dihydro-6H- benzof 2, 3 ][ l,5]oxazocino[ 5, 4-a]indol-2-yl)-N-methyl-6-(N- meth lmethylsulfonamido)benzofuran-3-carboxamide (Compound 79)
  • Step 1 Synthesis ofNl-(2-bromo-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-yl)- N2 N2-dimethylethane-l,2-diamine
  • N',N'-dimethylethane-l,2-diamine 39 mg, 0.440 mmol
  • CH 3 COOH 26 mg, 0.440 mmol
  • 2-bromo-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol- 7(8H)-one 100 mg, 0.293 mmol
  • NaBH(OAc) 3 93 mg, 0.440 mmol
  • Step 2 Synthesis of 5-(7-((2-(dimethylamino)ethyl)amino)-7,8-dihydro-6H- benzo[2,3] [l,5]oxazocino[5,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 80)
  • Step 2 Synthesis of ethyl 2-chloro-l 1-fluoro-l 2, 12a-dihydro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indole-6-carboxylate
  • Step 3 Synthesis of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indole-6- carboxylate
  • Step 5 Synthesis of 5-(l l-fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide: enantiomer 1 and enantiomer 2 (Compound 87 and 88)

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Abstract

The present invention relates to compounds of formula (I) that are useful as hepatitis C virus (HCV) NS5B polymerase inhibitors, the synthesis of such compounds, and the use of such compounds for inhibiting HCV NS5B polymerase activity, for treating or preventing HCV infections and for inhibiting HCV viral replication and/or viral production in a cell-based system.

Description

TETRACYCLIC HETEROCYCLE COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
FIELD OF THE INVENTION
The present invention relates to novel Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. Current treatments for HCV infection include immunotherapy with recombinant interferon-a alone or in combination with the nucleoside analog ribavirin.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3, amino acid residues 1-180), a helicase (NS3, full length), an NS3 protease cofactor (NS4A), a membrane protein (NS4B), a zinc metalloprotein (NS5A) and an RNA-dependent RNA polymerase (NS5B).
HCV NS5B polymerase is described, for example, in Behrens et al, EMBO J. 15(1) 12-22 (1996). Antagonists of NS5B activity are known to be inhibitors of HCV replication. See Carroll et al, J. Biol. Chem.. 278(14) 11979-84 (2003).
There is a clear and long-felt need to develop effective therapeutics for treatment of HCV infection. Specifically, there is a need to develop compounds that selectively inhibit HCV viral replication and that would be useful for treating HCV-infected patients.
SUMMARY OF THE INVENTION
aspect, the resent invention provides Compounds of Formula (I)
Figure imgf000002_0001
(I)
or a pharmaceutically acceptable salt thereof, wherein:
Q is:
Figure imgf000003_0001
A is phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered monocyclic cycloalkyl or 5 to 7-membered heterocycloalkyl, each of which can be optionally substituted with up to four R5 groups;
V is N or -C(R4)-;
W is N or -CH-;
X is -(CHR8)N-0-, -C(0)-0-,
Y1 is N or -C(R5)-;
Y2 is N or -C(R5)-;
Z is N, -C(R5)- or -C(O)-, such that when Z is -C(O)-, then the endocyclic double bond depicted in formula (Q2) between Z and Y1 is understood to be a single bond;
R1 represents up to 4 optional ring substituents, which can be the same or different, and are independently selected from halo, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, 3 to 7- membered monocyclic cycloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 haloalkyl) and -CN;
R2 is -C(0)N(R6)(R7) or -C(0)0-(Ci-C6 alkyl);
R3 is H, 4- to 6-membered heterocycloalkyl, 5 or 6-membered heteroaryl, -N(RU)2, halo, -CN, -N(RU)2, -C(0)0-(Ci-C6 alkyl) or -N(R9)-S(0)n-R10, wherein said 5 or 6- membered heterocycloalkyl can optionally have one of its ring carbon atoms replaced with a carbonyl group;
R4 is selected from H, halo, C1-C5 alkyl, 3 to 7-membered monocyclic cycloalkyl, Ci-C6 haloalkyl, -0-(Ci-C6 alkyl), -C(OH)-C(0)ORu and -0-(Ci-C6 haloalkyl);
each occurrence of R5 is independently selected from H, halo, C1-C5 alkyl, C1-C5 haloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 haloalkyl) and -CN, wherein said C1-C5 alkyl group can be optionally substituted with -OH or -N(RU)2;
R6 and R7 are each independently selected from hydrogen, -C(0)Rn, -C(0)ORu, -C(0)C(0)ORu, Ci-C6 alkyl, C1-C5 hydroxyalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;
each occurrence of R8 is independently selected from H, halo, -OH, C1-C5 alkyl, Ci-C6 hydroxyalkyl, phenyl, 5 or 6-membered monocyclic heteroaryl, -N(RU)2, C1-C5 haloalkyl, -(C1-C3 alkylene)p-(3 to 7-membered monocyclic cycloalkyl), -(C1-C3 alkylene)p-0-(Ci-C6 alkyl), -(C1-C3 alkylene)p-N(Rn)2, -(C1-C3 alkylene)- HC(0)-(Ci-C6 alkyl), -(C1-C3 alkylene)- OC(0)(Ci-C6 alkyl) HC(0)0-(Ci-C6 alkyl), -(C1-C3 alkylene)-OC(0)-(3 to 7-membered monocyclic heterocycloalkyl), -(C1-C3 alkylene)-NHC(0)(3 to 7-membered monocyclic heterocycloalkyl), -CH(0-(d-C6 alkyl))2, -0-(Ci-C6 haloalkyl), -C(0)ORu, -C(0)N(Rn)2, - CH2OC(0)CH( H2)-(Ci-C6 alkyl), - HS(0)2-(Ci-C6 alkyl), -CH2 HCH(R11)C(0)OR11, - R11- (C1-C3 alkylene)-N(Ru)2, - Ru-(Ci-C3 alkylene)-(3 to 7-membered monocyclic
heterocycloalkyl), - Ru-(Ci-C6 hydroxyalkyl) and -CN, or two R8 groups and the common carbon atom to which they are attached, can join to form a spirocyclic ring selected from 3 to 7- membered monocyclic cycloalkyl and 3 to 7-membered monocyclic heterocycloalkyl;
R9 is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 hydroxyalkyl, benzyl, -
(C1-C3 alkylene)-(3 to 7-membered monocyclic cycloalkyl) and 3 to 7-membered monocyclic cycloalkyl, wherein said C1-C5 alkyl group can be optionally substituted with a group selected from -N(Ru)2, -OR11, -COOH, -C(0)N(Rn)2, -S(0)2N(Rn)2 and 3 to 7-membered monocyclic heterocycloalkyl and wherein the phenyl moiety of said benzyl group can be optionally substituted with a boronic acid group;
R10 is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl, wherein said C1-C5 alkyl group can be optionally substituted with a group selected from -N(RU)2, -OR11, -COOH, -C(0)N(Rn)2, and -S(0)2N(Rn)2;
each occurrence of R11 is independently selected from H, C1-C5 alkyl, and 3 to 7- membered monocyclic cycloalkyl;
each occurrence of n is 1, 2 or 3; and
each occurrence of p is 0 or 1.
The Compounds of Formula (I) (also referred to herein as the "Tetracyclic
Heterocycle 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 Tetracyclic Heterocycle Compounds inhibit HCV viral replication by inhibiting HCV NS5B.
Accordingly, 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 Tetracyclic Heterocycle Compound.
The details of the invention are set forth in the accompanying detailed description below.
Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
Definitions and Abbreviations
The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, the structure is understood to predominate. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of " hydroxy alkyl," "haloalkyl," "-O-alkyl," etc...
As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
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. The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically effective amount" for the alleviation of one or more symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for reduction of the severity or likelihood of one or more symptoms of the disease or condition. In another embodiment, the effective amount is a "therapeutically effective amount" for inhibition of HCV viral replication and/or HCV viral production. The term also includes herein the amount of active compound sufficient to inhibit HCV NS5B activity and thereby elicit the response being sought (i.e., an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.
The term "preventing," as used herein with respect to an HCV viral infection or HCV- virus related disorder, refers to reducing the likelihood of HCV infection.
The term "alkyl," as used herein, 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 (C1-C5 alkyl) or from about 1 to about 3 carbon atoms (C1-C3 alkyl). Non- limiting examples of 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, -O-aiyl, -alkylene-O-alkyl, alkylthio, -NH2, -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. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
The term "alkenyl," as used herein, 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, -NH2, -NH(alkyl), -N(alkyl)2, - NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl. The term "C2-C6 alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.
The term "alkynyl," as used herein, 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-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -O-C(O)- alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl. The term "C2-C6 alkynyl" refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.
The term "alkylene," as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH(CH3)CH2CH2-, -CH(CH3)- and -CH2CH(CH3)CH2-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is - CH2-. The term "Ci-C6 alkylene" refers to an alkylene group having from 1 to 6 carbon atoms.
The term "aryl," as used herein, 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.
The term "cycloalkyl, " as used herein, 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 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms. The term "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. In one embodiment, a cycloalkyl group is unsubstituted. The term "3 to 7-membered cycloalkyl" refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, 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 (also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:
Figure imgf000008_0001
The term "cycloalkenyl," as used herein, 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. Non-limiting examples of 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. In one embodiment, a cycloalkenyl group is cyclopentenyl. In another embodiment, 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.
The term "halo," as used herein, means -F, -CI, -Br or -I.
The term "haloalkyl," as used herein, 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 -CH2F, -CHF2, -CF3, -CH2C1 and -CC13. The term "Ci-C6 haloalkyl" refers to a haloalkyl group having from 1 to 6 carbon atoms.
The term "hydroxyalkyl," as used herein, 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 -CH2OH, -CH2CH2OH, -CH2CH2CH2OH and -CH2CH(OH)CH3. The term "Ci-C6 hydroxyalkyl" refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.
The term "heteroaryl," as used herein, 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. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic and has 9 or 10 ring atoms. 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. A 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. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. The term "heteroaryl" also encompasses any fused polycyclic ring system containing at least one ring heteroatom selected from N, O and S, wherein at least one ring of the fused polycyclic ring system is aromatic. For example, the term "9 to 10-membered bicyclic heteroaryl" encompasses a non-aromatic 5 membered heterocyclic ring that is fused to a benzene or pyridyl ring. Non- limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2, l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6- membered heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6-membered heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.
The term "heterocycloalkyl, " as used herein, 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, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 7 ring atoms. In another embodiment, 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. The term "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, silacyclopentane, silapyrrolidine and the like, and all isomers thereof. Non-limiting illustrative examples of a silyl- containing heterocycloalkyl group include:
Figure imgf000011_0001
A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. Illustrative example of such heterocycloalkyl groups, include:
Figure imgf000011_0002
In one embodiment, 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 monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 7 ring atoms. The term "4 to 7-membered monocyclic cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms. The term "5 to 7-membered monocyclic cycloalkyl" refers to a monocyclic
heterocycloalkyl group having from 5 to 7 ring atoms. The term "7 to 11-membered bicyclic heterocycloalkyl" refers to a bicyclic heterocycloalkyl group having from 7 to 11 ring atoms. Unless otherwise indicated, an heterocycloalkyl group is unsubstituted. The term "heterocycloalkenyl," as used herein, 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. In one embodiment, a heterocycloalkenyl group has from 4 to 7 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, 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. Non-limiting examples of 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. In one embodiment, a heterocycloalkenyl group is a 5-membered heterocycloalkenyl. In another embodiment, 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.
The term "ring system substituent," as used herein, 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, -N02, -CN, -SF5, -C(0)OH, -C(0)0-alkyl, -C(0)0-aryl, - C(0)0-alkylene-aryl, -S(0)-alkyl, -S(0)2-alkyl, -S(0)-aryl, -S(0)2-aryl, -S(0)-heteroaryl, - S(0)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, - S(0)2-alkylene-aryl, -S(0)2-alkylene-heteroaiyl, -Si(alkyl)2, -Si(aryl)2, -Si(heteroaryl)2, -
Si(alkyl)(aryl), -Si(alkyl)(cycloalkyl), - Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -O- C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)- H(alkyl), -N(Yi)(Y2), -alkylene-N(Yi)(Y2), -C(0)N(Yi)(Y2) and -S(0)2N(Yi)(Y2), wherein Yi and Y2 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 moiety are methylenedioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000013_0001
The term "silylalkyl, " as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a -Si(Rx)3 group, wherein each occurrence of Rx is independently Ci-C6 alkyl, phenyl or a 3- to 6- membered cycloalkyl group. In one embodiment, a silylalkyl group has from 1 to 6 carbon atoms. In another embodiment, a silyl alkyl group contains a -Si(CH3)3 moiety. Non-limiting examples of silylalkyl groups include -CH2-Si(CH3)3 and -CH2CH2-Si(CH3)3.
The term "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. By "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.
The term "in substantially purified form," as used herein, 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. The term "in 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. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
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.
When any substituent or variable {e.g., alkyl, R6, Ra, etc.) occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
As used herein, the term "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.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and
Pergamon Press. The term "prodrug" means a compound {e.g., a drug precursor) that is transformed in vivo to provide a Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt or solvate of the compound. The transformation may occur by various mechanisms {e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
For example, if a Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, 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, (C2-Ci2)alkanoyloxymethyl, 1- (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, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2- C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di (Ci- C2)alkylcarbamoyl-(Ci-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a Tetracyclic Heterocycle Compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Ci-C6)alkanoyloxymethyl, l-((Ci-C6)alkanoyloxy)ethyl, 1- methyl- 1 -((C i -C6)alkanoyloxy)ethyl, (C i -C6)alkoxycarbonyloxymethyl, N-(C i - C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-Ce)alkanoyl, a-amino(Ci-C4)alkyl, a-amino(Ci- C4)alkylene-aryl, arylacyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl, where each a- aminoacyl group is 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.
If a Tetracyclic Heterocycle Compound incorporates an amine functional group, 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-, NRR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, a natural a-aminoacyl,
-C(OH)C(0)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (Ci-C4) alkyl and Y3 is (Ci-C6)alkyl; carboxy (Ci-C6)alkyl; amino(Ci-C4)alkyl or mono-N- or di-N,N- (Ci-C6)alkylaminoalkyl; -C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N,N-(Ci- C6)alkylamino morpholino; piperidin-l-yl or pyrrolidin-l-yl, and the like.
Pharmaceutically acceptable 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, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, Ci-4alkyl, -0-(Ci-4alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L- isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 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. Thus, for example, 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 room 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 Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention. Reference to a Tetracyclic Heterocycle Compound herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Tetracyclic Heterocycle
Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Tetracyclic Heterocycle 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 ("mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. In one embodiment, a compound of formula (I) is present as its dihydrochloride salt. In another embodiment, a compound of formula (I) is present as its dimesylate salt. Additionally, 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, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould,
International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug
Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
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. 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.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
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., hydrolyzing) 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. Also, some of the Tetracyclic Heterocycle 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.
It is also possible that the Tetracyclic Heterocycle Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, 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 Tetracyclic Heterocycle 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 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
In the Compounds of Formula (I), 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. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). 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. In one embodiment, a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.
Polymorphic forms of the Tetracyclic Heterocycle Compounds, and of the salts, solvates, hydrates, esters and prodrugs of the Tetracyclic Heterocycle Compounds, are intended to be included in the present invention.
The following abbreviations are used below and have the following meanings: Ac is acyl; BOC or Boc is tert-butyloxycarbonyl; (BPin)2 is bis (pinacolato)diboron; CDI is N,N- carbonyl diimidazole; dba is dibenzylideneacetone; DMF is N,N-dimethylformamide; dppf is diphenylphosphinoferrocene; EtOAc is ethyl acetate; HPLC is high performance liquid chromatography; HRMS is high resolution mass spectrometry; KOAc is potassium acetate;
LCMS is liquid chromatography/mass spectrometry; MeOH is methanol; Ms is mesyl (-S02CH3); NCS is N-chlorosuccinimide; Pd/C is palladium on carbon; PdCl2(dppf)2 is [Ι, - bis(diphenylphosphino)ferrocene] dichloro palladium(II); petroleum ether is petroleum ether; PPA is polyphosphoric acid; PTSA is p-toluenesulfonic acid; TLC is thin-layer chromatography; and XPhos is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.
The Compounds of Formula (I)
The present invention provides Tetracyclic Heterocycle Compounds of Formula
(I):
Figure imgf000019_0001
(I) wherein Q, R1, R2 and R3 are as defined above for the Compounds of Formula (I).
In one embodiment, is:
Figure imgf000020_0001
In another embodiment Q is:
Figure imgf000020_0002
In one embodiment, each occurrence of R1 is halo.
In another embodiment, R1 represents a single halo substituent.
In another embodiment, R1 represents a single F substituent.
In one embodiment, R2 is -C(0) H-(Ci-C6 alkyl).
In another embodiment, R2 is -C(0) H-CH3.
In one embodiment, R3 is -N(R9)-S(0)n-R10 wherein R9 and R10 are each independently C1-C5 alkyl.
In one embodiment, Q is Ql and A is phenyl.
In another embodiment, Q is Ql and A is pyridyl.
In one embodiment, Q is Ql and V is -CH-.
In another embodiment, Q is Ql and V is N.
In one embodiment, Q is Ql and W is N.
In one embodiment, Q is Ql and X is -CHR8-0-.
In another embodiment, Q is Ql, X is -CHR8-0- and R8 is H, methyl or cyclopropyl.
In another embodiment, Q is Ql and X is -CH2-0-.
In still another embodiment, Q is Ql and X is -CH2CH2-0-
In another embodiment, Q is Ql and X is -C(0)0-. In one embodiment, Q is Ql and Y1 is -CH-.
In another embodiment, Q is Ql and Y1 is -N-.
In one embodiment, Q is Ql and Y2 is -CH-.
In another embodiment, Q is Ql and Y2 is -N-.
In one embodiment, Q is Ql, Y1 is -CH- and Y2 is -N-.
In another embodiment, Q is Ql, Y1 is -N- and Y2 is -CH-.
In one embodiment, Q is Ql and Z is -CH-.
In another embodiment, Q is Ql and Z is N.
In one embodiment, Q is Ql and Y1, Y2 and Z are each -CH-.
In one embodiment, Q is Ql, A is phenyl and W is N.
In another embodiment, Q is Ql, A is phenyl, W is N, Y1 is CH and Y2 is CH.
In another embodiment, Q is Ql, A is phenyl, W is N, Y1 is N and Y2 is CH.
In another embodiment, Q is Ql, A is phenyl, W is N, Y1 is CH and Y2 is N.
In one embodiment, Q is Ql, A is pyridyl and W is N.
In another embodiment, Q is Ql, A is pyridyl, W is N, Y1 is CH and Y2 is CH.
In another embodiment, Q is Ql, A is pyridyl, W is N, Y1 is N and Y2 is CH.
In another embodiment, Q is Ql, A is pyridyl, W is N, Y1 is CH and Y2 is N.
In one embodiment, Q is Q2 and and A is phenyl.
In another embodiment, Q is Q2 and and A is pyridyl.
In one embodiment, Q is Q2 and X is -CHR8-0-.
In another embodiment, Q is Q2, X is -CHR8-0- and R8 is H, methyl or cyclopropyl.
In another embodiment, Q is Q2 and X is -CH2-0-.
In still another embodiment, Q is Q2 and X is -CH2CH2-0-.
In another embodiment, Q is Q2 and X is -C(0)0-.
In one embodiment, Q is Q2 and Y1 is -CH-.
In another embodiment, Q is Q2 and Y1 is -N-.
In one embodiment, Q is Q2 and Y2 is -CH-.
In another embodiment, Q is Q2 and Y2 is -N-.
In one embodiment, Q is Q2, Y1 is -CH- and Y2 is -N-.
In another embodiment, Q is Q2, Y1 is -N- and Y2 is -CH-.
In one embodiment, Q is Q2 and Z is -CH-. In another embodiment, Q is Q2 and Z is N.
In one embodiment, Q is Q2 and Y1, Y2 and Z are each -CH-.
In another embodiment, Q is Q2, A is phenyl, Z is CH, Y1 is CH and Y2 is CH.
In another embodiment, Q is Q2, A is phenyl, Z is CH, Y1 is N and Y2 is CH.
In another embodiment, Q is Q2, A is phenyl, Z is CH, Y1 is CH and Y2 is N.
In another embodiment, Q is Q2, A is phenyl, and Y1, Y2 and Z are each CH.
In one embodiment the compounds of formula (I) have the formula (la):
Figure imgf000022_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein:
L is N or -CH-;
V is N or -C(R4)-;
X is -(CHR8)n-0- or -C(0)-0-;
R1 is H, halo or Ci-C6 alkyl;
R4 is H or halo;
R5 represents a single and optional halo substituent;
R8 is H, Ci-C6 alkyl or 3 to 7-membered cycloalkyl;
R9 and R10 are each C1-C5 alkyl; and
n is 1 or 2.
In one embodiment, for the compounds of formula (la), V is -CH-.
In another embodiment, for the compounds of formula (la), V is N.
In one embodiment, for the compounds of formula (la), W is N.
In one embodiment, for the compounds of formula (la), X is -CHR8-0-.
In another embodiment, for the compounds of formula (la), X is -CHR8-0- and R8 is H, methyl or cyclopropyl.
In another embodiment, for the compounds of formula (la), X is -CH2-0-. In still another embodiment, for the compounds of formula (la), X is -CH2CH2-0-. In another embodiment, for the compounds of formula (la), X is -C(0)0-.
In one embodiment, for the compounds of formula (la):
L and V are each -CH- and X is -CH2-0-.
In another embodiment, for the compounds of formula (la):
V is N or -C(R4)-;
R1 is F;
R4 is H or CI;
R5 represents a single and optional F substituent;
R8 is H, methyl or cyclopropyl; and
R9 and R10 are each methyl.
In one embodiment the compounds of formula (I) have the formula (lb):
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof,
wherein:
V is N or -CH-;
Y1 is N or -C(R5)-;
Y2 is N or -CH-;
Rla is H or F;
R3 is -N(CH3)S(0)2CH3 or
Figure imgf000023_0002
R5 is H or -0-(Ci-C6 alkyl);
R5a and R5b are each independently H or F; and each occurrence of R is H, or both R groups, together with the common carbon which they are attached, join to form a 4- to 6-membered monocyclic heterocycloalkyl
In one embodiment, for the compounds of formula (lb), V is CH.
In another embodiment, for the compounds of formula (lb), V is N. In one embodiment, for the compounds of formula (lb), Y1 is CH and Y2 is CH. In another embodiment, for the compounds of formula (lb), Y1 is CH and Y2 is N. In another embodiment, for the compounds of formula (lb), Y1 is N and Y2 is CH. In another embodiment, for the compounds of formula (lb), V is N. In one embodiment, for the compounds of formula (lb), Rla is H.
In another embodiment, for the compounds of formula (lb), R3 is - N(CH3)S(0)2CH3.
In another embodiment, for the compounds of formula (lb), Rla is H and R3 is - N(CH3)S(0)2CH3.
In another embodiment, for the compounds of formula (lb), each occurrence of R8 is H.
In one embodiment, for the compounds of formula (lb), R5a is H and R5b is F. In another embodiment, for the compounds of formula (lb), R5a is F and R5b is H. In one embodiment, for the compounds of formula (lb), V is CH; Rla is H; R3 is - N(CH3)S(0)2CH3; and each occurrence of R8 is H.
In one embodiment, the compound of formula (lb) is:
Figure imgf000025_0001
or a pharmaceutically acceptable salt thereof.
In one embodiment, for the Compounds of Formula (I), variables Q, R1, R2 and R3 are selected independently of each other.
In another embodiment, the Compounds of Formula (I) are in substantially purified form.
In another embodiment of the invention, the compound of the invention is one of compounds 1-211, as depicted in the Examples below, or a pharmaceutically acceptable salt thereof.
Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
(c) The pharmaceutical composition of (b), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(d) 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 NS5B activity, or for inhibiting HCV viral replication, or for treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection.
(e) The combination of (d), wherein the HCV antiviral agents are one or more antiviral agents selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(f) A use of a compound of formula (I) in the preparation of a medicament for inhibiting HCV NS5B activity in a subject in need thereof.
(g) A use of a compound of formula (I) in the preparation of a medicament for preventing and/or treating infection by HCV in a subject in need thereof.
(h) 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 an effective amount of a compound of formula (I).
(i) The method of (h), wherein the compound of formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
(j) The method of (i), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors. (k) A method of inhibiting HCV viral replication and/or HCV viral production in a cell-based system, which comprises administering to the subject an effective amount of a compound of formula (I) in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
(1) The method of (k), wherein the HCV antiviral agent is an antiviral selected from the group consisting of direct inhibitors of HCV, including but not limited to NS3 and NS3/4A protease inhibitors, NS5A inhibitors and HCV NS5B polymerase inhibitors.
(m) A method of inhibiting HCV NS5B activity 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).
(n) 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 NS5B activity, or (b) inhibiting HCV viral replication, or (c) treating HCV infection and/or reducing the likelihood or severity of symptoms of HCV infection, or (d) use in medicine. In these uses, 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.
In the embodiments of the compounds and salts provided above, it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination provides a stable compound or salt and is consistent with the description of the embodiments. It is further to be understood that the embodiments of compositions and methods provided as (a) through (n) above are understood to include all embodiments of the compounds and/or salts, including such embodiments as result from combinations of embodiments.
Additional embodiments of the invention include the pharmaceutical compositions, combinations, uses and methods set forth in (a) through (n) above, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, 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.
Methods For Making the Compounds of Formula (I)
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.
Some commercially available starting materials and intermediates used for the synthesis of the Compounds of Formula (I) are available which contain intact fused poly cyclic tricyclic ring systems. These starting materials and intermediates are available from commercial suppliers such as Sigma- Aldrich (St. Louis, MO) and Acros Organics Co. (Fair Lawn, NJ). Such starting materials and intermediates compounds are used as received.
Scheme 1 shows methods useful for making the compounds of formula F, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is -CH-; W is N; X is - CH2)n-0-; Y and Z are each -CH-.
Scheme 1
Figure imgf000029_0001
wherein Ms is mesyl (-SO2CH3).
This scheme describes the preparation of compounds with the general structure of F. Starting from compound A, which coupling with aromatic halides can afford compounds B. Compounds C are generated by deprotecting of methyl with BBr3, and then the hydroxyl groups and the nitrogen of the left (aza-)indole in compounds C are cyclized with X(CH2)nX (X can be CI, Br or I) or CDI to furnish compounds D. Transition metal mediated coupling of compounds D with compound E (made as described below in Scheme 4) provides the target compounds of general structure F. In some other cases, compounds D can be converted to corresponding boronic esters G in the presence of transition metal catalyst, and coupling of compounds G with compound H (described in previous patent) also can provides the target compounds of general structure F.
Scheme 2 show a method useful for making the compounds of formula M, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is -CH-; W is N; X is - CH(cyclopropyl)-0-; Y and Z are each -CH-.
Scheme 2
Figure imgf000030_0001
This scheme describes the preparation of compounds L and M. Starting from compound H (can be prepared using method for compounds C), which reacting with NCS can afford compound I. Compounds J is generated by cyclization with cyclopropanecarbaldehyde in the presence of PTSA. Compounds J can be converted to corresponding boronic esters K in the presence of transition metal catalyst, and coupling of compounds K with compound H provides the target compound L. Compounds L can be transferred to compound M by reduction of chlorine through catalytic hydrogenation.
Scheme 3 shows a method useful for making the compounds of formula Q, which correspond to the Compounds of Formula (I), wherein A is phenyl; V is N; W is N; X is - (CH2)n-0-; Y and Z are each -CH-.
Scheme 3
Figure imgf000031_0001
Q
This scheme describes preparation of compounds with the general structure of Q. Starting from compound N, which reacting with 2-bromo-4-chloro-l-methoxybenzene can afford compounds O. Compounds O cyclized with X(CH2)nX (X can be CI, Br or I) in the presence of base to furnish compounds P. Transition metal mediated coupling of compounds P with compound E provides the target compounds of general structure Q.
Scheme 4 shows a method useful for making compound E, which is a
intermediate useful for making the Compounds of Formula (I).
Scheme 4
Figure imgf000031_0002
Intermediate boronic acid compound E can be made by reacting bromo-substitued benzofuran compound H with bis(pinacolato)diboron in the presence of an appropriate palladium catalyst.
Scheme 5 shows a method useful for making certain compounds of Formula (I). The cyclization was accomplished through an indoline intermediate. Scheme 5
Figure imgf000032_0001
One skilled in the art of organic synthesis will recognize that the synthesis of compounds with multiple reactive functional groups, such as -OH and H2, may require protection of certain functional groups (i.e., derivatization for the purpose of chemical
compatibility with a particular reaction condition). Suitable protecting groups for the various functional groups of these compounds and methods for their installation and removal are well- known in the art of organic chemistry. A summary of many of these methods can be found in Greene & Wuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, 3rd edition (1999).
One skilled in the art of organic synthesis will also recognize that one route for the synthesis of the Compounds of Formula (I) may be more desirable depending on the choice of appendage substituents. Additionally, one skilled in the relevant art will recognize that in some cases the order of reactions may differ from that presented herein to avoid functional group incompatibilities and thus adjust the synthetic route accordingly.
Compounds of formula F, M, Q and E may be further elaborated using methods that would be well-known to those skilled in the art of organic synthesis or, for example, the methods described in the Examples below, to make the full scope of the Compounds of Formula (I).
The starting materials used and the intermediates prepared using the methods set forth above in Schemes 1-5 may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and alike. Such materials can be characterized using conventional means, including physical constants and spectral data.
EXAMPLES
General Methods
The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI). 1H MR spectra were recorded at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures.
Example 1
Preparation of Compound 1
Figure imgf000033_0001
H202 (1.60 g, 47.12 mmol) was added slowly to the solution of compound 2,6- dichloropyridin-3-ylboronic acid (3 g, 15.71 mmol) in CH2C12 (30 mL) at 0 °C. After stirred at room temperature for about 15 hours, the mixture was quenched with sat. Na2S203 aqueous (50 mL) and adjusted to pH < 7 with IN HC1. The mixture was extracted with EtOAc (40 mL x 3). The organic layer was washed with brine (100 mL), dried over Na2S04, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloropyridin-3-ol (2.34 g, yield: 91.4%). 1H- MR (CDC13, 400 MHz) δ 7.30 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 8.4 Hz, 1H), 5.70 (br, 1H). MS (M+H)+: 164 / 166 / 168. Step 2 - Synthesis of 2, 6-dichloro- -methoxypyridine
Figure imgf000034_0001
To a solution of 2,6-dichloropyridin-3-ol (16.3 g, 0.1 mol) and K2C03 (41.4 g, 0.3 mol) in DMF (200 mL) were added Mel (21.3 g, 0.15 mol). The mixture was allowed to stir at 80 °C for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layer was washed with brine (200 mL x 3), dried over Na2S04, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H- MR (CDC13; 400 MHz) δ 7.12-7.18 (m, 2H), 3.86 (s, 3H). MS (M+H)+: 178 / 180 / 182. Step 3 - Synthesis of 2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole
Figure imgf000034_0002
To a degassed solution of compound 2,6-dichloro-3-methoxypyridine (8.9 g, 0.05 mol), (l-(tert-butoxycarbonyl)-lH-indol-2-yl)boronic acid (13 g, 0.05 mol) and K3P04 (31.8 g, 3.0 mol) in DMF (100 mL) was added Pd(dppf)Cl2 (3.65 g, 5 mmol) under N2. The mixture was heated at 60 °C for about 15 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the desired product of 2-(6-chloro-3-methoxypyridin-2-yl)-lH-indole (9.0 g, yield: 69.8%). 1H- MR (CDC13; 400 MHz) δ 9.52 (s, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.38-7.43 (m, 2H), 7.07-7.26 (m, 4H), 4.03 (s, 3H). MS (M+H)+: 259 / 261.
Step 4 - Synthesis of 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol
Figure imgf000035_0001
BBr3 (0.4 mL, 0.39 mmol) was added to the solution of 2-(6-chloro-3- methoxypyridin-2-yl)-lH-indole (50 mg, 0.19 mmol) in CH2C12 (0.5 mL) at -78 °C under N2. The mixture was allowed to stir at room temperature for 3 hours. The mixture was then quenched with CH3OH (10 mL) at -78 °C. After being concentrated in vacuo, the resulting resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 2.5 : 1) to provide 6- chloro-2-(lH-indol-2-yl)pyridin-3-ol (40 mg, yield: 85.1%), which was also prepared from 6- chloro-2-iodopyridin-3-ol and (l-(tert-butoxycarbonyl)-lH-indol-2-yl)boronic acid using similar procedure of step 3 of Example 1. 1H- MR (CDC13; 400 MHz) δ 10.09 (s, 1H), 9.72 (s, 1H), 7.50 (d, J= 7.9 Hz, 1H), 7.17-7.32 (m, 3H), 7.08-7.14 (m, 1H), 6.87-6.96 (m, 2H). MS (M+H)+: 245 / 247.
Step 5 - Synthesis of 2-chloro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indole with / withou 2- chloro-6, 11-dihydropyridof 2 ', 3 ':5, 6]pyrano[ 4, 3-b ] indole
Figure imgf000035_0002
A solution of 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (500 mg, 3.05 mmol) in
DMF (50 mL) was added dropwise to a mixture of chloroiodomethane (5.37 g, 30.5 mmol) and K2C03 (1.26 g, 9.15 mmol) in DMF (50 mL) at 100 °C. After addition, the mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL * 3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using chromatography (petroleum ether : EtOAc = 30 : 1) to provde the mixture of 2- chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole and 2-chloro-6, l 1- dihydropyrido[2',3':5,6]pyrano[4,3-b]indole (ratio = 3 : 1, 80 mg, yield: 15.3%), which was further purified with prep +: 257 / 259.
Figure imgf000035_0003
To a solution of 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (480 mg, 2.0 mmol) and
K2C03 (1.38 g, 10.0 mmol) in DMF (50 mL) stirring at 100 °C, chloroiodomethane (386 mg, 2.2 mmol) in DMF (10 mL) was added dropwise. After addition, the mixture was allowed to stir for another 0.5 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL * 3). The organic layer was washed with brine (100 mL * 3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 3 : 1) to provde the product 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (260 mg, yield: 50.7%). 1H- MR (CDC13, 400 MHz) δ 7.63 (d, J= 8.0 Hz, 1H), 7.22-7.27 (m, 3H), 7.19 (d, J= 2.4 Hz, 1H), 7.08-7.12 (m, 2H), 5.86 (s, 2H). MS (M+H)+: 257 / 259.
Step 6 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyrido [2' ' : 5, 6] [ 1 , 3] oxazino [3,4-a]indol-2-yl)benzofuran-3-carboxamide (Compound 1)
Figure imgf000036_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (502 mg, 1.0 mmol), 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (256 mg, 1.0 mmol) and K3P04 (636 mg, 3.0 mmol) in dioxane : H20 (1.5 mL : 0.4 mL) was added Pd2(dba)3 (91 mg, 0.1 mmol) and X-Phos (91 mg, 0.2 mmol) under N2. The mixture was heated to 110 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the desired product of Compound 1 (275 mg, yield: 46.1%). 1H- MR (CDC13; 400 MHz) δ
7.88-7.94 (m, 3H), 7.61-7.63 (m, 2H), 7.40 (s, 2H), 7.09-7.28 (m, 6H), 5.94 (s, 2H), 5.86 (d, J = 4.4 Hz, 1H), 3.29 (s, 3H), 2.92 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 597.
Compounds 2-40, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents. Compound MS
Structure NMR
No (M+H)+
^-NMR (CDC13, 400 MHz) δ
7.92-7.99 (m, 3H), 7.64 (s, IH),
7.44-7.49 (m, 2H), 7.29-7.32 (m,
3 IH), 7.00-7.24 (m, 5H), 6.03 (d, J = 615
F 0=S=0 4.4 Hz, IH), 5.95 (s, 2H), 3.33 (s,
1
3H), 2.97 (d, J = 4.8 Hz, 3H), 2.73
(s, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.61
(s, IH), 8.35 (s, IH), 8.00-8.03 (m,
2H), 7.74 (t, J = 4.0 Hz, 2H), 7.41
4 (s, IH), 7.37 (d, J = 4.8 Hz, 2H), 598
7.18-7.22 (m, 3H), 6.07 (s, 2H),
Ms
3.44 (s, 3H), 3.02 (s, 3H), 2.84 (s,
3H).
^-NMR (CDCI3, 400 MHz) δ 8.65
(s, IH), 8.36 (s, IH), 8.01-8.04 (m,
2H), 7.72 (s, IH), 7.48 (s, IH),
5 7.13-7.23 (m, 4H), 6.89 (t, J = 8.0 616
Hz, IH), 5.97-6.09 (br, 3H), 5.98 (d,
^~~^"~^^^Ms
J = 4.0 Hz, IH), 3.48 (s, 3H), 3.04
(d, J = 5.2 Hz, 3H), 2.85 (s, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.62
(s, IH), 8.47 (s, IH), 8.00-8.08 (m,
2H), 7.73 (s, IH), 7.10-7.41 (m,
6 616
6H), 6.07 (s, 2H), 6.00 (d, J = 4.0
F^~~^"^^^ Hz, IH), 3.45 (s, 3H), 3.04 (d, J =
4.8 Hz, 3H), 2.85 (s, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.59
(d, J = 1.2 Hz, IH), 8.27 (s, IH),
8.01-8.05 (m, 2H), 7.81 (s, IH),
7.75 (s, IH), 7.71 (d, J = 8.0 Hz,
7 IH), 7.34 (d, .7 = 2.4 Hz, 2H), 612
7.16-7.26 (m, 3H), 5.97 (d, J = 4.0
Hz, IH), 4.67 (s, 4H), 3.41 (s, 3H),
3.03 (d, J = 1.2 Hz, 3H), 2.80 (s,
3H). 1 H-NMR (OMSO-d6, 400 MHz) δ
8.74 (s, 1H), 8.62 (d, J = 4.0 Hz,
1H), 8.02-8.07 (m, 4H), 7.69 (s,
1H), 7.41-7.46 (m, 3H), 7.25-7.31
630 (m, 1H), 6.90-6.95 (m, 1H),
4.72-4.77 (m, 4H), 3.40 (s, 3H),
F
2.93 (s, 3H), 2.84 (d, J = 4.4 Hz,
3H).
1 H-NMR (CDC13, 400 MHz) δ 8.65
(s, 1H), 8.33 (s, 1H), 8.03-8.07 (m, 2H), 7.73-7.77 (m, 2H), 7.45 (s,
1H), 7.37-7.38 (m, 2H), 7.18-7.24
612 (m, 3H), 6.65-6.69 (m, 1H), 6.20 (s, o=s=o
1 1H), 3.48 (s, 3H), 3.04 (d, J = 4.8
Hz, 3H), 2.83 (s, 3H), 1.71 (d, J =
5.6 Hz, 3H).
1 H-NMR (CDCI3, 400 MHz) δ 7.96
(m, 2H), 7.85 (m, 2H), 7.64 (m, 2H), 7.31-7.36 (m, 2H), 7.17-7.25 (m,
596 5H), 6.86 (s, 1H), 5.96 (s, 2H), 5.88 o=s=o
1 (s, 1H), 3.15 (s, 3H), 3.00 (d, J = 5.2
Hz, 3H), 2.77 (s, 3H).
1 H-NMR (Methanol-^, 400 MHz) δ 8.51 (s, 1H),8.24 (s, 1H), 8.04 (s,
1H), 7.92-7.95 (m, 3H), 7.71(d, J =
8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.42 (s, 1H), 7.37 (t, J = 8.0 597 o-s-o Hz, 1H), 7.29 (t, J = 8.8 Hz, 1H),
1 7.20 (t, J = 8.0 Hz, 1H), 6.17 (s,
3H), 3.39 (s, 3H), 2.98 (s, 3H), 2.93
(s, 3H)
1 H-NMR (CDCI3, 400 MHz) δ 8.04
(s, 1H), 7.65-7.99 (m, 2H), 7.65 (s, 1H), 7.52-7.59 (m, 4H), 7.21-7.37
622 (m, 2H), 7.19-7.23 (m, 2H), 6.06 (s, o=s=o
3H), 3.34 (s, 3H), 3.01 (d, J = 5.2
Hz, 3H), 2.80 (s, 3H).
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
^-NMR (CDC13, 400 MHz) δ
7.95-8.02 (m, 2H), 7.88 (s, IH),
7.74 (s, IH), 7.14-7.21 (m, 3H),
7.09 (d, J = 8.0 Hz, IH), 7.04-7.07
(m, 2H), 6.83 (q, J = 10.0 Hz, 8.0 645 Hz, IH ), 5.99 (s, 2H), 5.96 (d, J =
Figure imgf000044_0001
4.0 Hz, IH), 3.83 (s, 3H), 3.26 (s,
3H), 2.97 (d, J = 4.8 Hz, 3H), 2.78
(s, 3H).
^-NMR (CDCI3, 400 MHz) δ 7.99
(s, IH), 7.93-7.96 (m, , 2H), 7.65 (s, IH), 7.43-7.49 (m, 2H), 7.12-7.21
(m, 4H), 7.10 (d, J = 8.0 Hz, IH), j O XrC F 6.83 (t, J = 8.4 Hz, IH), 629
V o=s=o 6.53~6.57(m, lH), 6.06 (d, J = 4.8
F 1
(Enantiomer 1, peak 1 on SFC) Hz, IH), 3.38 (s, 3H), , 2.98 (d, J =
4.0 Hz, 3H), 2.68 (s, 3H), 1.66 (d, J
= 5.6 Hz, 3H).
^-NMR (CDCI3, 400 MHz) δ 7.99
(s, IH), 7.93-7.96 (m, , 2H), 7.65 (s, IH), 7.43-7.49 (m, 2H), 7.12-7.21
(m, 4H), 7.10 (d, J = 8.0 Hz, IH), j N0 XrC F 6.83 (t, J = 8.4 Hz, IH), 629
V o=s=o 6.53~6.57(m, lH), 6.06 (d, J = 4.8
F I
(Enantiomer 2, peak 2 on SFC) Hz, IH), 3.38 (s, 3H), , 2.98 (d, J =
4.0 Hz, 3H), 2.68 (s, 3H), 1.66 (d, J
= 5.6 Hz, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.49
(s, IH), 8.23 (s, IH), 7.99-8.03 (m, 2H), 7.72 (s, IH), 7.16-7.20 (m,
2H), 6.94 (d, J = 2.0 Hz, IH), 6.78
(s, IH), 6.29 (t, J = 3.2 Hz, IH), 626 6.04 (d, J = 4.4 Hz, IH), 4.14-4.21
Figure imgf000044_0002
(m, 4H), 3.34 (s, 3H), 3.01 (d, J =
4.8 Hz, 3H), 2.79 (s, 3H), 2.06-2.08 (m, 2H). ^-NMR (Methanol-^, 400 MHz) δ
8.64 (s, 1H), 8.16 (s, 1H), 7.97-8.00
(m, 2H), 7.88 (s, 1H), 7.36 (d, J =
8.4 Hz, 1H), 7.22-7.28 (m, 4H),
40 644
6.78-6.82 (m, 1H), 4.44 (t, J = 5.2
si o=s=o Hz, 2H), 4.19 (t, J = 5.2 Hz, 2H),
1
3.46 (s, 3H), 2.95 (s, 3H), 2.90 (s,
3H), 2.14-2.15 (m, 2H).
Example 2
Preparation of Compound 41
Figure imgf000045_0001
The procedure of compound 41 was similar to step 6 of Example 1, using 2- chloro-6, l l-dihydropyrido[2',3':5,6]pyrano[4,3-b]indole obtained from step 5 of Example 1. 1H- MR (CDC13, 400 MHz) δ 9.71 (s, 1H), 7.99 (s, 1H), 7.88-7.91 (m, 2H), 7.52 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.29 (d, J= 8.4 Hz, 1H), 7.19 (s, 1H), 7.05-7.19 (m, 4H), 5.97 (s, 1H), 5.73 (s, 2H), 3.08 (s, 3H), 2.93 (d, J= 5.2 Hz, 3H), 2.89 (s, 3H). MS (M+H)+: 597.
Example 3
Preparation of Compound 42
Figure imgf000046_0001
Synthesis of 4-bromo-2- lH-indol-2-yl)phenol
Figure imgf000046_0002
l-(5-bromo-2-hydroxyphenyl)ethanone (7.1 g, 33 mmol) and phenylhydrazine (4.3 g, 40 mmol) were stirred in 45 mL of dry ethanol. Acetic acid (27 drops) was added and the mixture was refluxed for 5 hours. After cooling to room temperature, the precipitates were collected by filtration to provide the crude product as a light yellow solid, which was stirred in 100 mL of xylene and 50 g of polyphosphoric acid at 85 °C for 8 hours. Water was added to the warm crude, and then the mixture was stirred for 10 minutes before poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel
(petroleum ether : EtOAc = 10 : 1) provided 4-bromo-2-(lH-indol-2-yl)phenol as a light yellow powder (2.1 g, 22.1%). 1H- MR (CDC13, 400 MHz) δ 10.08 (s, 1H), 9.56 (s, 1H), 7.88 (s, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.14-7.19 (m, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.85-6.88 (m, 2H). MS (M+H)+: 288 / 290.
Synthesis -(5-bromo-2-(2-bromoethoxy)phenyl)-lH-indole
Figure imgf000046_0003
To a mixture of 4-bromo-2-(lH-indol-2-yl)phenol (1.44 g, 5 mmol) and 2- bromoethanol (1.12 g, 9 mmol) in 20 mL of THF was added DBAD (2.07 g, 9 mmol) followed by triphenylphosphine (2.36 g, 9 mmol) in portions at room temperature with stirring. After 1 hour, the reaction was concentrated to near dryness, and purified using flash column
chromatography (hexane / EtOAc 30: 1) to provide the crude product of 2-(5-bromo-2-(2- bromoethoxy)phenyl)-lH-indole (1.98 g, 100%). MS (M+H)+: 394 / 396 / 398. Synthesis of 2-bromo-6, 7-dihydrobenzo[6, 7] [l,4]oxazepino[4,5-a]indole
Figure imgf000047_0001
A solution of compound 2-(5-bromo-2-(2-bromoethoxy)phenyl)-lH-indole (1.97 g, 5 mmol) in 30 mL of DMF was cooled to 0 °C at N2 atmosphere, NaH (600 mg, 15 mmol) was added at the same temperature. The reaction mixture was stirred at room temperature. After 8 hours, the reaction was quenched by water, extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo.
Purification by flash chromatography on silica gel (petroleum ether : EtOAc = 50 : 1) provided 2-bromo-6,7-dihydrobenzo[6,7][l,4]oxazepino[4,5-a]indole as light yellow powder (0.8 g, 51%), which was also prepared from 4-bromo-2-(lH-indol-2-yl)phenol and 1,2-dibromoethane using similar method described in step 5 of Example 1. 1H- MR (CDC13, 400 MHz) δ 7.96 (s, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.25-7.27 (m, 1H), 7.16 (t, J= 6.8 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 6.91 (s, 1H), 4.53-4.55 (m, 2H), 4.47-4.49 (m, 2H). MS (M+H)+: 314 / 316.
Step 4 - Synthesis of 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6, 7- dihydrobenzof 6, 7][ l,4]oxazepino[ 4, 5-a] indole
Figure imgf000047_0002
A mixture of 2-bromo-6,7-dihydrobenzo[6,7][l,4]oxazepino[4,5-a]indole (314 mg, 1 mmol), Bispinacolatodiboron (381 mg, 1.5 mmol), KOAc (393 mg, 4 mmol) and Pd(dppf) Cl2 (73 mg, 0.1 mmol) in 10 mL of 1,4-dioxane was stirred at 90°C for 8 h under N2. The mixture was concentrated in vacuo to provide crude product, which was purified using silica gel column chromatography to provide 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7- dihydrobenzo[6,7][l,4]oxazepino[4,5-a]indole (300 mg, yield: 83.1%). 1H- MR (CDC13, 400 MHz) δ 8.35 (s, 1H), 7.65-7.69 (m, 2H), 7.30 (d, J= 8.4 Hz, 1H), 7.23 (t, J= 7.2 Hz, 1H), 7.14 (t, J= 7.2 Hz, 1H), 7.06-7.08 (m, 2H), 4.57 (t, J= 4.2 Hz, 2H), 4.50 (t, J= 4.2 Hz, 2H), 1.37 (s, 12H). MS (M+H)+: 362.
Step 5 - Synthesis of 5-(6, 7-dihydrobenzo[6, 7] [l,4]oxazepino[4,5-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 42)
Figure imgf000048_0001
42
A mixture of compound 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,7- dihydrobenzo[6,7][l,4]oxazepino[4,5-a]indole (72 mg, 0.2 mmol), 5-bromo-2-(4-fluorophenyl)- N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (91 mg, 0.2 mmol), K3P04-3H20 (160 mg, 0.6 mmol) and Pd(dppf)Cl2 (15 mg, 0.02 mmol) in 2 mL of DMF was stirred at 90 °C for 8 h under N2, then the mixture was purified using prep-HPLC to provide Compound 42 (30 mg, yield: 24.9%). 1H- MR (CDC13, 400 MHz) δ 7.92-7.97 (m, 3H), 7.81 (s, 1H), 7.63-7.65 (m, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.12-7.25 (m, 5H), 6.97 (s, 1H), 6.00 (d, J = 4.0 Hz, 1H), 4.62 (t, J= 4.2 Hz, 2H), 4.54 (t, J= 4.2 Hz, 2H), 3.18 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 610.
Example 4
Preparation of Compound 43
Figure imgf000048_0002
Step 1 - Synthesis of ((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane
Figure imgf000049_0001
A mixture of 2-bromo-4-chloro-l-methoxybenzene (1 g, 4.5 mmol), Cul (43 mg,
0.23 mmol), Pd(PPh3)2Cl2 (0.16 g, 0.23 mmol) in Et3 (10 mL) was degassed, Then
ethynyltrimethylsilane (0.5 g, 5 mmol) was added to the solution, the mixture was stirred at 80 °C for 6 hours. Then the mixture was cooled to 25 °C, and added to H20 (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2S04. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 10 : 1) to provide the product of ((5-chloro-2- methoxyphenyl)ethynyl)trimethylsilane (1 g, yield: 90%). 1H- MR (CDC13, 400 MHz) δ 7.40 (s, 1H), 7.21-7.23 (m, 1H), 6.76-6.78 (d, J= 9.2 Hz, 1H), 3.86 (s, 3H), 0.26 (s, 9H). MS (M+H)+: 239 / 241
Step 2 - Synthesis of 4-chloro-2-eth nyl-l-methoxybenzene
Figure imgf000049_0002
((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (0.4 g, 1.7 mmol) was dissolved in MeOH (1 mL), K2C03 (0.69 g, 5 mol) was added to it. Then the mixture was stirred at 25 °C for 1 hour, and added to H20 (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2S04. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 10 : 1) to provide the product of 4-chloro-2-ethynyl-l-methoxybenzene (0.25 g, yield: 80%). 1H- MR (CDC13, 400 MHz) δ 7.43 (s, 1H), 7.28-7.29 (m, 1H), 6.81-6.85 (m, 1H), 3.89 (s, 3H), 3.34 (s, 1H). MS (M+H)+: 167 / 169.
Step 3 - Synthesis of 2-(5-chloro-2-methoxyphenyl)-4-fluoro-lH-indole
Figure imgf000049_0003
A mixture of 4-chloro-2-ethynyl-l-methoxybenzene (255 mg, 1.5 mmol), N-(2- bromo-3 -fluorophenyl) -2,2,2-trifluoroacetamide (400 mg, 1.4 mmol), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) was stirred in TBAF3H20 (1.43 g, 7 mmol) at 110 °C for 12 hours. The reaction mixture was cooled to 25 °C and added to water, then extracted with ethyl acetate and washed with brine, dried over Na2S04. After concentrated, the crude product of 2-(5-chloro-2-methoxyphenyl)-4- fluoro-lH-indole (100 mg, yield: 20%) was obtained. MS (M+H)+: 276 / 278.
Step 4 - Synthesis of 4-chloro-2- 4-fluoro-lH-indol-2-yl)phenol
Figure imgf000050_0001
2-(5-chloro-2-methoxyphenyl)-4-fluoro-lH-indole (50 mg, 0.2 mmol) was dissolved in dichloromethane (1 mL), and then BBr3 (150 mg, 0.6 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 1 hour, and then stirred at 25 °C for 12 hours. MeOH (1 mL) and H20 (20 mL) were added to the solution. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2S04. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 5 : 1) to provide the product of 4-chloro-2-(4-fluoro-lH-indol-2-yl)phenol (10 mg, yield: 25%). 1H- MR (CDC13, 400 MHz) δ 9.54 (s, 1H), 7.65 (s, 1H), 7.06-7.12 (m, 2H), 6.88 (s, 1H), 6.79-6.81 (m, 1H), 6.70-6.74 (m, 1H). MS (M+H)+: 262 / 263. Step 5 - Synthesis of 2-chloro-l l- uoro-6H-benzo[5, 6] ' [1,3] oxazino[ 3, 4-a] indole
Figure imgf000050_0002
To a solution of 4-chloro-2-(4-fluoro-lH-indol-2-yl)phenol (40 mg, 0.15 mmol) in DMF (1 mL), K2C03 (40 mg, 0.31 mmol) and CH2Br2 (53 mg, 0.31 mmol) were added at 25 °C. The mixture was stirred at 80 °C for 2 hours, and cooled to 25 °C. H20 (50 mL) was added, then the mixture was extracted with ethyl acetate and washed with brine, dried over Na2S04.
After concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 10 : 1) to provide the product of 2-chloro-l l-fluoro-6H-benzo[5,6][l,3]oxazino[3,4-a]indole (50 mg, yield: 45%). 1H- MR (CDC13, 400 MHz) δ 7.68 (s, 1H), 7.14-7.23 (m, 2H), 7.03-7.09 (m, 2H), 6.90 (s, 1H), 6.81-6.86 (m, 1H), 5.88 (s, 2H). MS (M+H)+: 274 / 276.
Step 6 - Synthesis of 5-(l l-fluoro-6H-benzo[5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl) -N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 43)
Figure imgf000051_0001
A mixture of 2-chloro-l l-fluoro-6H-benzo[5,6][l,3]oxazino[3,4-a]indole (30 mg, 0.11 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (55 mg, 0.11 mmol),
Κ3Ρ04·3Η20 (88 mg, 0.33 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), X-Phos (11 mg, 0.022 mmol) was stirred in dixane / H20 (5 mL, 4: 1) at 110 °C for 12 hours. Then the mixture was cooled to 25 °C, water was added to it. The mixture was extracted with ethyl acetate and washed with brine, dried over Na2S04. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 3 : 1) to provide the product of Compound 43 (25 mg, yield: 40%). 1H- MR (CDC13, 400 MHz) δ 9.94-7.97 (m, 2H),
7.83-7.86 (m, 2H), 7.62 (s, 1H), 7.37-7.40 (m, 1H), 7.09-7.24 (m, 5H), 6.93 (s, 1H), 6.80-6.85 (m, 1H), 5.95 (s, 2H), 5.85 (br, 1H), 3.16 (s, 3H), 3.00-3.01 (d, J= 5.2 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 614.
Compound 44, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Compound MS
Structure NMR
No (M+H)+
Figure imgf000052_0001
Example 5
Preparation of Compound 45
Figure imgf000052_0002
To 5-methoxy-lH-pyrrolo[3,2-b]pyridine (9 g, 60.8 mmol) in dichloromethane (200 mL) was added (Boc)20 (9.2 g, 91.2 mmol), DMAP (1.34 g, 12.16 mmol) and Et3N (7.37 g, 73 mmol) under N2. The mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and washed with H20, brine, dried over Na2S04. After concentrated, the crude product of tert-butyl 5-methoxy-lH-pyrrolo[3,2-b]pyridine-l- carboxylate (10 g, yield: 56%). 1H- MR (CDC13, 400 MHz) δ 8.21 (s, 1H), 7.69 (s, 1H), 6.65 (d, J = 9.2 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H), 1.63 (s, 9H). MS (M+H)+: 249.
Synthesis of (l-(tert-butoxycarbonyl)-5-methoxy-lH-pyrrolo[ 3, 2-b ]pyridin-2-yl)boronic
Figure imgf000052_0003
To a solution of tert-butyl 5-methoxy-lH-pyrrolo[3,2-b]pyridine-l-carboxylate (3 g, 12.08 mmol) in 40 mL of dry THF was added dropwise t-BuLi (1.16 g, 18.12 mmol) at -78 °C. Then the solution was stirred at -78 °C for 1 hour. Then triisopropyl borate (4.55 g, 24.17 mmol) was added dropwise to the solution still at -78 °C. The mixture was stirred at -78 °C for 2 hours and quenched the reaction with 1 M of HC1 at low temperature to pH = 3-4. After it was extracted with EtOAc, the combined organic phase was washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using column (petroleum ether : ethyl acetate = 3 : 1) to provide (l-(tert-butoxycarbonyl)-5-methoxy-lH-pyrrolo[3,2-b]pyridin-2- yl)boronic acid (1.3 g, yield: 37%). 1H- MR (CDC13, 400 MHz) δ 8.10 (d, J= 9.2 Hz, 1H), 7.46 (s, 1H), 6.88-6.84 (m, 2H), 6.70 (d, J= 9.2 Hz, 1H), 3.98 (s, 3H), 1.71 (s, 9H). MS (M+H)+: 293.
Step 3 - Synthesis of tert-butyl 2-(6-chloro-3-hydroxypyridin-2-yl)-5-methoxy-lH-pyrrolo[3,2- b ] pyridine- 1-carbox late
Figure imgf000053_0001
To a degassed solution of (l-(tert-butoxycarbonyl)-5-methoxy-lH-pyrrolo[3,2- b]pyridin-2-yl)boronic acid (500 mg, 1.17 mmol), NaHC03 (287 mg, 3.42 mmol) and 6-chloro- 2-iodopyridin-3-ol (525 mg, 2.05 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (10 mg) under N2. The mixture was heated at 70 °C for 5 hours, concentrated in vacuo to remove 1,4- dioxane and extracted with EtOAc. After washed with brine and dried over Na2S04, the solvent was removed by distillation. After concentrated, the crude product of tert-butyl 2-(6-chloro-3- hydroxypyridin-2-yl)-5-methoxy-lH-pyrrolo[3,2-b]pyridine-l-carboxylate (260 mg, yield: 40%). MS (M+H)+: 376 / 378. Step 4 - Synthesis of 6-chloro-2- 5-methoxy-lH-pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol
Me
Figure imgf000053_0002
To a stirred solution of tert-butyl 2-(6-chloro-3-hydroxypyridin-2-yl)-5-methoxy- lH-pyrrolo[3,2-b]pyridine-l-carboxylate (260 mg, 0.69 mmol) in dichloromethane (6.0 mL) was added TFA (118 mg, 1.04 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was diluted with H20 and extract with EtOAc. The organics were washed with brine and dried over Na2S04. After concentrated, the crude product of 6-chloro-2-(5-methoxy-lH- pyrrolo[3,2-b]pyridin-2-yl)pyridin-3-ol (128 mg, yield: 67%). MS (M+H)+: 276 / 278.
Step 5 - Synthesis of 2-chloro-10-methoxy-6H-pyrido[2,3-e]pyrido[2',3':4,5]pyrrolo[l,2- c [l,3]oxazine
Figure imgf000054_0001
To a stirring solution of 6-chloro-2-(5-methoxy-lH-pyrrolo[3,2-b]pyridin-2- yl)pyridin-3-ol (200 mg, 0.727 mmol) and Cs2C03 (472 mg, 1.45 mmol) in DMF (15 mL) was added chloroiodomethane (192 mg, 1.09 mmol) in DMF (2 mL) dropwise at 100 °C under N2. The mixture was stirred at 100 °C for 1 hour. The mixture was diluted with H20 and extracted with EtOAc. The organics were washed with brine and dried over Na2S04. After concentrated, the resulting residue was purified using Pre-TLC to provide 2-chloro-10-methoxy-6H- pyrido[2,3-e]pyrido[2',3':4,5]pyrrolo[l,2-c][l,3]oxazine (110 mg, yield: 52%). 1H- MR (CDC13, 400 MHz) 7.44 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 5.81 (s, 2H), 3.95 (s, 3H). MS (M+H)+: 288 / 290.
Step 6 - Synthesis of 2-(4-fluorophenyl)-5-(10-methoxy-6H-pyrido[2,3- e Jpyridof 2 ', 3 ': 4, 5 ]pyrrolo[ 1, 2-c ][ 1, 3 ]oxazin-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 45)
Figure imgf000054_0002
To a solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5- (4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (100 mg, 0.199 mmol), 2-chloro-10-methoxy-6H-pyrido[2,3-e]pyrido[2',3':4,5]pyrrolo[l,2-c][l,3]oxazine (64 mg, 0.18 mmol) and K3PO4 (104 mg, 0.398 mmol) in 3 mL of 1,4-dioxane and 0.2 mL of water were added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under nitrogen. The reaction mixture was heated at 100 °C for 5 hours, concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated to provide the compound 45 (30 mg, yield: 20%) through the prep-HPLC. 1H- MR (CDC13, 400 MHz) δ 7.91 (s, 1H), 7.88 (d, J = 5.6 Hz, 2H), 7.60 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (s, 2H), 7.15-7.10 (m, 3H), 6.63 (d, J = 8.8 Hz, 1H), 5.90 (s, 1H), 5.88 (s, 2H), 3.94 (s, 3H), 3.33 (s, 3H), 2.92 (d, J = 4.8 Hz, 3H), 2.62 (s, 3H). MS (M+H)+: 628.
Example 6
Preparation of Compound 46
Figure imgf000055_0001
46
Step 1 - Synthesis of 2-(3-( enzyloxy)-6-chloropyridin-2-yl)-4-fluoro-lH-pyrrolo[2,3-cJpyridme
Figure imgf000055_0002
To a degassed solution of 2,2,2-trifluoro-N-(5-fluoro-4-iodopyridin-3- yl)acetamide (1 g, 2.99 mmol, prepared using similar method described in Example 4) and 3- (benzyloxy)-2-ethynyl-6-methylpyridine (735 mg, 3.29 mmol) in 1,4-dioxane (20 mL) was added PPh3 (235 mg, 0.90 mmol), Cul (171 mg, 0.90 mmol) and K2C03 (827 mg, 5.99 mmol) under N2. The mixture was heated at 110 °C for 10 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was extract with EtOAc and washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using column
(petroleum ether : EtOAc = 5 : 1) to provide 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro- lH-pyrrolo[2,3-c]pyridine (500 mg, yield: 25%). 1H- MR (CDC13, 400 MHz) δ 9.94 (s, 1H), 8.64 (s, 1H), 8.09 (s, 1H), 7.48-7.41 (m, 6H), 7.32 (d, J= 8.8 Hz, 1H), 7.25-7.18 (m, 1H), 5.31 (s, 2H). MS (M+H)+: 354 / 356. Step 2 - Synthesis of 5-(5-(benzyloxy)-6-(4-fluoro-lH-pyrrolo[2, 3-c]pyridin-2-yl)pyridin-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000056_0001
To a degassed solution of 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-lH- pyrrolo[2,3-c]pyridine (300 mg, 0.85 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (387 mg, 0.77 mmol) in 1,4-dioxane (5.0 mL) was added Pd2(dba)3 (10 mg), X- Phos (10 mg) and K3P04 (452 mg, 1.70 mmol) under N2. The mixture was heated at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After it was concentrated, the resulting residue was purified using column (petroleum ether : EtOAc = 2 : 1) to provide 5-(5-(benzyloxy)-6-(4-fluoro- lH-pyrrolo[2,3-c]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (165 mg, yield: 31%). 1H- MR (CDC13, 400 MHz) δ 10.73 (s, 1H), 8.49 (s, 1H), 7.99 (d, J= 8.0 Hz, 2H), 7.92 (dd, J= 8.0, 8.0 Hz, 2H), 7.50-7.45 (m, 3H), 7.43-7.40 (m, 5H), 7.16 (t, J= 8.0 Hz, 2H), 6.56 (s, 1H), 5.32 (s, 12H), 3.10 (s, 3H), 2.91 (d, J= 4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 694.
Step 3 - Synthesis of 5-(6-(4-fluoro-lH-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000056_0002
To a degassed solution of 5-(5-(benzyloxy)-6-(4-fluoro-lH-pyrrolo[2,3-c]pyridin-
2- yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(
carboxamide (150 mg, 0.22 mmol) was dissolved in THF (5 mL) and charged with 10% palladium on carbon (0.1 g). The mixture was hydrogenated at room temperature under hydrogen pressure for 4 hours. The reaction mixture was filtered and the filtrate was extract with EtOAc and washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using prep-TLC to provide 5-(6-(4-fluoro-lH-pyrrolo[2,3-c]pyridin-2-yl)-5- hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-
3- carboxamide (120 mg, yield: 92%). 1H- MR (CDC13, 400 MHz) δ 12.00 (s, 1H), 11.17 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.01 (t, J= 6.0 Hz„ 3H), 7.91 (s, 1H), 7.52 (s, 2H), 7.41-7.35 (m, 3H), 3.19 (s, 3H), 2.95 (s, 3H), 2.80 (d, J= 4.0 Hz, 3H). MS (M+H)+: 604.
Step 4 - Synthesis of 5-( 1 l-fluoro-6H-pyridof 2, 3-e Jpyridof 4 ', 3 ': 4, 5 Jpyrrolof 1, 2-c ][ 1, 3 ]oxazin-2- yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-m
( ompound 46
Figure imgf000057_0001
To a stirring solution of 5-(6-(4-fluoro-lH-pyrrolo[2,3-c]pyridin-2-yl)-5- hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran- 3-carboxamide (100 mg, 0.17 mmol) and Cs2C03 (108 mg, 0.33 mmol) in DMF (3 mL) was added chloroidomethane (35 mg, 0.2 mmol) dropwise at 100 °C under N2. The mixture was heated for 8 hours. The mixture was diluted with H20 and extracted with EtOAc. The organics were washed with brine and dried over Na2S04. The crude product was purified using prep- HPLC to obtain the product of Compound 46 (30 mg, yield: 30%). 1H- MR (CDC13, 400 MHz) δ 8.61 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.95 (t, J= 6.0 Hz, 2H), 7.65 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.53 (d J= 8.0 Hz, 1H), 7.25-7.19 (m, 3H), 6.10 (s, 2H), 5.99 (s, 1H), 3.37 (s, 3H), 3.00 (d, J= 4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 616. Compound 47, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Figure imgf000058_0003
Example 7
Preparation of Compound 48
Figure imgf000058_0001
Step 1 - Synthesis of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,S-b]pyridine
Figure imgf000058_0002
NaH (4.90 g, 203.2 mmol) was added to a solution of lH-pyrrolo[2,3-b]pyridine (20.0 g, 169.3 mmol) in dry DMF (200 mL) under N2 protection. The mixture was stirred at 0 °C for 1 hour. Then SEMC1 (42.2 g, 253.95 mmol) was added to the reaction mixture, and the mixture was stirred at 0 °C for 4 hours. After concentrated in vacuo to remove DMF, ice cold H4CI (sat. aq.) was added and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered and the solvent was concentrated in vacuo under reduced pressure. The crude product was purified using column chromatography
(petroleum ether : EtOAc = 10 : 1) to provide the product of l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (31.2 g, yield: 74%). 1H- MR
(CDCI3, 400 MHz) δ 8.33 (dd, J= 4.8 Hz, 1.6 Hz, 1H), 7.91 (dd, J= 7.6 Hz, 1.6 Hz, 1H), 7.34 (d, J= 3.6 Hz, 1H), 7.08 (dd, J= 7.6 Hz, 4.8 Hz, 1H), 6.51 (d, J= 3.6 Hz, 1H), 5.68 (s, 2H), 3.53 (t, J= 8.4 Hz, 2H), 0.90 (t, J= 8.4 Hz, 2H), -0.08 (s, 9H). MS (M+H)+: 249.
Step 2 - Synthesis of (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]py
acid
Figure imgf000059_0001
A hexane solution of «-BuLi (60 mL, 150.97 mmol) was added slowly to a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (25.0 g, 100.65 mmol) in dry THF (200 mL) at -70 °C under N2 protection. The mixture was stirred at -45 °C for 2 hour. After (i-PrO)3B (30.29 g, 161.03 mmol) was added, the mixture was stirred overnight warming to RT. Then the reaction mixture was quenched with 1M aqueous HC1 and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered and the solvent was concentrated in vacuo under reduced pressure. The crude product was purified using column chromatography (petroleum ether : EtOAc = 5 : 1) to provide the product of (l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (14.4 g, yield: 49%). 1H- MR (CDC13, 400 MHz) δ 8.49 (dd, J= 4.8 Hz, 1.6 Hz, 1H), 8.07 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 7.21 (dd, J= 8.0 Hz, 4.8 Hz, 1H), 6.92 (s, 1H), 6.02 (s, 2H), 3.74 (t, J= 8.4 Hz, 2H), 1.08 (t, J= 8.4 Hz, 2H), 0.04 (s, 9H). MS (M+H)+: 293. Step 3 - Synthesis of 6-chloro-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin- 2-yl)pyridin-3-ol
Figure imgf000059_0002
To a mixture of 6-chloro-2-iodopyridin-3-ol (8.39 g, 32.85 mmol), (l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (8.00 g, 27.38 mmol) and Κ3Ρ04·3Η20 (22 mg, 82.13 mmol) in 1,4-dioxane (120 mL), Pd(dppf)Cl2 (50 mg) was added under N2 protection. After stirred overnight at 80 °C, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 5 : 1) to provide the product of 6-chloro-2-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol (3.01 g, yield: 29%). 1H- MR (CDC13, 400 MHz) δ 8.40 (dd, J= 4.8 Hz, 1.6 Hz, 1H), 7.96 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.17 (dd, J= 8.0 Hz, 4.8 Hz, 1H), 6.82 (s, 1H), 5.85 (s, 2H), 3.65 (t, J= 8.4 Hz, 2H), 0.89 (t, J= 8.4 Hz, 2H), -0.08 (s, 9H). MS (M+H)+: 376 / 378.
Step 4 - Synthesis o 6-chloro-2-(lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol
Figure imgf000060_0001
6-chloro-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-2- yl)pyridin-3-ol (320 mg, 1.10 mmol) was added to HC1 / 1,4-dioxane (15 mL), and the reaction mixture was heated to 100 °C and stirred for 10 hours. Then the mixture was concentrated in vacuo, diluted with EtOAc, washed with brine, dried over Na2S04 and concentrated to provde the crude product of compound 5 (200 mg, yield: 74%), which was used for the next step without further purification. 1H- MR (DMSO-d6, 400 MHz) δ 11.59 (s, 1H), 11.29 (br s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 8.01 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.30 (s, 1H), 7.27 (d, J= 8.4 Hz, 1H), 7.07 (dd, J= 8.0 Hz, 4.8 Hz, 1H). MS (M+H)+: 246 / 248.
Step 5 - Synthesis of 2-chloro-6H- rido[ 2, 3-e Jpyridof 3 ' 2 ': 4, 5 Jpyrrolof 1, 2-c ][ 1, 3 Joxazine
Figure imgf000060_0002
To a mixture of chloroiodomethane (2.01 g, 11.40 mmol), K2C03 (338 mg, 2.44 mmol) in DMF (15 mL), 6-chloro-2-(lH-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol (200 mg, 0.81 mmol) in DMF (5 mL) was added dropwise at 100 °C under N2 protection. After stirred at 100 °C for 2 hours, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The crude product was purified using prep-TLC (petroleum ether : EtOAc = 8 : 1) to provide the product of 2-chloro-6H-pyrido[2,3-e]pyrido[3',2':4,5]pyrrolo[l,2-c][l,3]oxazine (20 mg, yield: 9%). 1H- MR (CDC13, 400 MHz) δ 8.35 (dd, J= 4.8 Hz, 1.6 Hz, 1H), 7.99 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.36 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.4 Hz, 1H), 7.16 (s, 1H), 7.13 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 6.14 (s, 2H). MS (M+H)+: 258 / 260.
Step 6 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6H- pyrido[ 2, 3-e Jpyridof 3 ', 2 ': 4, 5 ]pyrrolo[ l,2-c][l,3 ]oxazin-2-yl) benzofuran-3-carboxamide (Compound 48)
Figure imgf000061_0001
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (40 mg, 0.08 mmol), 2- chloro-6H-pyrido[2,3-e]pyrido[3',2':4,5]pyrrolo[l,2-c][l,3]oxazine (27 mg, 0.10 mmol) and
Κ3Ρ04·3Η20 (64 mg, 0.24 mmol) in 1,4-dioxane / water (1.5 mL / 0.2 mL), Pd2(dba)3 (5 mg), X- Phos (10 mg) were added under N2 protection. After stirred overnight at 80 °C, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane : MeOH = 20 : 1) to provide the product of Compound 48 (30 mg, yield: 48%). 1H- MR (CDC13, 400 MHz) δ 8.34-8.37 (m, 1H), 8.04 (s, 1H), 7.93-8.00 (m, 3H), 7.68 (s, 1H), 7.48-7.56 (m, 2H), 7.17-7.24 (m, 2H), 7.10-7.16 (m, 2H), 6.22 (s, 2H), 5.96 (br s, 1H), 3.53 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H), 2.76 (s, 3H). MS (M+H)+: 598.
Compounds 49 and 50, depicted in the table below, were prepared using the method described above and substituting the appropriate reagents and/or reactants.
Compound MS
Structure NMR
No (M+H)+ ^-NMR (CDC13, 400 MHz) δ 8.30
(d, J = 1.2 Hz, 1H), 7.87-7.97 (m,
5H), 7.61 (s, 1H), 7.73-7.77 (m,
1H), 7.18-7.24 (m, 3H). 7.08-7.12
49 597
(m, 1H), 6.80 (s, 1H), 6.16 (s. 2H),
o=s=o 5.87 (d, J = 4.4 Hz, 1H), 3.13 (s,
1
3H), 3.00 (d, J = 5.2 Hz, 3H), 2.82
(s, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.67
(s, 1H), 8.43 (dd, J = 4.8, 1.6 Hz,
1H), 8.27 (s, 1H), 8.11 (s. 1H),
8.10-8.03 (m, 3H), 7.63 (s. 1H),
50 598
7.25-7.15 (m. 4H). 6.64 (d, J = 2.8
o=s=o
1 Hz, 1H), 6.29 (s. 2H). 3.20 (s, 3H),
3.03 (d, J = 4.2 Hz, 3H), 3.02 (s,
3H).
Example 8
Preparation of Compound 51
Step 1 - Synthesis of 2 of 3, 4-a] indole
Figure imgf000062_0001
A solution of dibromotoluene (382 mg, 1.527 mmol, prepared using similar method described for Example 1) in DMF (2 mL) was added slowly to a mixture of compound 6- chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (200 mg, 0.763 mmol) and Cs2C03 (746 mg, 2.289 mmol) in DMF (10 mL) at 100 °C. After 10 min, the mixture was concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (25 mL χ 3). The organic layer was washed with brine (50 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : ethyl acetate = 50 : 1) to provide 2-chloro-l l-fluoro-6-phenyl-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (187 mg, yield: 70.0%). 1H- MR (CDC13, 400 MHz) δ 7.43 (s, 1H), 7.23-7.35 (m, 3H), 7.18 (s, 1H), 7.10 (s, 1H), 7.03-7.08 (m, 4H), 6.79 (m, 1H), 6.65 (d, J= 8.4 Hz, 1H). MS (M+H)+: 351 / 353.
Step 2 - Synthesis of 5-(ll-fluoro-6-phenyl-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofura^
(Compound 51)
Figure imgf000063_0001
Compound 51 (45 mg, yield: 57.0%) was made using the method described in Example 1, Step 1H- MR (CDC13; 400 MHz) δ 7.90-7.93 (m, 3H), 7.60 (s, 1H), 7.04-7.40 (m, 12H), 6.81-6.85 (m, 1H), 6.76 (d, J= 8.4 Hz, 1H), 5.95 (br s, 1H), 3.34 (s, 3H), 2.94 (d, J= 4.8 Hz, 3H), 2.30 (s, 3H). MS (M+H)+: 691.
Example 9
Preparation of Compound 52
Figure imgf000063_0002
Step 1 - Synthesis of 2-chloro-l l-((2-(trimethylsilyl)ethoxy)methyl)-6, l 1- dihydropyridof 2 ', 3 ':5, 6]pyrano[ 4, 3-b ]- 7-aza-indole
Figure imgf000064_0001
To a solution of mixture 6-chloro-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3- b]pyridin-2-yl)pyridin-3-ol (1.00 g, 2.66 mmol) and paraform (250 mg, 8.33 mmol) in 1,4- dioxane was added HCl / dioxane (4 M, 2 mL, 8.0 mmol). The reaction mixture was stirred at 70 °C for 3 hours. Then it was concentrated in vacuo, dissolved in EtOAc, washed with Na2C03 (aq.), brine, dried over Na2S04 and concentrated in vacuo. The resulting resulting residue was purified using column chromatography (petroleum ether : EtOAc = 8 : 1) to provide the product of 2-chloro- 11 -((2-(trimethylsilyl)ethoxy)methyl)-6, 11 -dihydropyrido [2', 3 ' : 5 , 6]pyrano [4, 3 -b] -7- aza-indole (150 mg, yield: 17%). 1H- MR (CDC13, 400 MHz) δ 8.41 (dd, J= 4.8 Hz, 1.6 Hz, 1H), 7.45 (dd, J= 8.0, 1.6 Hz, 1H), 7.18-7.10 (m, 2H), 7.07 (d, J= 8.8 Hz, 1H), 6.31 (s, 2H), 5.64 (s, 2H), 3.70 (t, J= 8.4 Hz, 2H), 0.96 (t, J= 8.4 Hz, 2H), -0.09 (s, 9H). MS (M+H)+: 388 / 390.
Step 2 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(l l-((2- (trimethylsilyl)ethoxy)methyl)-6, l 1 -dihydropyrido f 2', 3': 5, 6Jpyranof 4, 3-bJ-7-aza-indol-2- yl) benzofuran-3-carboxamide
Figure imgf000064_0002
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (118 mg, 0.23 mmol), 2-chloro- 11 -((2-(trimethylsilyl)ethoxy)methyl)-6, 1 1 -dihydropyrido [2', 3 ' : 5 , 6]pyrano [4, 3 -b] -7- aza-indole (100 mg, 0.26 mmol) and Κ3Ρ04·3Η20 (187 mg, 0.70 mmol) in 1,4-dioxane / H20 (2.0 mL / 0.2 mL), Pd2(dba)3 / X-Phos (10 mg / 10 mg) was added under N2 protection. The reaction mixture was stirred at 100 °C for 4 hours. Then it was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting resulting residue was purified using prep-TLC (dichloromethane : MeOH = 20 : 1) to provide the product 2-(4-fluorophenyl)-N-methyl-6- [methyl(methylsulfonyl)amino]-5-(l l-{[2-(trimethylsilyl)ethoxy]methyl}-6, l 1- dihydropyrido[2'',3'^5',6']pyrano[3',4^4,5]pyrrolo[2,3-b]pyridin-2-yl)-l-benzofuran-3- carboxamide (80 mg, yield: 48%). 1H- MR (CDC13, 400 MHz) δ 8.38 (d, J= 1.6 Hz, 1H), 8.12 (s, 1H), 8.04-8.00 (m, 2H), 7.79 (dd, J= 7.6, 1.6 Hz, 1H), 7.62 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.30 (d, J= 8.4 Hz, 1H), 7.17-7.23 (m, 2H), 7.14 (dd, J= 14.8, 8.0 Hz, 1H), 6.38 (s, 2H), 6.04 (d, J= 3.2 Hz, 1H), 5.67 (s, 2H), 3.49 (t, J= 8.4 Hz, 2H), 3.29 (s, 3H), 3.02 (d, J= 5.2 Hz, 3H), 2.79 (s, 3H), 0.76 (t, J= 8.4 Hz, 2H), 0.26 (s, 9H). MS (M+H)+: 728. Step 3 - Synthesis of 5-(6, l l-dihydropyrido[2",3' ':5', 6']pyrano[3',4 ':4,5]pyrrolo[2,3-b]pyridin-2- yl)-2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino
(Compound 52)
Figure imgf000065_0001
2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(l l-((2- (trimethylsilyl)ethoxy)methyl)-6, l l-dihydropyrido[2',3':5,6]pyrano[4,3-b]-7-aza-indol-2- yl)benzofuran-3-carboxamide (100 mg, 0.11 mmol) was added to HC1 / dioxane (4 M, 10 mL), and the reaction mixture was stirred at 80 °C for 4 hours. Then the mixture was concentrated in vacuo, diluted with EtOAc, washed with brine, dried over Na2S04 and concentrated in vacuo. The crude product was purified using prep-HPLC to provide the product of Compound 52 (30 mg, yield: 46%). 1H- MR (DMSO-i¾ 400 MHz) δ 12.34 (br s, 1H), 8.52 (d, J= 4.8 Hz, 1H),
8.27 (d, J= 4.0 Hz, 1H), 8.04-7.95 (m, 3H), 7.93 (s, 1H), 7.50-7.38 (m, 4H), 7.13 (d, J = 8.0 Hz, 1H), 5.75 (s, 2H), 3.27 (s, 3H), 2.99 (s, 3H), 2.84 (d, J= 4.4 Hz, 3H). MS (M+H)+: 598.
Example 10
Preparation of Compound 53
Figure imgf000066_0001
Step 1 - Synthesis of 2-bromo-6H-benzo 5, 6][l,3]oxazino[3,4-a]indol-6-one
Figure imgf000066_0002
Carbonyldiimidazole (490 mg, 2 mmol) and DMAP (50 mg) were added to a solution of 4-bromo-2-(lH-indol-2-yl)phenol (576 mg, 2 mmol) in 20 mL of dichloromethane and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water and brine, dried over Na2S04, filtered, and
concentrated in vacuo. Purification by flash chromatography on silica gel (hexane / EtOAc 20: 1) provided 2-bromo-6H-benzo[5,6][l,3]oxazino[3,4-a]indol-6-one as light yellow powder (500 mg, 79.6%). 1H- MR (CDC13, 400 MHz) δ 8.49 (d, J= 8.4 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J= 7.2 Hz, 1H), 7.41-7.53 (m, 3H), 7.22 (d, J= 8.8 Hz, 1H), 7.07 (s, 1H). MS (M+H)+: 314 / 316.
Step 2 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6- benzo -a Jindol-2-yl) benzofuran-3-carboxamide ( ompound 53 )
Figure imgf000066_0003
A mixture of 2-bromo-6H-benzo[5,6][l,3]oxazino[3,4-a]indol-6-one (47 mg, 0.15 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (51 mg, 0.1 mmol), K3P043H20 (80 mg, 0.3 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 2 mL of DMF was heated in a microwave reactor at 100 °C for 20 minutes, and then the mixture was purified using prep-HPLC to provide
Compound 53 (2.7 mg, yield: 4.4%). 1H- MR (CDC13, 400 MHz) δ 8.52 (d, J= 7.6 Hz, 1H), 8.07 (s, 1H), 7.92-7.96 (m, 3H), 7.70 (d, J= 7.6 Hz, 1H), 7.62 (s, 1H), 7.41-7.54 (m, 4H), 7.21-7.23 (m, 2H), 7.12 (s, 1H), 5.89 (s, 1H), 3.11 (s, 3H), 3.00 (d, J = 4.8 Hz, 3H), 2.88 (s, MS (M+H)+: 610.
Example 11
Preparation of Compound 54
Figure imgf000067_0001
Synthesis of 2- 3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-lH-indole
Figure imgf000067_0002
A mixture of 6-chloro-2-(4-fluoro- 1 H-indol-2-yl)pyridin-3 -ol ( 100 mg, 0.38 mmol, prepared using similar method described in Example 1), BnBr (97 mg, 0.572 mmol) and K2C03 (158 mg, 1.146 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was then concentrated in vacuo. The resulting resulting residue was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=3 : l) to provide 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro- lH-indole (100 mg, yield: 74.6%). 1H- MR (CDC13, 400 MHz) δ 9.64 (s, 1H), 7.12-7.48 (m, 10H), 6.76 (t, J= 8.8 Hz, 1H), 5.33 (s, 2H). MS (M+H)+: 353 / 355. Step 2 - Synthesis of 5-(5-(benzyloxy)-6-(4fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000067_0003
A mixture of 2-(3-(benzyloxy)-6-chloropyridin-2-yl)-4-fluoro-lH-indole (160 mg, 0.454 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (228 mg, 0.454 mmol),
Κ3Ρ04Ή20 (362 mg, 1.362 mmol), Pd2(dba)3 (21 mg, 0.023 mmol) and X-Phos (22 mg, 0.046 mmol) in dioxane/H20 (2 mL/0.4 mL) was stirred at 80 °C for 2 hours under N2 atmosphere. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with brine (20 mL><3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using Prep-TLC (petroleum ether:EA=l : 1) to provide 5-(5-(benzyloxy)-6-(4-fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (120 mg, yield: 38.2%). 1H- MR (CDC13; 400 MHz) δ 9.97 (s, 1H), 7.93 (s, 1H), 7.88-7.91 (m, 2H), 7.55 (s, 1H), 7.33-7.48 (m, 7H), 6.69-7.19 (m, 5H), 6.65-6.69 (m, 1H), 5.83 (d, J= 4.4Hz, 1H), 5.31 (s, 2H), 3.08 (s, 3H), 2.91 (d, J= 4.8Hz, 3H), 2.75 (s, 3H). MS (M+H)+: 693. Step 3 - Synthesis of 5-(6-(4-fluoro-lH-indol-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N- methyl-6- N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000068_0001
A mixture of 5-(5-(benzyloxy)-6-(4-fluoro-lH-indol-2-yl)pyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (120 mg, 0.173 mmol) and Pd/C (20 mg) in methanol (10 mL) was stirred under H2 atmosphere at room temperature for 1 hour. The mixture was then filtered through Celite and concentrated to provide 5-(6-(4-fluoro-lH-indol-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, yield: 57.7%). 1H- MR
(Methanol-^, 400 MHz) δ 7.95-8.00 (m, 4H), 7.80 (s, 1H), 7.37 (t, J= 8.8 Hz, 2H), 7.22-7.30 (m, 4H), 6.64-6.69 (m, 1H), 3.23 (s, 3H), 2.94 (s, 3H), 2.90 (s, 3H). MS (M+H)+: 603.
Step 4 - Synthesis of 5-(l l-fluoro-6-oxo-6H-pyrido [2' , 3' : 5, 6] ' [l,3]oxazino[3,4-a]indol-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
(Compound 54)
Figure imgf000069_0001
A mixture of 5-(6-(4-fluoro-lH-indol-2-yl)-5-hydroxypyridin-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 0.100 mol) and triphosgene (59 mg, 0.199 mmol) in CH3COOH (2 mL) was stirred at 100 °C for 2 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine (30 mL), dried over Na2S04 and
concentrated in vacuo. The resulting residue was purified using Prep-HPLC to provide compound 54 (40 mg, yield: 63.5%). 1H- MR (DMSO-de, 400 MHz) δ 8.54 (d, J= 4.8 Hz, 1H), 8.20 (d, J= 8.0 Hz, 1H), 8.07 (s, 1H), 7.98-8.03 (m, 3H), 7.86 (s, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.44-7.52 (m, 1H), 7.40 (t, J= 8.8 Hz, 3H), 7.27 (t, J= 8.8 Hz, 1H), 2.92 (s, 3H), 2.80 (d, J = 4.4 Hz, 3H), 2.50 (s, 3H). MS (M+H)+: 629.
Example 12
Preparation of Compound 55
Figure imgf000069_0002
A mixture of 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol, described in Example 1) and NCS (160 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether : EtOAc = 2 : 1) to provide 6-chloro-2-(3-chloro-lH-indol-2-yl)pyridin-3-ol (180 mg, yield:
64.7%). 1H- MR (CDCI3, 400 MHz) δ 9.03 (s, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.15-7.36 (m, 5H), 6.20-6.40 (br s, 1H). MS (M+H)+: 279 / 281. Synthesis of 2, 12-dichloro-6H- rido[ 2 ' 3 ':5, 6] [1,3 Joxazinof 3, 4-aJindole
Figure imgf000070_0001
A solution of 6-chloro-2-(3-chloro-lH-indol-2-yl)pyridin-3-ol (128 mg, 0.46 mmol) and Cs2C03 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100 °C (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 4 : 1) to provide 2, 12-dichloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (100 mg, yield: 75.2%). 1H- MR (CDC13, 400 MHz) δ 7.65 (d, J= 8.0 Hz, 1H), 7.11-7.31 (m, 5H), 5.82 (s, 2H). MS (M+H)+: 291 / 293.
Step 3 - Synthesis of 5-(12-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 55)
Figure imgf000070_0002
55
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (110 mg, 0.22 mmol), 2, 12-dichloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (64 mg, 0.22 mmol) and K3P04 (176 mg, 0.66 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (10 mg, 0.02 mmol) under N2. The mixture was heated to 80 °C and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 1 : 1) to provide the desired product of compound 55 (60 mg, yield: 43.2%). 1H- MR (CDC13; 400 MHz) δ 8.13 (s, 1H), 7.94-7.98 (m, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.28-7.31 (m, 2H), 7.11-7.20 (m, 3H), 5.85-5.95 (br s, 3H), 3.32 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 631.
Compounds 56 and 57, depicted in the table below, were prepared using similar method described above and substituting the appropriate reagents and/or reactants.
Figure imgf000071_0002
Example 13
Preparation of Compound 58
Figure imgf000071_0001
A mixture of 6-chloro-2-(lH-indol-2-yl)pyridin-3-ol (244 mg, 1 mmol) and 1- (chloromethyl)-4-fluoro-l, 4-diazoniabicyclo[2.2.2]octane tetrafluoroborate (425 mg, 1.2 mmol) in Acetone (2 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated and purified using prep-TLC (petroleum ether : EtOAc = 2 : 1) to provde desired product of 6-chloro-2-(3-fluoro-lH-indol-2-yl)pyridin-3-ol (120 mg, yield: 46.2%). 1H- MR (Methanol-^, 400 MHz) δ 7.55 (d, J= 8.0 Hz, 1H), 7.39-7.44 (m, 1H), 7.25-7.34 (m, 1H), 6.97-7.20 (m, 3H). MS (M+H)+: 263 / 265.
Synthesis of 2-chloro-12- uoro-6H-pyrido[ 2 ', 3 ':5, 6] [1,3 Joxazinof 3, 4-aJindole
Figure imgf000072_0001
A solution of 6-chloro-2-(3-fluoro-lH-indol-2-yl)pyridin-3-ol (120 mg, 0.46 mmol) and Cs2C03 (452 mg, 1.39 mmol) in DMF (6 mL) was stirred at 100 °C (internal temperature), then chloroiodomethane (173 mg, 0.92 mmol) in DMF (1 mL) was added dropwise. After the reaction was completed according to TLC, the mixture was filtered and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 4 : 1) to provide 2-chloro-12-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (60 mg, yield: 47.6%). 1H- MR (CDC13, 400 MHz) δ 7.63 (d, J= 8.0 Hz, 2H), 7.06-7.28 (m, 4H), 5.76 (s, 2H). MS (M+H)+: 275 / 277.
Step 3 - Synthesis of 5-(12-fluoro-6H-pyrido[2',3':5, 6Jfl,3Joxazino[3,4-aJindol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 58)
Figure imgf000072_0002
58
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (110 mg, 0.22 mmol), 2-chloro-12-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (60 mg, 0.220 mmol) and K3P04 (176 mg, 0.66 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (10 mg, 0.02 mmol) under N2. The mixture was heated to 80 °C and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 1 : 1) to provide the desired product of compound 58 (60 mg, yield: 44.4%). 1H- MR (CDC13; 400 MHz) δ 7.94-8.00 (m, 3H), 7.66-7.68 (m, 2H), 7.46 (s, 2H), 7.29-7.35 (m, 2H), 7.19 (t, J = 8.4 Hz, 3H), 6.02 (s, 1H), 5.91 (s, 2H), 3.39 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 615. Compounds 59, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Figure imgf000073_0002
Example 14
Preparation of Compound 60
Figure imgf000073_0001
60
Step 1 - Synthesis of 5-(12-bromo-6H-pyridof2',3':5,6Jfl,3Joxazinof3,4-aJmdol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000074_0001
NBS (33 mg, 0.19 mmol) was added to a solution of compound 1 (100 mg, 0.17 mmol, described in Example 1) in THF (1 mL). The mixture was stirred at room temperature for 1 hour and then purified using prep-TLC (petroleum ether : EtOAc = 1 : 1) to provide 5-(12- bromo-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 88.5%). 1H-NMR (CDC13, 400 MHz) δ 8.27 (s, 1H), 8.01-8.04 (m, 2H), 7.62-7.67 (m, 3H), 7.47 (d, J= 8.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.16-7.26 (m, 3H), 6.06 (br s, 1H), 5.97 (s, 2H), 3.36 (s, 3H), 3.02 (d, 7= 4.8 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 675 / 677.
Step 2 - Synthesis of 5-(12-cyano-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benz (Compound 60)
Figure imgf000074_0002
A mixture of 5-(12-bromo-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-
(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.07 mmol) and CuCN (14 mg, 0.15 mmol) in NMP (2 mL) was stirred at 180 °C for 2 h under microwave irradiate conditions. The mixture was then filtered through celite and diluted with water (20 mL). The mixture extracted with EtOAc (15 mL * 3). The organic layer was washed with brine (15 mL * 3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 2 : 3) to provide compound 60 (40 mg, yield:87.0%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.48 (d, 7= 4.8 Hz, 1H), 7.98-8.06 (m, 4H), 7.71-7.80 (m, 4H), 7.31-7.44 (m, 4H), 6.36 (s, 2H), 3.39 (s, 3H), 2.94 (s, 3H), 2.80 (d, 7= 4.8 Hz, 3H). MS (M+H)+: 622. Example 15
Preparation of Compound 61
Figure imgf000075_0001
Synthesis of 2-bromo-6, 6-dimethyl-6, 1 l-dihydrochromeno[ 4, 3-b Jindole
Figure imgf000075_0002
To the solution of 4-bromo-2-(lH-indol-2-yl)phenol (200 mg, 0.69 mmol) in acetone (5 mL) was added PTSA (26 mg, 0.14 mmol), it was stirred at 150 °C in a sealed tube. Then the solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 2-bromo-6,6-dimethyl-6, 11 -dihvdrochromeno [4, 3-b] indole (180 mg, yield: 79.3%). MS (M+H)+: 327 / 329.
Step 2 - Synthesis of 6,6-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6,l 1- dihydrochromen -b ] indole
Figure imgf000075_0003
To a flask were added 2-bromo-6, 6-dimethyl-6, 11 -dihvdrochromeno [4,3 -b] indole
(100 mg, 0.30 mmol), (BPin)2 (116 mg, 0.46 mmol), Pd(dppf)Cl2 (10 mg), AcOK (74 mg, 0.76 mmol) and toluene (1.2 mL), it was stirred at 100 °C. TLC showed the starting material was consumed completely. The solvent was removed and the crude product was purified using prep- TLC to provide the product of 6,6-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6, 1 l-dihydrochromeno[4,3-b]indole (80 mg, yield: 70.2%). 1H- MR (CDC13, 400 MHz) δ 8.45 (s, 1H), 7.81 (s, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.37 (d, J= 8.0 Hz, 1H), 7.21-7.13 (m, 2H), 6.94 (d, J= 8.0 Hz, 1H), 1.83 (s, 6H), 1.39 (s, 12H). MS (M+H)+: 375. Step 3 - Synthesis of 5-(6, 6-dimethyl-6, l l-dihydrochromeno[4,3-b]indol-2-yl)-2-(4- βuorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 61)
Figure imgf000076_0001
Compound 61 was made using the method described in step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 8.89 (s, 1H), 7.86 (d, J= 5.2 Hz, 2H), 7.30 (d, J= 2.4 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J= 8.0 Hz, 1H), 7.48 (s, 1H), 7.43 (d, J= 8.0 Hz, 1H), 7.22-7.11 (m, 5H), 6.95 (d, J= 4.4 Hz, 1H), 6.0 (s, 1H), 2.96 (t, J= 8.8 Hz, 9H), 1.78 (s, 6H). MS (M+H)+: 624.
Compounds 62, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Figure imgf000076_0002
Example 16
Preparation of Compound 63
Figure imgf000077_0001
63
Synthesis of 2-(5-bromo-2-methoxyphenyl)-lH-indole
Figure imgf000077_0002
The mixture of l-(5-bromo-2-methoxyphenyl)ethanone (10 g, 43.6 mmol), phenylhydrazine (7.07 g, 65.5 mmol) was stirred in PPA (50 mL) at 110 °C for 2 hours. The reaction mixture was added to water and basified to pH = 7, then extracted with ethyl acetate and washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography to provide the product of 2-(5-bromo-2-methoxyphenyl)-lH- indole (10 g, yield: 71%). 1H- MR (CDC13, 400 MHz) δ 9.57 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.34-7.42 (m, 2H), 7.09-7.21 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 4.00 (s, 3H). MS (M+H)+: 302 / 304.
Step 2 - Synthesis of 2-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH- indole
Figure imgf000077_0003
To a stirring solution of 2-(5-bromo-2-methoxyphenyl)-lH-indole (1.25 g, 3.90 mmol) in Toluene, KOAc (1.15 g, 11.7 mmol) and (Bpin)2 (1.5 g, 5.86 mmol) were added, then Pd(dppf)Cl2 (150 mg) was added under N2 protection. The mixture was stirred at 90 °C for 3 hours. The mixture was concentrated in vacuo. The resulting residue was purified using column chromatography to provide the product of2-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-lH-indole (1.0 mg, yield: 77%). 1H- MR (CDC13, 400 MHz) δ 9.51 (s, 1H), 8.24 (d, J = 1.6 Hz, 1H), 7.68-7.71 (m, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 6.97-7.15 (m, 4H), 4.00 (s, 3H), 1.33 (s, 12H). MS (M+H)+: 350. Step 3 - Synthesis of 5-(3-(lH-indol-2-yl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000078_0001
To a mixture of 2-(2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-lH-indole (2.3 g, 6.59 mmol), (2.0 g, 4.39 mmol) and Κ3Ρ04·3Η20 (3.5 mg, 13.2 mmol) in DMF (20 mL), Pd(PPh3) (300 mg) was added under N2 protection. The mixture was heated at 90 °C for 3 hours. Water was added, extracted with ethyl acetate and washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography to provide the product of 5-(3-(lH-indol-2-yl)-4-methoxyphenyl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (800 mg, yield: 31%). 1H- MR (CDC13, 400 MHz) δ 9.66 (s, 1H), 7.89-7.93 (m, 3H), 7.78 (s, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.32-7.39 (m, 2H), 7.03-7.21 (m, 5H), 6.91 (d, J = 1.2 Hz, 1H), 5.83 (d, J = 4.8 Hz, 1H), 4.03 (s, 3H), 3.07 (s, 3H), 2.94 (d, J = 4.8 Hz, 3H), 2.75 (s, 3H). MS (M+H)+: 598.
Step 4 - Synthesis of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(lH-indol-2-yl)phenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000078_0002
To a solution of 5-(3-(lH-indol-2-yl)-4-methoxyphenyl)-2-(4-fluorophenyl)-N- methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 g, 0.16 mmol) in dichloromethane (2 mL) was added dropwise BBr3 (0.2 mL) at 0 °C, Then warmed up to room temperatureand stirred for 5 hours. Water was added, extracted with dichloromethane and washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using Prep-TLC to provide the product of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(lH-indol-2- yl)phenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 31%). 1H- MR (CDCI3, 400 MHz) δ 9.30 (s, 1H), 8.75 (s, 1H), 7.79-8.30 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 6.91-7.19 (m, 7H), 6.65 (d, J = 1.2 Hz, 1H), 6.01 (d, J = 4.4 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.61 (s, 3H), 2.43 (s, 3H). MS (M+H)+: 584.
Step 5 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(6-phenyl- -dihydrochromenof 4, 3-b ]indol-2-yl)benzofuran-3-carboxamide (compound 63)
Figure imgf000079_0001
63
A mixture of 2-(4-fluorophenyl)-5-(4-hydroxy-3-(lH-indol-2-yl)phenyl)-N- methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 g, 0.08 mmol), PTSA (3.0 mg, 0.017 mmol), and benzaldehyde (42 mg, 0.41 mmol) in xylene (2 mL) was stirred at 130 °C for 2 h under microwave. Water was added, extracted with EtOAc, the organic layer was washed with brine, dried over Na2S04. After concentrated, the resulting residue was purified using prep-TLC to provide the product of compound 63 (20 mg, yield: 38%). 1H- MR (CDC13, 400 MHz) δ 8.96 (s, 1H), 7.88-7.92 (m, 2H), 7.76 (s, 1H), 7.65 (s, 1H), 7.50 (s, 1H), 7.32-7.47 (m, 6H), 7.14-7.17 (m, 4H), 6.96-6.99 (m, 2H), 6.86 (s, 1H), 6.55 (s, 1H), 5.91 (d, J = 4.8 Hz, 1H), 3.02 (s, 3H), 2.98 (d, J = 4.8 Hz, 3H), 2.94 (s, 3H). MS (M+H) +: 672.
Compounds 64 and 65, depicted in the table below, were prepared using method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H)+
^-NMR (CDCI3, 400 MHz) δ 8.95
(s, 1H), 7.46-7.88 (m, 7H),
7.11-7.22 (m, 5H), 6.95 (d, J= 8.4
64 652
Hz, 1H), 5.92-5.95 (m, 1H), 5.43 (s,
*<.S, .
o' po 1H), 3.01 (d, J = 4.8 Hz, 3H), 2.96
(s, 3H), 2.92 (s, 3H). ^-NMR (CDC13, 400 MHz) δ 9.95
(s, 1H), 7.80-7.83 (m, 2H), 7.64 (s,
1H), 7.41-7.50 (m, 4H), 7.12-7.20
(m, 3H), 7.07-7.11 (m, 2H), 6.87 (d,
65 650
J = 8.0 Hz, 1H), 6.07-6.08 (m, 1H),
o-s II— 2.95 (d, J = 4.8 Hz, 3H), 2.92 (s,
o
6H), 2.13-2.16 (m, 4H), 2.00-2.02
(m, 2H), 1.82-1.86 (m, 2H).
Example 17
Figure imgf000080_0001
Step 1 - Synthesis of 2-chloro-7-fluoro-6-(thiophen-2-yl)-6, 11- dihydropyridof 2 ', 3 ':5 6]pyrano[ 4, 3-b ] indole
Figure imgf000080_0002
A mixture of compound 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (60 mg, 0.224 mmol), thiophene-2-carbaldehyde (50 mg, 0.448 mmol) and PTSA (85 mg, 0.448 mmol) in toluene (1 mL) was stirred at 60 °C for 4 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (15 mL * 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep- TLC (petroleum ether:EtOAc= 20: 1) to provide 2-chloro-7-fluoro-6-(thiophen-2-yl)-6, l l- dihydropyrido[2',3':5,6]pyrano[4,3-b]indole (40 mg, yield: 50.0%). 1H- MR (CDC13, 400 MHz) δ 9.28 (s, 1H), 7.07-7.18 (m, 5H), 6.98 (d, J= 8.4 Hz, 1H), 6.81-6.86 (m, 2H), 6.66-6.70 (m, 1H). MS (M+H)+: 357 / 359. Step 2 - Synthesis of 5-(7-fluoro-6-(thiophen-2-yl)-6, l l-dihydropyrido[2 ',3 ':5, 6]pyrano[4,3- b]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfo
carboxamide (Compound 66)
Figure imgf000081_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (110 mg, 0.22 mmol), 2-chloro-7-fluoro-6-(thiophen-2-yl)-6, l 1- dihydropyrido[2',3':5,6]pyrano[4,3-b]indole (78 mg, 0.22 mmol) and K3P04 (176 mg, 0.66 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (10 mg, 0.011 mmol) and X-Phos (10 mg, 0.022 mmol) under N2. The mixture was heated to 80 °C and then stirred for 1 hour. The reaction mixture was cooled to RT, diluted with EtOAc and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using Prep-TLC (petroleum ethenEtOAc = 1 : 1) to provide the desired product of compound 66 (65 mg, yield 42.7%). 1H- MR (CDC13, 400 MHz) δ 9.94 (s, 1H), 7.96 (s, 1H), 7.89-7.91 (m, 2H), 7.51 (s, 1H), 7.04-7.34 (m, 8H), 6.91 (s, 1H), 6.85 (t, J= 4.0 Hz, 1H), 6.68 (t, J= 9.2 Hz, 1H), 5.81 (br s, J= 3.6 Hz, 1H), 3.02 (s, 3H), 2.93 (s, 6H). MS (M+H)+: 697.
Compound 67, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Compound MS
Structure NMR
No (M+H)+ ^-NMR (CDC13, 400 MHz) δ 10.09
(s, 1H), 7.96 (s, 1H), 7.85-7.89 (m,
2H), 7.75 (d, J= 3.2 Hz, 1H), 7.49
67 (s, 1H), 7.34 (d, J= 8.4 Hz, 1H), 698
7.05-7.26 (m, 7H), 6.67-6.72 (m,
Figure imgf000082_0001
1H), 5.87 (br s, J = 4.4 Hz, 1H), 3.02
(s, 3H), 2.91-2.95 (m, 6H).
Example 18
Preparation of Compound 68
Figure imgf000082_0002
To a solution of Compound 12 (150 mg, 0.24 mmol) in MeOH (15 mL) was added 0.5 mL of H3 H2O and Raney Ni (30 mg). The mixture was degassed with H2 (30 psi) and then stirred for 5 hours at room temperature. Then the mixture was filtered and the filtrate was concentrated in vacuo to provide the pure compound 68 (130 mg, yield: 86%) by prep- HPLC. 1H- MR (Methanol-^, 400 MHz) δ 7.90 (dd, J = 5.6 Hz, J2 = 8.4 Hz, 2H), 7.84 (d, J = 12.4 Hz, 2H), 7.51 (s, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.19-7.26 (m, 4H), 7.12 (d, J = 7.2 Hz, 1H), 6.01 (s, 2H), 4.27 (s, 2H), 3.25 (d, J = 4.8 Hz, 3H), 2.89 (s, 3H), 2.87 (s, 3H). MS (M+H)+: 626. Compound 69, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Compound MS
Structure NMR
No (M+H)+ ^-NMR (CDC13, 400 MHz) δ 7.94
(s, 1H), 7.89-7.93 (m, 2H), 7.62 (s,
1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40
(s, 2H), 7.12-7.18 (m, 3H),
69 626
6.99-7.07 (m, 2H), 6.40 (s, 2H),
o=s=o
1 5.91 (s, 1H), 4.13 (s, 2H), 3.31 (s,
3H), 2.93 (d, J = 4.8 Hz, 3H), 2.62
(s, 3H).
Example 19
Preparation of Compound 70
Figure imgf000083_0001
To a solution of compound 68 (50 mg, 0.08 mmol) in anhydrous dichloromethane (1 mL) was added HCHO (aq. in water, 0.5 mL) at room temperature. The mixture was stirred for 3 hours at room temperature, then Na(CH3COO)3BH (102 mg, 0.48 mmol) was added dropwise and the reaction mixture was stirred another 5 hours at room temperature. And then the mixture was quenched with water and extracted with dichloromethane. The organic phase was washed with brine, dried over Na2S04, and concentrated to provide the compound 70 (30 mg, yield: 58%) by the prep-HPLC. 1H- MR (Methanol-^, 400 MHz) δ 7.88 (dd, J = 5.6 Hz, J2 = 8.8 Hz, 2H), 7.80 (d, J = 18.4 Hz, 2H), 7.46 (s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.14-7.20 (m, 3H), 7.04 (d, J = 7.2 Hz, 1H), 5.97 (s, 2H), 3.89 (s, 2H), 3.24 (d, J = 6.4 Hz, 3H), 2.85 (s, 3H), 2.81 (s, 3H), 2.35 (s, 6H). MS (M+H)+: 654. Compound 71, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Figure imgf000084_0003
Example 20
Preparation of Compound 72
Figure imgf000084_0001
Synthesis o 2-chloro-6H-pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] 'indole- 11 ' -carbaldehyde
Figure imgf000084_0002
To a solution of 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l- carbonitrile (500 mg, 1.77 mmol) in toluene (10 mL) was added DIBAL-H (505 mg, 3.55 mmol) in portion under nitrogen at -78 °C and then the mixture was stirred at -78 °C for 6 hours. The reaction mixture was quenched with ice water and extracted with EtOAc. Then the combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo to provide the 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l-carbaldehyde (200 mg, yield: 40%) through the column chromatography (petroleum ether : EtOAc = 5 : 1 - 2 : 1). 1H- MR (CDC13, 400 MHz) δ 10.29 (s, 1H), 8.03 (s, 1H), 7.69 (dd, J = 0.8 Hz, J2 = 7.2 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.05 (s, 2H). MS (M+H)+: 285 / 287.
Step 2 - Synthesis of 2-(4-fluorophenyl)-5-(l l-formyl-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000085_0001
To a solution of 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l- carbaldehyde (31 mg, 0.11 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (50 mg, 0.10 mmol) and Κ3Ρ04·3Η20 (53 mg, 0.19 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL) was added X-Phos (5 mg) and Pd2(dba)3 (5 mg) under nitrogen. The mixture was heated at 100 °C for 16 hours, and then filtered through the celite pad. The filtrate was extracted with EtOAc, then the combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo to provide the 2-(4-fluorophenyl)-5-(l l-formyl-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, yield: 80%) by the prep-TLC (dichloromethane : MeOH = 30 : 1). MS (M+H)+: 625.
Step 3 - Synthesis of 2-(4-fluorophenyl)-5-(l l-(hydroxymethyl)-6H-pyrido[2',3':5, 6][l,3] oxazino[3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benz
(Compound 72)
Figure imgf000086_0001
To a solution of 2-(4-fluorophenyl)-5-(l l-formyl-6H-pyrido[2',3':5,6][l,3] oxazino [3,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.08 mmol) in MeOH (2 mL) was added NaBH4 (12 mg, 0.32 mmol, diluted with 2 mL of MeOH) in portion under nitrogen at 0 °C and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. Then the combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo to provide the compound 72 (30 mg, yield: 60%) by the prep-HPLC. 1H- MR (CDC13, 400 MHz) δ 7.95-7.99 (m, 3H), 7.63 (s, 1H), 7.47 (dd, J = 8.4 Hz, J2 = 14.8 Hz, 2H), 7.37 (s, 1H), 7.16-7.20 (m, 3H), 7.12 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.37 (brs, 1H), 5.93 (s, 2H), 4.81 (s, 2H), 3.31 (s, 3H), 2.87 (d, J = 5.2 Hz, 3H), 2.79 (s, 3H). MS (M+H)+: 627.
Example 21
Preparation of Compound 73
Figure imgf000086_0002
73
Step 1 - Synthesis of methyl 2-chloro-6H-pyrido[2',3':5, 6] ' [1,3] oxazino [3, 4-a] indole- 11- carboxylate
Figure imgf000086_0003
A mixture of 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l 1- carbonitrile (300 mg, 1.06 mmol) in MeOH (4N HCI, 15 mL) was heated at 80 °C for overnight. The reaction mixture was concentrated in vacuo. The resulting residue was suspended in water and extracted with EtOAc. The organic layers was washed with brine (100 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : ethyl acetate = 5 : 1) to provide product of methyl 2-chloro- 6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l 1-carboxylate (120 mg, yield: 36%). 1H- MR (CDCI3, 400 MHz) δ 7.98 (dd, J= 7.2 Hz, 1.2 Hz, 1H), 7.85 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.33-7.38 (m, 2H), 7.21 (d, J= 8.0 Hz, 1H), 5.97 (s, 2H), 4.03 (s, 3H). MS (M+H)+: 315 / 317.
Step 2 - Synthesis of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido [2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole- 11- carboxylate
Figure imgf000087_0001
To a degassed solution of methyl 2-chloro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a] indole- 11-carboxylate (40 mg, 0.13 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide ( 50 mg, 0.10 mmol) in 1, 4-dioxane (3 mL), Pd2(dba)3 (10 mg), X-Phos (10 mg) and K3P04 (60 mg, 0.23 mmol) were added under N2. The mixture was heated to 100 °C for 2 hours. The reaction mixture was cooled to RT, filtered and washed with EtOAc. The filtrate was washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (dichloromethane : MeOH = 100 : 1) to provide the product of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l- carboxylate (55 mg, yield: 84%). MS (M+H)+: 655. Step 3 - Synthesis of 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido [2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole- 11- carboxylic acid
Figure imgf000088_0001
To a solution of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3^5,6][l,3]oxazino[3,4-a]indole-l l- carboxylate (160 mg, 0.24 mmol) in dioxane (2 mL) and water (2 mL), LiOH-H20 (30 mg, 0.71 mmol) was added and the mixture was heated to reflux for 2 hours. Then removed dioxane and the mixture was diluted with water, adjusted to pH = 3-4 by 1 N HC1, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using PTLC (dichloromethane :
MeOH = 20 : 1) to provide 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l- carboxylic acid (120 mg, yield: 76%). 1H- MR (Methanol-^, 400 MHz) δ 7.97-8.02 (m, 2H), 7.86-7.91 (m, 3H), 7.81 (s, 1H), 7.74 (d, J= 8.4 Hz, 1H), 7.59 (s, 2H), 7.31-7.36 (m, 1H), 7.24-7.29 (m, 2H), 6.14 (s, 2H), 3.35 (s, 3H), 2.96 (s, 3H), 2.88 (s, 3H). MS (M+H)+: 641. Step 4 - Synthesis of 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido [2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole- 11- carboxamide (Compound 73)
Figure imgf000088_0002
2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido) benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-l l-carboxylic acid (80 mg, 0.13 mmol), HOBt (20 mg, 0.15 mmol) and EDCI (53 mg, 0.27 mmol) in DMF (5 mL) was allowed to stir at room temperature. After 30 minutes, ammonium chloride (20 mg, 0.15 mmol) and Et3N (140 mg, 1.3 mmol) were added to the mixture, and the mixture was allowed to stir overnight at room temperature. After the solvent was removed, H20 and NaHC03 (aq.) were added and the mixture was stirred at room temperature for 1 hour. After filtrated, the cake was washed with H20 and dried to provide compound 73 (40 mg, yield: 50%). 1H- MR (CDC13, 400 MHz) δ 7.94-7.97 (m, 2H), 7.82-7.86 (m, 2H), 7.60-7.64 (m, 2H), 7.53-7.55 (m, 3H), 7.21-7.31 (m, 3H), 6.08 (s, 2H), 3.34 (s, 3H), 2.95 (d, J= 4.8Hz, 3H), 2.85 (s, 3H). MS (M+H)+: 640.
Example 22
Preparation of Compound 74
Figure imgf000089_0001
A mixture of Compound 16 (50 mg, 0.08 mmol) in dichloromethane (2 mL) was added 3-chlorobenzo peroxoic acid (50 mg, 0.27 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04. After concentrated, the resulting residue was purified using prep-TLC (dichloromethane : EtOAc = 5 : 1) to provide the product of compound 74 (10 mg, yield: 19%). 1H- MR (CDC13, 400 MHz) 5 8.11 (s, 1H), 7.98 (dd, J= 8.8, 5.2 Hz, 2H), 7.92 (s, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.20-7.24 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 6.86 (dd, J= 10.0 Hz, 1H), 6.01 (s, 2H), 5.96 (s, 1H), 3.38 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.89 (s, 3H). MS (M+H)+: 631.
Example 23
Preparation of Compound 75
Figure imgf000090_0001
Figure imgf000090_0002
To a solution of compound 4-bromo-2-(lH-indol-2-yl)phenol (1 g, 3.48 mmol) in DMF (35 mL) was added CsF (1.59 g, 10.45 mmol) and oxiran-2-ylmethyl 3- nitrobenzenesulfonate (1.81 g, 6.97 mmol). The resulting mixture was stirred at room
temperature overnight and then diluted with ethyl acetate and washed with water and brine. The crude product was purified using chromatography (petroleum ether :EA = 14: 1) to provide compound 2-(5-bromo-2-(oxiran-2-ylmethoxy)phenyl)-lH-indole (1 g, yield: 84.0%). 1H- MR (DMSO-d6 400 MHz) δ 11.33 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.51 (d, J= 7.6 Hz, 1H),
7.38-7.44 (m, 2H), 7.07-7.12 (m, 3H), 6.97 (t, J= 7.2 Hz, 1H), 4.49-4.53 (m, 1H), 3.97-4.01 (m, 1H), 3.46-3.49 (m, 1H), 2.88 (t, J= 4.4 Hz, 1H), 2.74-2.76 (m, 1H). MS (M+H)+: 344 / 346.
Step 3 - Synthesis of 2-bromo-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol
Figure imgf000090_0003
A solution of compound 2-(5-chloro-2-(oxiran-2-ylmethoxy)phenyl)-lH-indole (1 g, 2.91 mmol) in dioxane (50 mL) was treated with CS2CO3 (1.89 g, 5.81 mmol), and the resulting suspension heated to reflux for 48 hours. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate (200 mL). The mixture was washed with water and brine. The mixture was dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using chromatography (petroleum ethenEA = 10: 1) to provide 2-bromo-7,8-dihydro-6H- benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol (500 mg, yield: 50.0%). 1H- MR (DMSO-d6 400 MHz) δ 7.40-7.55 (m, 4H), 7.13-7.18 (m, 2H), 7.04 (t, J= 7.6 Hz, 1H), 6.66 (s, 1H), 5.43 (d, J = 4.0 Hz, 1H), 3.78-4.24 (m, 4H). MS (M+H)+: 344 / 346. Step 4 - Synthesis of 2-(4-fluorophenyl)-5-(7-hydroxy-7,8-dihydro-6H-benzo[2,3] [l,5]oxazocino [5,4-a]indol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofw
ompound 75)
Figure imgf000091_0001
(m, 3H), 7.33-7.37 (m, 2H), 7.02-7.16 (m, 5H), 6.63 (s, 1H), 5.88 (d, J= 5.2 Hz, 1H), 4.00-4.21 (m, 5H), 3.08 (s, 3H), 2.86 (d, J= 4.8 Hz, 3H), 2.66 (s, 3H), 2.46-2.48 (m, 1H). MS (M+H)+: 640. Example 24
Pre aration of Compound 76
Step 1 - Synthesis of 2- o[5,4-a]indole
Figure imgf000091_0002
DAST (94 mg, 0.583 mmol) was added to a solution of 2-bromo-7,8-dihydro-6H- benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol (100 mg, 0.29 mmol) in CH2C12 (1 mL) under N2 at - 78 °C. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ethenEA = 10: 1) to provide 2-bromo-7-fluoro-7,8-dihydro-6H- benzo[2,3][l,5]oxazocino[5,4-a]indole (40 mg, yield: 40.0%). MS (M+H)+: 346 / 348.
Step 2 - Synthesis of 5-(7-fluoro-7,8-dihydro-6H-benzo[2,3] [l,5]oxazocino[5,4-a]indol-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
(Compound 76)
Figure imgf000092_0001
The procedure of compound 76 (40 mg, yield: 54.0%) was similar to that of Example 1. 1H- MR (CDC13, 400 MHz) δ 7.84-7.85 (m, 2H), 7.74 (s, 1H), 7.52-7.57 (m, 3H), 7.36-7.39 (m, 2H), 7.06-7.21 (m, 5H), 6.68 (s, 1H), 5.83 (d, J= 4.8 Hz, 1H), 4.80-4.91 (m, 1H), 4.37-4.50 (m, 2H), 4.04-4.26 (m, 2H), 3.11 (s, 3H), 2.89 (s, 3H), 2.69 (s, 3H). MS (M+H)+: 642.
Example 25
Preparation of Compound 77
Figure imgf000092_0002
77
Step 1 - Synthesis of 2-bromo-6H-benzo[2,3] [l,5]oxazocino[5,4-a]indol-7(8H)~
Figure imgf000093_0001
DMP (742 mg, 1.749 mmol) was added to the solution of 2-bromo-7,8-dihydro- 6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol (500 mg, 1.46 mmol) in CH2C12 (5 mL) at 0 °C. The mixture was stirred at room temperature overnight. The mixture was then diluted with saturated Na2S203 and NaHC03 (30 mL, 30 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ethenEA = 3 : 1) to provide 2-bromo-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7(8H)-one (350 mg, yield: 70.4%). 1H- MR (CDC13; 400 MHz) δ 7.55-7.68 (m, 2H), 7.53 (t, J= 6.0 Hz, 1H), 7.35-7.37 (m, 1H), 7.28-7.30 (m, 1H), 7.17-7.24 (m, 1H), 7.08 (t, J= 8.4 Hz, 1H), 6.70 (d, J= 0.8 Hz, 1H), 4.73 (s, 2H), 4.55 (s, 2H). MS (M+H)+: 342 / 344.
Step 2 - Synthesis of 2-bromo-7, 7-difluoro-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4- a indole
Figure imgf000093_0002
DAST (94 mg, 0.58 mmol) was added to a solution of 2-bromo-6H- benzo[2,3][l,5]oxazocino[5,4-a]indol-7(8H)-one (100 mg, 0.292 mmol) in CH2C12 (1 mL) under N2 at -78 °C . The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (15 mL χ 3). The organic layer was washed with brine (20 mL x 2), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ethenEA = 10: 1) to provide 2-bromo-7,7- difluoro-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indole (40 mg, yield: 37.7%). MS (M+H)+: 364 / 366. 1H- MR (CDC13; 400 MHz) δ 7.57-7.59 (m, 2H), 7.36-7.42 (m, 2H), 7.21-7.25 (m, 1H), 7.11 (t, J= 7.2 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 6.64 (s, 1H), 4.43 (t, J = 7.2 Hz, 2H), 4.13 (t, J= 10.4 Hz, 2H). MS (M+H)+: 364 / 366. Step 3 - Synthesis of 5-(7, 7-difluoro-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a] yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxam (Compound 77
Figure imgf000094_0001
The procedure of compound 77 (40 mg, yield: 54.8%) was similar to that of
Example 1. 1H- MR (CDC13, 400 MHz) δ 7.89-7.91 (m, 2H), 7.81 (s, 1H), 7.57-7.63 (m, 3H), 7.43-7.49 (m5 2H), 7.14-7.30 (m, 5H), 6.77 (s, 1H), 5.85 (d, J= 4.4 Hz, 1H), 4.55 (t, J= 10.8 Hz, 2H), 4.26 (t, J= 10.8 Hz, 2H), 3.16 (s, 3H), 2.95 (d, J= 6.0 Hz, 3H), 2.79 (s, 3H). MS (M+H)+: 660.
Example 26
Preparation of Compound 78
Figure imgf000094_0002
Step 1 - Synthesis of 2-bromo-7-methyl-7,8-dihydro-6H-benzo[2,3] [l,5]oxazocino[5,4-a]indol- 7-ol
Figure imgf000094_0003
MgBrCH3 (0.12 mL, 0.352 mmol) was added to the solution of 2-bromo-6H- benzo[2,3][l,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.176 mmol) in THF (1 mL) at 0 °C under N2. The mixture was stirred at room temperature for 30 minutes. The mixture was then quenched with saturated H4C1 (10 mL) and extracted with ethyl acetate (10 mL χ 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ethenEA = 3 : 1) to provide 2-bromo- 7-methyl-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol (30 mg, yield: 47.6%). 1H- MR (CDC13, 400 MHz) δ 7.56-7.59 (m, 2H), 7.36-7.40 (m, 2H), 7.18-7.22 (m, 1H), 7.08 (t, J = 7.2 Hz, 1H), 6.93 (d, J= 8.8 Hz, 1H), 6.61 (s, 1H), 3.81-4.15 (m, 4H), 2.34 (s, 1H), 1.24 (s, 3H). MS (M+H)+: 358 / 360.
Step 2 - Synthesis of 2-(4-fluorophenyl)-5-(7-hydroxy-7-methyl-7,8-dihydro-6H- benzof 2, 3 ][ l,5]oxazocino[ 5, 4-a]indol-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide(Compound 78)
Figure imgf000095_0001
78
The procedure of compound 78 (30 mg, yield: 54.5%) was similar to step 6 of Example 1. 1H- MR (CDC13; 400 MHz) δ 7.90-7.93 (m, 2H), 7.80 (s, 1H), 7.58-7.64 (m, 3H), 7.44-7.48 (m, 2H), 7.11-7.26 (m, 5H), 6.73 (s, 1H), 5.87 (d, J= 5.2 Hz, 1H), 3.96-4.26 (m, 4H), 3.18 (s, 3H), 2.97 (d, J= 4.8 Hz, 3H), 2.75 (s, 3H), 1.34 (s, 3H). MS (M+H)+: 654.
Example 27
Preparation of Compound 79
Figure imgf000095_0002
Step 1 - Synthesis of 2-bromo-'/ 7-(trifluoromethyl)-7 8-dihydro-6H-benzo[2,3) '[1 ,5]oxazocino[5 ,4- aJindol-7-ol
Figure imgf000096_0001
A mixture of 2-bromo-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.18 mmol), TMSCF3 (275 mg, 0.194 mmol) and CsF (3 mg, 0.018 mmol) in DME (1 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with TBAF (5 mL) and stirred for 1 hour at room temperature. The mixture was then diluted with water (25 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine (20 mL x 2), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ethenEA = 3 : 1) to provide 2-bromo-7-(trifluoromethyl)-7,8-dihydro-6H- benzo[2,3][l,5]oxazocino[5,4-a]indol-7-ol (40 mg, yield: 55.6%). MS (M+H)+: 412 / 414.
Step 2 - Synthesis of 2-(4-fluorophenyl)-5-(7-hydroxy-7-(trifluoromethyl)-7,8-dihydro-6H- benzof 2, 3 ][ l,5]oxazocino[ 5, 4-a]indol-2-yl)-N-methyl-6-(N- meth lmethylsulfonamido)benzofuran-3-carboxamide (Compound 79)
Figure imgf000096_0002
79
The procedure of compound 79 (30 mg, yield: 43.5%) was similar to that of
Example 1. 1H- MR (CDC13; 400 MHz) δ 7.84-7.87 (m, 2H), 7.77 (s, 1H), 7.41-7.59 (m, 5H), 7.09-7.24 (m, 5H), 6.71 (s, 1H), 5.78 (d, J= 5.2 Hz, 1H), 4.46-4.57 (m, 2H), 4.17 -4.29 (m, 2H), 3.11 (s, 3H), 2.90 (d, J= 5.2 Hz, 3H), 2.73 (s, 3H). MS (M+H)+: 708.
Example 28
Preparation of Compound 80
Figure imgf000097_0001
80
Step 1 - Synthesis ofNl-(2-bromo-7,8-dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-yl)- N2 N2-dimethylethane-l,2-diamine
Figure imgf000097_0002
N',N'-dimethylethane-l,2-diamine (39 mg, 0.440 mmol) and CH3COOH (26 mg, 0.440 mmol) were added to the mixture of 2-bromo-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol- 7(8H)-one (100 mg, 0.293 mmol) in 1,2-dichloroethane (2 mL). The mixture was stirred at room temperature for 20 minutes. Then NaBH(OAc)3 (93 mg, 0.440 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NaHC03 (30 mL) and extracted with ethyl acetate (15 mL χ 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using p-TLC (dichloro methane : MeOH = 1 : 1) to provide Nl-(2-bromo-7,8- dihydro-6H-benzo[2,3][l,5]oxazocino[5,4-a]indol-7-yl)-N2,N2-dimethylethane-l,2-diamine. 1H- MR (CDC13; 400 MHz) δ 7.51-7.56 (m, 2H), 7.42 (s, 1H), 7.29-7.32 (m, 1H), 7.16-7.18 (m, 1H), 7.06 (t, J= 7.2 Hz, 1H), 6.85 (d, J= 8.8 Hz, 1H), 6.56 (s, 1H), 3.86-4.32 (m, 4H),
2.81-3.03 (m, 5H), 2.59 (s, 6H). MS (M+H)+: 414 / 416.
Step 2 - Synthesis of 5-(7-((2-(dimethylamino)ethyl)amino)-7,8-dihydro-6H- benzo[2,3] [l,5]oxazocino[5,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 80)
Figure imgf000098_0001
The procedure of compound 80 (50 mg, yield: 36.5%) was similar to that of Example 1. 1H- MR (Methanol-d4, 400 MHz) δ 7.90-7.94 (m, 2H), 7.78 (s, 1H), 7.64-7.68 (m, 2H), 7.56-7.59 (m, 2H), 7.44-7.47 (m, 1H), 7.16-7.26 (m, 4H), 7.10 (t, J = 7.6 Hz, 1H), 6.82 (s, 1H), 4.75-4.90 (m, 1H), 4.07-4.38 (m, 3H), 3.64 (s, 3H), 3.53-3.54 (m, 2H), 3.14 (s, 3H), 2.90-2.98 (m, 2H). MS (M+H)+: 710.
Compounds 81-86, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H)+
1 H-NMR (Methanol-d4 400 MHz) δ
7.88-7.92 (m, 2H), 7.75 (s, 1H),
7.63-7.68 (m, 2H), 7.55 (d, J = 8.4
Hz, 2H), 7.43-7.46 (m, 1H),
7.16-7.24 (m, 4H), 7.09 (t, J= 7.6
81 724
Hz, 1H), 6.82 (s, 1H), 4.06-4.40 (m,
3H), 3.69 (d, .7 = 7.2 Hz, 1H),
3.25-3.38 (m, 5H), 3.12 (s, 3H),
2.91 (t, J = 8.4 Hz, 2H), 2.24 (d, J =
7.2 Hz, 2H).
Figure imgf000099_0001
^-NMR (CDC13, 400 MHz) δ
\ 7.93-7.96 (m, 2H), 7.82 (s, 1H),
7.48-7.73 (m, 5H), 7.10-7.28 (m,
86 5H), 6.87 (s, 1H), 4.98-5.01 (m, 697
o=s=o 1H), 4.49-4.61 (m, 2H), 4.15-4.19
(m, 1H), 3.77-3.98 (m, 3H), 3.58
(br, 2H), 2.92-3.18 (m, 12H).
Example 29
Preparation of Compound 87 & 88
Figure imgf000100_0001
A mixture of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (10 g, 38 mmol) and metal Sn (23 g, 190 mmol) in CH3CH2OH / con. HC1 (60 mL / 40 mL) was stirred under reflux for 3 hours. The mixture was cooled to room temperature and adjusted to pH = 7 by saturated NaOH and filtered though a Celit pad. The filtrate was extracted with EtOAc, washed by brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using silica gel chromatography (petroleum ether : EtOAc = 10 : 1 ) to get 6-chloro-2-(4-fluoroindolin- 2-yl) pyridin-3-ol (8 g, yield: 80%). 1H-NMR (CDC13, 400 MHz) δ 9.86 (s, 1H), 7.10-7.20 (m, 3H), 6.33-6.91 (m, 2H), 5.15-5.21 (m, 1H), 4.61 (s, 1H), 3.65-3.71 (m, 1H), 3.04-3.11 (m, 1H). MS (M+H)+: 265.
Step 2 - Synthesis of ethyl 2-chloro-l 1-fluoro-l 2, 12a-dihydro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indole-6-carboxylate
Figure imgf000101_0001
To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and Glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.3 lg, 3.23mmol) was added. The mixture was stirred at 50 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 10 : 1) to provde ethyl 2-chloro-l 1-fiuoro- 12, 12a- dihydro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole -6-carboxylate (10.2 g, yield: 90.3%). 1H- MR (CDC13, 400 MHz) δ 7.04-7.13 (m, 3H), 6.63 (d, J= 8.0Hz, 1H), 6.55 (t, J= 8.4Hz, 1H), 6.03 (s, 1H), 5.09 (d, J= 8.8Hz, 1H), 4.22-4.34 (m, 2H), 3.73 (d, J= 16.4Hz, 1H), 3.44-3.51 (m, 1H), 1.29 (d, J= 7.2Hz, 3H). MS (M+H)+: 349.
Step 3 - Synthesis of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indole-6- carboxylate
Figure imgf000101_0002
To a solution of ethyl 2-chloro-l l-fluoro-12, 12a-dihydro-6H-pyrido
[2',3':5,6][l,3]oxazino[3,4-a]indole-6-carboxylate (10.22 g, 29.36 mmol) and DDQ (8.67 g, 38.17 mmol) in toluene (80 mL) was stirred at 80 °C for 2 hours. The mixture was then diluted with water (50 mL) and extracted with EtOAc (30 mL* 3). The organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 20 : 1) to provde ethyl 2-chloro-l 1- fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole- 6-carboxylate (8.64 g, yield: 85%), which was also prepared from 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol and methyl 2,2- dibromoacetate in the presence of base, such as DBU etc. 1H- MR (CDC13; 400 MHz) δ 7.33 (d, J= 8.4 Hz, 1H), 7.30 (s, 1H), 7.09-7.18 (m, 3H), 6.78-6.83 (m, 1H), 6.52 (s, 1H), 3.96-4.09 (m, 2H), 1.02 (t, J= 7.2 Hz, 3H). MS (M+H)+: 347. Step 4 - Synthesis of (2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino [3,4-a]indol-6- yljmethanol
Figure imgf000102_0001
To a solution of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3': 5,6] [1,3] oxazino[3,4- a]indole-6-carboxylate (3 g, 8.73 mmol) and NaBH4 (1.58 g, 43.67 mmol) in CH3OH / dichloromethane (30 mL / 10 mL) was stirred at room temperature for 2 hours. The mixture was poured to H20 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo to provide (2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl) methanol (2.54 g, yield: 95.5%). 1H- MR
(DMSO- 6, 400 MHz) δ 7.60 (d, J= 8.8 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.8 Hz, 1H), 7.22-7.28 (m, 1H), 7.08 (s, 1H), 6.94 (dd, J= 10.4, 8.4 Hz, 1H), 6.78 (t, J= 4.0 Hz, 1H), 5.29 (t, J= 6.0 Hz, 1H), 3.71-3.78 (m, 1H), 3.61-3.67 (m, 1H). MS (M+H)+: 305. Step 5 - Synthesis of 5-(l l-fluoro-6-(hydroxymethyl)-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide: enantiomer 1 and enantiomer 2 (Compound 87 and 88)
Figure imgf000102_0002
87 (Enantiomer 1 , peak 1 on SFC) 88 (Enantiomer 2, peak 2 on SFC) The procedure of racemic 5-(l l-fluoro-6-(hydroxymethyl)-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide was similar to step 6 of Example 1. And after SFC separation, two single enantiomers were obtained. Column: Chiralpak AD-3
50*4.6mm I D., 3um Mobile phase:60%ethanol(0.05% DEA) in C02. Flow rate: 3mL/min Wavelength: 220 nm. Compound 87: RT=0.541 min, Compound 88: RT=2.074 minutes.
Compound 87, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) δ 8.02 (s, 1H), 7.93-7.97 (m, 2H), 7.65 (s, 1H), 7.45-7.48 (m, 2H), 7.15-7.22 (m, 5H), 6.82-6.87 (m, 1H), 6.43-6.46 (m, 1H), 5.95 (brs, 1H), 3.86-4.00 (m, 2H), 3.38 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.71 (s, 3H), 2.02 (brs, 1H), MS (M+H)+: 645.
Compound 88, enantiomer 2 (peak 2 on SFC), 1H- MR (CDC13, 400 MHz) δ 8.02 (s, 1H), 7.93-7.97 (m, 2H), 7.65 (s, 1H), 7.45-7.48 (m, 2H), 7.15-7.22 (m, 5H), 6.82-6.87 (m, 1H), 6.43-6.46 (m, 1H), 5.95 (brs, 1H), 3.86-4.00 (m, 2H), 3.38 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.71 (s, 3H), 2.02 (brs, 1H), MS (M+H)+: 645.
Compounds 89-97, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H) +
^-NMR (CDC13, 400 MHz) δ 8.52
(s, 1H), 7.95-8.05 (m, 3H), 7.90 (s,
1H), 7.58 (s, 1H), 7.13-7.24 (m,
4H), 7.10 (s, 1H), 6.84 (t, J= 8.4 Hz,
89 1H), 6.46-6.49 (m, 1H), 6.21-6.24 645
Figure imgf000103_0001
(m, 1H), 3.87-3.93 (m, 1H),
Enantiomer 1 3.68-3.73 (m, 1H), 3.19 (s, 3H),
2.93 (d, J = 4.4 Hz, 3H), 2.85 (s,
3H). ^-NMR (CDC13, 400 MHz) δ 8.52
(s, IH), 7.95-8.05 (m, 3H), 7.90 (s, IH), 7.58 (s, IH), 7.13-7.24 (m,
4H), 7.10 (s, IH), 6.84 (t, J= 8.4 Hz,
90 IH), 6.46-6.49 (m, IH), 6.21-6.24 645
Figure imgf000104_0001
(m, IH), 3.87-3.93 (m, IH),
Enantiomer 2 3.68-3.73 (m, IH), 3.19 (s, 3H),
2.93 (d, J = 4.4 Hz, 3H), 2.85 (s,
3H).
^-NMR (CDCI3, 400 MHz) δ
7.92-7.98 (m, IH), 7.82-7.91 (m,
2H), 7.58 (s, IH), 7.38 (s, IH),
7.30-7.35 (m, IH), 7.21-7.28 (m,
2H), 7.05-7.16 (m, 3H), 6.71-6.81
91 659
(m, IH), 5.92 (d, J = 4.8 Hz, IH),
F °=f=0
4.09-4.18 (m, IH), 3.90-4.00 (m,
Enantiomer 1 IH), 3.31 (s, 3H), 2.89 (d, J = 5.2Hz,
3H), 2.62 (s, 3H), 2.10-2.20 (m,
IH), 2.00 (s, 3H).
^-NMR (CDCI3, 400 MHz) δ
7.92-7.98 (m, IH), 7.82-7.91 (m,
2H), 7.58 (s, IH), 7.38 (s, IH),
7.30-7.35 (m, IH), 7.21-7.28 (m,
2H), 7.05-7.16 (m, 3H), 6.71-6.81
92 659
(m, IH), 5.92 (d, J = 4.8Hz, IH),
F °=f=0
4.09-4.18 (m, IH), 3.90-4.00 (m,
Enantiomer 2 IH), 3.31 (s, 3H), 2.89 (d, J = 5.2Hz,
3H), 2.62 (s, 3H), 2.10-2.20 (m,
IH), 2.00 (s, 3H).
^-NMR (CDCI3, 400 MHz) δ 8.04
(s, IH), 7.90-7.99 (m, 2H), 7.66 (s, IH), 7.48 (s, 2H), 7.13-7.25 (m,
5H), 6.79-6.88 (m, IH), 6.21 (d, J =
93 689
5.6 Hz, IH), 5.93 (br s, IH), 4.49 (d, J = 5.6 Hz, IH), 3.43
F (s, 3H), 3.40
(s, IH), 3.08 (s, 3H), 3.00 (d, J = 5.2 Hz, 3H), 2.71 (s, 3H). ^-NMR (CDC13, 400 MHz) δ 8.02
(s, IH), 7.92 (dd, J = 5.2, 8.4Hz,
2H), 7.62 (s, IH), 7.34-7.45 (m,
3H), 7.29 (s, IH), 7.11-7.24 (m,
94 3H), 6.81 (t, J = 8.8Hz, IH), 6.08 675
( br s, IH), 4.27-4.37 (m, 2H),
Figure imgf000105_0001
4.15-4.25 (m, 2H), 3.35 (s, 3H),
2.93 (d, J = 5.2Hz, 3H), 2.66-2.78
(m, 5H)
^-NMR (Methanol-^, 00 MHz) δ 7.97-8.01 (m, 2H), 7.89 (s, IH),
7.86 (s, IH), 7.56 (s, 2H), 7.18-7.33 (m, 5H), 6.79-6.84 (m, IH), 6.72 (t,
95 659
o=s=o J = 4.8 Hz, IH), 3.78-3.83 (m, IH), F 1
3.65-3.69 (m, IH), 3.35 (s, 3H),
Enantiomer 1
3.20 (s, 3H), 2.95 (s, 3H), 2.85 (s,
3H).
^-NMR (Methanol-^, 400 MHz) δ 7.97-8.01 (m, 2H), 7.89 (s, IH),
7.86 (s, IH), 7.56 (s, 2H), 7.18-7.33 (m, 5H), 6.79-6.84 (m, IH), 6.72 (t,
96 659
o=s=o J = 4.8 Hz, IH), 3.78-3.83 (m, IH), F 1
3.65-3.69 (m, IH), 3.35 (s, 3H),
Enantiomer 2
3.20 (s, 3H), 2.95 (s, 3H), 2.85 (s,
3H).
^-NMR (CDCI3, 400 MHz) δ 7.98
(s, IH), 7.92-7.95 (m, 2H), 7.79 (d, J = 8.4Hz, IH), 7.63 (s, IH), 7.48 (s, 2H), 7.32 (s, IH), 7.23-7.29 (m,
97 ¾(χ ' IH), 7.19 (t, J = 8.4Hz, 2H), 657
6.87-6.92 (m, IH), 5.92 (br s, IH), o=s=o
F 1 5.48 (d, J = 8.4Hz, 2H), 5.22 (d, J =
8.4Hz, 2H), 3.35 (s, 3H), 2.96 (d, J =
4.8Hz, 3H), 2.74 (s, 3H).
Example 30 Preparation of Compound 98
Figure imgf000106_0001
Step 1 - Synthesis of 2-chloro-l l-fluoro-6-(fluoromethyl)-6H-pyrido[2' ,3' : 5, 6] [1 ,3]oxazino[3 ,4- a] indole
Figure imgf000106_0002
DAST (64 mg, 0.29 mmol) was added to a solution of (2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl)methanol (60 mg, 0.2 mmol) in CH2C12 (0.5 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 hour. The mixture was then heated to reflux and stirred for another 3 hours. The mixture was then diluted with water (30 mL) and extracted with CH2C12 (15 mL * 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 4 : 1) to provide 2-chloro-l l-fluoro-6-(fluoromethyl)-6H- pyrido[2',3':5,6][l,3] oxazino[3,4-a]indole (30 mg, yield:50.0%). 1H- MR (CDC13, 400 MHz) δ 7.29-7.33 (m, 2H), 7.13-7.20 (m, 2H), 7.03 (d, J= 8.4 Hz, 1H), 6.78-6.83 (m, 1H), 6.46-6.51 (m, 1H), 4.35-4.63 (m, 2H). MS (M+H)+: 307 / 309.
Step 2 - Synthesis of 5-(l l-fluoro-6-(fluoromethyl)-6H-pyrido[2 ',3 ':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (Compound 98)
Figure imgf000107_0001
The procedure of Compound 98 (25 mg, yield 37.9%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 7.96 (s, 1H), 7.88-7.91 (m, 2H), 7.60 (s, 1H), 7.45 (s, 2H), 7.13-7.18 (m, 4H), 7.06 (d, J= 8.4 Hz, 1H), 6.81 (t, J= 8.8 Hz, 1H), 6.51-6.56 (m, 1H), 5.82 (br s, 1H), 4.44-4.71 (m, 2H), 3.33 (s, 3H), 2.93 (d, J= 4.8 Hz, 3H), 2.63 (s, 3H). MS (M+H)+: 647.
Example 31
Preparation of Compound 99 and Compound 100
Figure imgf000107_0002
99 (Enantiomer 1 , peak 1 on SFC) 100 (Enantiomer 2, peak 2 on SFC)
Step 1 - Synthesis of 6-(2-(benzyloxy)ethyl)-2-chloro-l l-fluoro-12, 12a-dihydro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole
Figure imgf000107_0003
To a solution of 3-(benzyloxy)propanal (465 mg, 2.83 mmol) and 6-chloro-2-(4- fluoroindolin-2-yl)pyridin-3-ol (500 mg, 1.89 mmol) in MeCN (15 mL) was added TFA (10 mg, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The it was basified by NaHC03 (aq.), and then it was concentrated in vacuo, the resulting residue was purified using column chromatography (petroleum ether : EtOAc = 10 : 1) to provide 6-(2-(benzyloxy)ethyl)-2- chloro-1 l-fluoro-12, 12a-dihydro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (540 mg, yield: 69%). 1H- MR (CDCI3, 400 MHz) δ 7.28-7.38 (m, 5H), 7.04-7.10 (m, 2H), 6.95 (d, J= 8.8 1H), 6.60 (d, J= 8.0 Hz, 1H), 6.50 (t, J= 8.0 Hz, 1H), 5.93 (t, J= 7.2 Hz, 1H), 5.02 (d, J= S.i Hz, 1H), 4.55 (d, J= 2.4 Hz, 1H), 3.62-3.71 (m, 3H), 3.40-3.48 (m, 1H), 2.19-2.27 (m, 2H). MS (M+H)+: 411.
Step 2 - Synthesis of 6-(2-(benzyloxy)ethyl)-2-chloro-l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole
Figure imgf000108_0001
To a solution of 6-(2-(benzyloxy)ethyl)-2-chloro-l l-fluoro-12, 12a-dihydro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (500 mg, 1.22 mmol) in toluene (7 mL) was added DDQ (552 mg, 2.43 mmol). The mixture was stirred at 80 °C for 2 hours. Then it was concentrated in vacuo, the resulting residue was purified using prep-HPLC to provide 6-(2- (benzyloxy)ethyl)-2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (44 mg, yield: 9%). 1H- MR (CDC13, 400 MHz) δ 7.32-7.43 (m, 5H), 7.22-7.28 (m, 1H), 7.11-7.20 (m, 3H),6.80~6.86 (m, 1H), 6.65 (t, J= 6.4 Hz, 1H), 4.48 (dd, J= 8.0 Hz, 1H), 4.51 (d, J= 12.0 Hz, 1H), 4.46 (d, J= 12.0 Hz, 1H), 3.55-3.62 (m, 1H), 3.25-3.33 (m, 1H), 2.15-2.23 (m, 1H), 2.02-2.12 (m, 1H). MS (M+H)+: 409.
Step 3 - Synthesis of 5-(6-(2-(benzyloxy)ethyl)- 1 l-fluoro-6H-pyrido[2' , 3' : 5 , 6] [ 1 , 3] oxazinoi aJindol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofura
carboxamide
Figure imgf000108_0002
The procedure of racemic 5-(6-(2-(benzyloxy)ethyl)-l l-fluoro-6H- pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (89 mg, yield: 79.0%) was similar to Example 1. 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.96 (dd, J= 8.8, 5.6 Hz, 2H), 7.66 (s, 1H), 7.46-7.50 (m, 1H), 7.31-7.44 (m, 6H), 7.14-7.24 (m, 5H), 6.80-6.87 (m, 1H), 6.70 (t, J = 6.4 Hz, 1H), 5.95 (br s, 1H), 4.47-4.57 (m, 2H), 3.62-3.69 (m, 1H), 3.31-3.42 (m, 4H), 2.99 (d, J= 4.8 Hz, 3H), 2.70 (s, 3H), 2.20-2.30 (m, 1H), 2.08-2.18 (m, 1H). MS (M+H)+: 749.
Step 4 - Synthesis of 5-(l l-fluoro-6-(2-hydroxyethyl)-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (Compound 99 and Compound 100)
Figure imgf000109_0001
99 (Enantiomer 1 , peak 1 on SFC) 100 (Enantiomer 2, peak 2 on SFC)
To a solution of 5-(6-(2-(benzyloxy)ethyl)-l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (85 mg, 0.11 mmol) in MeOH (3 mL) was added Pd / C (30 mg, 10%) under H2 protection The mixture was stirred at room temperature overnight. The it was filtered to remove Pd / C, the filtrate was concentrated in vacuo, the resulting residue was purified using prep-TLC (dichloromethane : MeOH = 20 : 1) to provide 5- ( 11 -fluoro-6-(2-hydroxyethyl)-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3 -carboxamide (60 mg, yield: 85%). And after SFC separation, two enantiomers were obtained. Column: Chiralpak AD- 3 50*4.6mm I D., 3um Mobile phase: 60% ethanol (0.05% DEA) in C02 Flow rate: 3mL/min Wavelength: 220nm. Compound 99: RT= 0.529 min, Compound 100: RT= 1.909 min
Compound 99, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) (CDC13, 400 MHz) δ 8.02 (s, 1H), 7.96 (dd, J= 8.8, 5.6 Hz, 2H), 7.66 (s, 1H), 7.47 (q, J= 8.8 Hz, 2H), 7.14-7.25 (m, 5H), 6.80-6.87 (m, 1H), 6.70 (dd, J= 7.2, 5.2 Hz, 1H), 5.94 (br s, 1H), 3.83-3.91 (m, 1H), 3.62-3.71 (m, 1H), 3.39 (s, 3H), 3.00 (d, J= 5.2 Hz, 3H), 2.72 (s, 3H), 2.16-2.26 (m, 1H), 2.01-2.12 (m, 1H), 1.79 (br. s., 1H). MS (M+H)+: 659.
Compound 100, enantiomer 2 (peak 2 on SFC), 1H- MR (CDC13, 400 MHz) (CDC13, 400 MHz) δ 8.02 (s, 1H), 7.96 (dd, J= 8.8, 5.6 Hz, 2H), 7.66 (s, 1H), 7.47 (q, J= 8.8 Hz, 2H), 7.14-7.25 (m, 5H), 6.80-6.87 (m, 1H), 6.70 (dd, J= 7.2, 5.2 Hz, 1H), 5.94 (br s, 1H), 3.83-3.91 (m., 1H), 3.62-3.71 (m, 1H), 3.39 (s, 3H), 3.00 (d, J= 5.2 Hz, 3H), 2.72 (s, 3H), 2.16-2.26 (m, 1H), 2.01-2.12 (m, 1H), 1.79 (br. s., 1H). MS (M+H)+: 659. Example 32
Preparation of Compound 101
Figure imgf000110_0001
Step 1 - Synthesis of 2-(2-chloro-ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-6- yl)propan-2-ol
Figure imgf000110_0002
A mixture of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole-6-carboxylate (120 mg, 0.33 mol) in THF (1 mL) was added MeMgBr (0.4 mL, 1.2 mmol) slowly at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 2 hours. After the reaction completed, the mixture was quenched with H4C1 (aq., sat., 30 mL) at room temperature and extracted with EtOAc (20 mL* 3). The organic layer was washed with brine
(20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 3 : 1) to provde 2-(2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl)propan-2-ol (70 mg, yield: 63.6%). 1H- MR (CDC13; 400 MHz) δ 7.06-7.19 (m, 4H), 6.73-6.77 (m, 1H), 6.07 (s, 1H), 1.26 (s, 3H), 1.03 (s, 3H). MS (M+H)+: 333. Step 2 - Synthesis of 5-(l l-fluoro-6-(2-hydroxypropan-2-yl)-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4 '-fluorophenyl) -N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 101)
Figure imgf000111_0001
101
The procedure of Compound 101 (40 mg, yield: 50.0%) was similar to step 2 of Example 2. 1H- MR (CDC13, 400 MHz) δ 7.97 (s, 1H), 7.86-7.89 (m, 2H), 7.60 (s, 1H), 7.40 (d, J= 8.4Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 10.0 Hz, 1H), 7.11-7.17 (m, 4H),
6.78-6.82 (m, 1H), 6.17 (s, 1H), 6.10 (br s, 1H), 3.34 (s, 3H), 2.91 (d, J= 4.8 Hz, 3H), 2.65 (s, 3H), 1.86 (s, 1H), 1.33 (s, 3H), 1.15 (s, 3H). MS (M+H)+: 673.
Example 33
Pre aration of Compound 102
Figure imgf000111_0002
102
Step 1 - Synthesis of (2S)-(1 l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyridof 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-aJindol-6- yl)meth l 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate
Figure imgf000111_0003
87 To a solution of 5-(l l-fluoro-6-(hydroxymethyl)-6H-pyrido
[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, 0.05 mmol, Compound 87, single enantiomer) and N-Boc-L- Valine (20 mg, 0.09 mmol) in dichloromethane, EDCI (20 mg, 0.10 mmol), DMAP (8 mg, 0.06 mmol) and Et3N (0.01 mL) were added. The reaction mixture was stirred at room temperature overnight. Then H20 was added, and extracted with
dichloromethane. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using prep-TLC
(dichloromethane : MeOH = 40 : 1) to provide (2S)-(l l-fluoro-2-(2-(4-fluorophenyl)-3- (methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-6-yl)methyl 2-((tert-butoxycarbonyl)amino)-3 - methylbutanoate (30 mg, yield: 76%). 1H- MR (CDC13, 400 MHz) δ 7.98-8.02 (m, 3H), 7.67 (s, 1H), 7.46-7.54 (m, 2H), 7.19-7.25 (m, 5H), 6.84-6.89 (m, 1H), 6.62-6.65 (m, 1H), 5.98 (br s, 1H), 4.91 (d, J= 8.4 Hz, 1H), 4.42-4.48 (m, 1H), 4.30-4.35 (m, 1H), 4.18 (br s, 1H), 3.38 (s, 3H), 3.01 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H), 1.90-1.95 (m, 1H), 1.45 (s, 9H), 0.88 (d, J= 6.4 Hz, 3H), 0.79 (d, J= 6.4 Hz, 3H). MS (M+H)+: 844.
Step 2 - Synthesis of (S)-((S)-1 l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazino f 3, 4-a]indol-6- ljmethyl 2-amino-3-methylbutanoate (Compound 102)
Figure imgf000112_0001
To a solution of (2S)-(l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6- (N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6- yl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (30 mg, 0.04 mmol) in
dichloromethane (2 mL), TFA (0.5 mL) was added. The mixture was stirred at room
temperature overnight. The mixture was poured into sat NaHC03 solution (20 mL) and extracted with dichloromethane. The combined organic phase was dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using prep-TLC (dichloromethane : MeOH = 40 : 1) to provide the product Compound 102 (25 mg, yield: 94%). 1H- MR (CDC13, 400 MHz) δ 8.03 (s, 1H), 7.95-7.99 (m, 2H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.19-7.25 (m, 5H), 6.84-6.89 (m, 1H), 6.63-6.66 (m, 1H), 5.95 (br s, 1H),
4.41-4.47 (m5 m), 4.32-4.37 (m, 1H), 3.39 (s, 3H), 3.23 (d, J = 5.2 Hz, 1H), 3.01 (d, J = 4.8 Hz, 3H), 2.74 (s, 3H), 1.82-1.91 (m, 1H), 0.91 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). MS (M+H)+: 744.
Compounds 103-104, depicted in the table below, were prepared using method described above and substituting the appropriate reactants and/or reagents.
Figure imgf000113_0001
Example 34
Preparation of Compound 105 and 106
Figure imgf000114_0001
105 (Enantiomer 1, peak 1 on SFC) 106 (Enantiomer 2, peak 2 on SFC)
Step 1 - Synthesis of 2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] ' [1,3] oxazino[ 3, 4-a] indole carboxylic acid
Figure imgf000114_0002
A mixture of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3': 5,6] [1,3] oxazino[3,4- a]indole-6-carboxylate (606 mg, 1.75 mmol) and LiOH (168 mg, 7.00 mmol) in dioxane / H20 (6 mL / 5mL) was stirred at 80 °C for 2 hours. The reaction was monitored using TLC. When the reaction was completed, 1 N HCl aqueous was added to the mixture until pH 4. The mixture was extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated under reduce pressure, afforded 2-chloro-l 1 -fluoro- 6H-pyrido[2',3':5,6] [l,3]oxazino[3,4-a]indole-6-carboxylic acid (590 mg, yield: 99%). 1H- MR(400 MHz, DMSO- 6) δ 7.74 (d, J= 8.8 Hz, 1H), 7.43-7.56 (m, 2H), 7.37 (s, 1H), 7.25-7.34 (m, 1H), 7.15 (s, 1H), 6.92-7.02 (m, 1H). MS (M+H)+: 319.
Step 2 - Synthesis of 2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indole-6- carboxamide
Figure imgf000114_0003
A mixture of 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-6- carboxylic acid (60 mg, 0.19 mmol), H4C1 (20 mg, 0.38 mmol), HOBT (38 mg, 0.28 mmol), EDCI (54 mg, 0.28 mmol) and triethylamine (76 mg, 0.75 mmol) in DMF (1 mL) was stirred at room temperature overnight under N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (dichloro methane : MeOH = 30 : 1) to provde 2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-6-carboxamide (20 mg, yield: 33.3%). 1H- MR (Methanol-^, 400 MHz) δ 7.54 (d, J = 8.4Hz, 1H), 7.28-7.31 (m, 2H), 7.20-7.24 (m, 2H), 6.90 (s, 1H), 6.82-6.84 (m, 1H). MS (M+H)+: 318.
Step 3 - Synthesis of 1 l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4- carboxamide: two enatiomers (Compound 105 and 106)
Figure imgf000115_0001
105 (Enantiomer 1, peak 1 on SFC) 106 (Enantiomer 2, peak 2 on SFC)
The procedure of racemic l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)- 6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole- 6-carboxamide was similar to step 6 of Example 1. And after SFC separation, Compound 105 and 106 were obtained. Column: Chiralpak AS-H 150x4.6mm ID., 5um Mobile phase:
methanol (0.05% DEA) in C02 from5% to 40%. Flow rate: 3mL/min Wavelength: 220nm. Compound 105: RT= 5.010 min, Compound 106: RT= 6.066 min
Compound 105, enantiomer 1 (peak 1 on SFC), 1H- MR (DMSO-i¾, 400 MHz) δ 8.55 (s, 1H), 8.13 (s, 1H), 7.81-8.01 (m, 3H), 7.81 (s, 1H), 7.68-7.74 (m, 2H), 7.57 (d, J = 8.4Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.39 (t, J = 8.8Hz, 2H), 7.20-7.25 (m, 1H), 7.08 (d, J = 5.6Hz, 2H), 6.89-6.94 (m, 1H), 3.28 (s, 3H), 2.80-2.82 (m, 6H). MS (M+H)+: 658.
Compound 106, enantiomer 2 (peak 2 on SFC), 1H- MR (DMSO-i¾, 400 MHz) δ 8.55 (s, 1H), 8.13 (s, 1H), 7.81-8.01 (m, 3H), 7.81 (s, 1H), 7.68-7.74 (m, 2H), 7.57 (d, J = 8.4Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.39 (t, J = 8.8Hz, 2H), 7.20-7.25 (m, 1H), 7.08 (d, J = 5.6Hz, 2H), 6.89-6.94 (m, 1H), 3.28 (s, 3H), 2.80-2.82 (m, 6H). MS (M+H)+: 658.
Compounds 107-113, depicted in the table below, were prepared using the method described in Example 8 and substituting the appropriate reagents and/or reactants.
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Example 35
Preparation of Compound 114 and 115
Figure imgf000118_0002
114 (Enantiomer 1, peak 1 on SFC) 115 (Enantiomer 2, peak 2 on SFC)
Step 1 - Synthesis of (2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4-a] indol-6- yljmethyl methanesulfona
Figure imgf000118_0003
To a solution of (2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino [3,4- a]indol-6-yl)methanol (1.00 g, 3.29 mmol) in dry pyridine (10 mL) at room temperature was added dropwise MsCl (1.23 g, 10.74 mmol) at 0 °C. Then the reaction mixture was stirred at room temperature for 2 hours under N2 protection. The reaction was poured into water and filtered. The filter cake was washed with water and dried to provde (2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino [3,4-a]indol-6-yl)methyl methanesulfonate (1.20 g, yield: 90.1%). 1H- MR (DMSO- 6, 400 MHz) δ 7.37-7.51 (m, 2H), 7.28-7.33 (m, 2H), 7.18-7.24 (d, J= 8.4 Hz, 1H), 6.9-6.98 (m, 1H), 6.65-6.72 (m, 1H), 4.46-4.53 (m, 1H), 4.31-4.38 (m, 1H), 2.90 (s, 3H). MS (M+H)+: 383. Step 2 - Synthesis of 6-(azidomethyl)-2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a] indole
Figure imgf000119_0001
To a solution of (2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 6-yl)methyl methanesulfonate (5 g, 13.08 mmol) in DMF (50 mL), NaN3 (4.18 g, 39.25 mmol) was added at room temperature. The mixture was stirred at 60 °C for 6 hours under N2 protection. After H20 was added, the mixture was extracted with EtOAc(20 mL* 3). The combined organic phases were washed with water and brine, dried over Na2S04 and concentrated to provide 6- (azidomethyl)-2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (4.2 g, yield: 97.4%). The crude product was used in the next step without purification. 1H- MR (CDC13,
400 MHz) δ 3.62-3.71 (m, 1H), 3.72-3.81 (m, 1H), 5.28-5.34 (t, J= 5.6 Hz, 1H), 6.76-6.83 (t, J = 4.4 Hz, 1H), 6.92-7.00 (m, 1H), 7.05-7.13 (s, 1H), 7.23-7.31 (m, 1H), 7.39-7.51 (m, 2H), 7.57-7.67 (d, J= 8.8 Hz, 1H). MS (M+H)+: 330. Step 3 - Synthesis of 5-(6-(azidomethyl)-l l-fluoro-6H-pyrido[2 ',3 ': 5 , 6] '[1 ,3]oxazino[3,4-a]indol- 2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carbo
Figure imgf000119_0002
To a mixture of 6-(azidomethyl)-2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (1.4 g, 4.25 mmol), 2-(4-fluorophenyl)-N-methyl-6- (N-methylmethylsulfonamido)- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (1.8 g, 3.73 mmol) and Κ3Ρ04·3Η20 (3.4 g, 12.75 mmol) in Dioxane / water (10 mL / 1 mL), Pd2(dba)3 (195 mg, 0.21 mmol) and X-Phos (200 mg, 0.42 mmol) were added. The reaction mixture was stirred at 90 °C for 2 hours under N2 protection. Then cooled to room temperature and added EtOAc, then filtered through a Celite pad. The combined organic phase was washed with water and brine, dried over Na2S04. The solvent was concentrated in vacuo giving 5 -(6-(azidomethyl)- 11 -fluoro-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide. The crude product was used in the next step without purification. 1H- MR (CDC13, 400 MHz) δ 2.73 (s, 3H), 2.97-3.03 (d, J= 4.8 Hz, 3H), 3.04-3.15 (d, J= 10.8 Hz, 1H), 3.20-3.32 (m, 1H), 3.40 (s, 3H), 5.93-6.02 (m, 1H), 6.33-6.40 (m, 1H), 6.81-6.89 (m, 1H), 7.14-7.26 (m, 5H), 7.45-7.53 (m, 2H), 7.67 (s, 1H), 7.93-8.01 (m, 2H), 8.03 (s, 1H). MS (M+H)+: 670.
Step 4 - Synthesis of (S)-5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide: two enantiomers (Compound 114 and 115)
Figure imgf000120_0001
114 (Enantiomer 1 , peak 1 on SFC) 115 (Enantiomer 2, peak 2 on SFC)
To a solution of 5-(6-(azidomethyl)-l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (2.8 g, 4.1 mmol) in MeOH (25 mL) at room temperature, 5% wet Pd /C (300 mg) was added and stirred under hydrogen atmosphere (30 psi) overnight. The reaction mixture was filtered. The filtrate was concentrated and the resulting residue was purified using silica gel column chromatography (dichloromethane :
MeOH = 20 : 1) to provde racemic 5-(6-(aminomethyl)-l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (1.5 g, yield: 62.5%). And after SFC separation, Compound 114 and 115 were obtained. Column: Chiralpak AD-3 50*4.6mm ID., 3um Mobile phase:60%ethanol(0.05% DEA) in C02. Flow rate: 3mL/min Wavelength: 220 nm. Compound 114: RT= 0.605 min, Compound 115: RT= 1.393 minutes. Compound 114, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) δ 8.03 (s, 1H), 7.93-8.01 (m, 2H), 7.67 (s, 1H), 7.45-7.53 (m, 2H), 7.14-7.26 (m, 5H), 6.81-6.89 (m, 1H), 6.33-6.40 (m, 1H), 5.93-6.02 (m, 1H), 3.40 (s, 3H), 3.20-3.32 (m, 1H), 3.04-3.15 (d, J = 10.8 Hz, 1H), 2.97-3.03 (d, J= 4.8 Hz, 3H), 2.73 (s, 3H), MS (M+H)+: 644.
Compound 115, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) δ
8.03 (s, 1H), 7.93-8.01 (m, 2H), 7.67 (s, 1H), 7.45-7.53 (m, 2H), 7.14-7.26 (m, 5H), 6.81-6.89 (m, 1H), 6.33-6.40 (m, 1H), 5.93-6.02 (m, 1H), 3.40 (s, 3H), 3.20-3.32 (m, 1H), 3.04-3.15 (d, J = 10.8 Hz, 1H), 2.97-3.03 (d, J= 4.8 Hz, 3H), 2.73 (s, 3H), MS (M+H)+: 644. Example 36
Preparation of Compound 116
Figure imgf000121_0001
116
Step 1 - Synthesis of ethyl 2-(((l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)- 6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-6- yl)methyl) amino) acetate
Figure imgf000121_0002
To a solution of 5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.31 mmol) and ethyl 2- oxoacetate (64 mg, 0.62 mmol) in CH2C12 (4 mL) was added acetic acid (4 mg, 0.06 mmol). The mixture was stirred at room temperature for 1 hour, and then NaBH(AcO)3 (144 mg, 0.68 mmol) added to the mixture. After stirring overnight, the mixture diluted with CH2C12, washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-HPLC give the product of ethyl 2-((( 11 -fluoro-2-(2-(4-fluorophenyl)- 3 - (methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl)methyl)amino)acetate (45 mg, yield: 20%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.96 (dd, J= 8.4, 5.2 Hz, 2H), 7.67 (s, 1H), 7.50 (s, 2H), 7.13-7.25 (m, 5H), 6.84 (dd, J= 9.2, 8.0 Hz, 1H), 6.50 (dd, J= 7.6, 3.6 Hz, 1H), 5.99 (br s, 1H), 4.12 (q, J= 7.2 Hz, 2H), 3.29-3.44 (m, 5H), 3.20 (dd, J= 12.8, 8.4 Hz, 1H), 3.00 (d, J= 4.8 Hz, 3H), 2.86-2.96 (m, 1H), 2.67 (s, 3H), 1.22 (t, J= 7.2 Hz, 3H). MS (M+H)+: 730.
Step 2 - Synthesis of 2-(((l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-6- yl)methyl) amino) acetic acid (Compound 116)
Figure imgf000122_0001
To a solution of ethyl 2-(((l l-fluoro-2-(2-(4-fluorophenyl)-3- (methylcarbamoyl)- 6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 6-yl)methyl)amino)acetate (35 mg, 0.048 mmol) in 1,4-dioxane /H20 (3.0 mL / 0.5 mL) was added LiOH-H20 (20 mg, 0.45 mmol). The mixture was stirred at room temperature overnight. Then it was concentrated in vacuo, neutralized with HCl (aq. 5%), extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated to provide Compound 116 (30 mg, yield: 91%). 1H- MR (DMSO-^, 400 MHz) δ 8.58 (d, J= 4.8 Hz, 1H), 8.00-8.07 (m, 2H), 7.85 (s, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.43 (t, J= 8.8 Hz, 2H), 7.20-7.29 (m, 1H), 7.09 (s, 1H), 6.89-6.97 (m, 1H), 6.85 (br. s, 1H), 3.19 (s, 3H), 3.07 (m, 2H), 2.88 (s, 3H), 2.83 (s, 3H). MS (M+H)+: 702.
Compounds 117-120, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H) +
Figure imgf000123_0001
Figure imgf000124_0001
Example 37
Preparation of Compound 121 and 122
Figure imgf000124_0002
121 (Enantiomer 1, peak 1 on SFC) 122 (Enantiomer 2, peak 2 on SFC)
A mixture of 5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (200 mg, 0.31 mmol), and 30% formaldehyde (1 mL), AcOH (0.1 mL) and NaBH3CN (96 mg, 1.55 mmol) in MeOH (2 mL) was stirred at room temperature for 2 hours under N2 protection. Then quenched with water and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloro methane : MeOH=20: 1) to provde 5 -(6-((dimethylamino)methyl)- 11 -fluoro-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2- yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 48%). And after SFC separation, two enantiomers were obtained. Column:
Chiralpak AD-3 50*4.6mm I D., 3um Mobile phase:60%ethanol(0.05% DEA) in C02. Flow rate: 3mL/min Wavelength: 220nm. Compound 121 : RT= 0.865 min, Compound 122: RT= 4.536 minutes.
Compound 121, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) 58.05 (s, 1H), 7.92-8.01 (m, 2H), 7.68 (s, 1H), 7.51 (s, 2H), 7.12-7.26 (m, 5H), 6.82-6.91 (m, 1H), 6.51-6.62 (m, 1H), 5.90-5.96 (m, 1H), 3.42 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.85-2.93 (m, 1H), 2.70 (s, 3H), 2.55-2.63 (m, 1H), 2.28-2.45 (m, 6H). MS (M+H)+: 672.
Compound 122, enantiomer 2 (peak 2 on SFC), 1H- MR (CDC13, 400 MHz)
58.05 (s, 1H), 7.92-8.01 (m, 2H), 7.68 (s, 1H), 7.51 (s, 2H), 7.12-7.26 (m, 5H), 6.82-6.91 (m, 1H), 6.51-6.62 (m, 1H), 5.90-5.96 (m, 1H), 3.42 (s, 3H), 3.02 (d, J= 4.8 Hz, 3H), 2.85-2.93 (m, 1H), 2.70 (s, 3H), 2.55-2.63 (m, 1H), 2.28-2.45 (m, 6H). MS (M+H)+: 672.
Example 38
Preparation of Compound 123
Figure imgf000125_0001
123
Step 1 - Synthesis of 2-chloro-l l-fluoro-6H-pyrido[2 ',3 ':5, 6] [l,3]oxazino[3,4-a]indole-6- carboxylic acid
Figure imgf000125_0002
A mixture of ethyl 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole-6-carboxylate (606 mg, 1.75 mmol) and LiOH (168 mg, 7.00 mmol) in dioxane / H20 (6 mL / 5mL) was stirred at 80 °C for 2 hours. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH 4-5 with 1 N HCl aqueous. The mixture was extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated under reduce pressure, afforded the desired product of 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-6-carboxylic acid (crude: 590 mg, yield: 99%). 1H- MR (400MHz, DMSO- 6) δ 7.74 (d, J= 8.6 Hz, 1H), 7.56-7.43 (m, 2H), 7.37 (s, 1H), 7.34-7.25 (m, 1H), 7.15 (s, 1H), 7.02-6.92 (m, 1H). MS (M+H)+: 319.
Step 2 - Synthesis of (2-chloro-l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3, 4-a]indol-6- yl) (morpholino)methan
Figure imgf000126_0001
A solution of 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole-6- carboxylic acid (300 mg, 0.94 mmol) in SOCl2 (5 mL) was reflux for 2.0 hours, then
concentrated the solution and afforded to the residue. A mixture of the residue, Et3N (0.2 mL) and morpholine (250 mg, 2.87 mmol) in dichloromethane (5 mL) was stirred at room
temperature for overnight. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC
(petroleum ether : EtOAc = 1 : 1) to provde (2-chloro-l 1 -fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6-yl)(morpholino)methanone (120 mg, yield: 32.9%). 1H- MR (CDC13, 400 MHz) 57.37-7.47 (s, 1H), 7.24 (d, J= 4.4, 1H), 7.11-7.20 (m, 2H), 6.94 (d, J= 8.4 Hz, 1H), 6.79-6.86 (m, 1H), 6.70-6.75 (m, 1H), 3.79-3.90 (m, 2H), 3.62-3.73 (m, , 4H), 3.51-3.59 (m, 1H), 3.36-3.45 (m, 1H). MS (M+H)+: 388.
Step 3 - Synthesis of 2-chloro-l l-fluoro-6-(morpholinomethyl)-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a] indole
Figure imgf000127_0001
To a solution of (2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 6-yl)(morpholino)methanone (60 mg, 0.16 mmol) in THF (2 mL) was added to BH3-SMe2 (1 mL, 1 mmol) at 0 °C. After being stirred for overnight, MeOH and water was added, the mixture was extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether: EtOAc=2: l) to provde 2-chloro-l l-fluoro-6-(morpholinomethyl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (50 mg, yield: 86.2%). 1H- MR (CDC13, 400 MHz) δ 7.28-7.34 (m, 1H), 7.22-7.26 (m, 1H), 7.13-7.22 (m, 2H), 7.09 (d, J= 8.4, 1H), 6.79-6.86 (m, 1H), 6.43 (t, J= 4.8 Hz, 1H), 3.45-3.53 (m, 2H), 3.34-3.43 (m, 2H), 2.80-2.88 (m, 1H),
2.63-2.70 (m, 1H), 2.30-2.39 (m, 2H), 2.21-2.29 (m, 2H). MS (M+H)+: 374.
Step 4 - Synthesis of 5-(l l-fluoro-6-(morpholinomethyl)-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonam
carboxamide (Compound 123)
Figure imgf000127_0002
The procedure of Compound 123 (35 mg, yield:40%) was similar to step 2 of Example 2. 1H- MR (CDC13, 400 MHz) δ 8.05 (s, 1H), 7.91-8.01 (m, 2H), 7.67 (s, 1H), 7.48-7.54 (d, J= 8.4 Hz, 1H), 7.39-7.47 (m, 1H), 7.13-7.26 (m, 5H), 6.81-6.89 (m, 1H), 6.51 (d, J= 4.5 Hz, 1H), 5.90-6.00 (m, 1H), 3.52-3.60 (m, 2H), 3.34-3.51 (m, 5H), 3.00 (d, J= 4.8 Hz, 3H), 2.88-2.95 (m, 1H), 2.67-2.82 (m, 4H), 2.39-2.49 (m, 2H), 2.27-2.37 (m, 2H). MS (M+H)+: 714. Example 39
Pre aration of Compound 124
Figure imgf000128_0001
124
A mixture of 5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6] [1,3]
oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.11 mmol), (S)-l- (methoxycarbonyl)pyrrolidine-2-carboxylic acid (38 mg, 0.22 mmol), EDCI (12 mg, 0.27 mmol), DMAP (40 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) in CH2C12 (2 mL) was stirred at room temperature overnight. The mixture was then purified using Prep-TLC (CH2Cl2:EtOAc = 1 : 1) to provde (2S)-methyl 2-(((l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-6- yl)methyl)carbamoyl)pyrrolidine-l-carboxylate (60 mg, yield: 69.0%). 1H- MR (CDC13,
400MHz) δ 7.86-8.05 (m, 3H), 7.28-7.69 (m, 4H), 7.16-7.27 (m, 5H), 6.85 (d, J= 9.2Hz, 1H), 6.60 (dd, J= 5.2, 7.2Hz, 1H), 5.98-6.25 (m, 1H), 4.31 (br. s, 1H), 3.65 (br. s, 5H), 3.39 (s, 5H), 2.97 (d, J= 3.2 Hz, 3H), 2.72 (br. s, 3H), 1.90-2.49 (m, 2H), 1.63-1.79 (m, 2H). MS (M+H)+: 799.
Compounds 125-127, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents. Compound MS
Structure NMR
No (M+H) +
^-NMR (CDC13, 400 MHz) δ 7.91
(br. s, 3H), 7.34-7.60 (m, 3H),
7.15-7.26 (m, 5H), 6.76-6.89 (m,
2H), 6.55 (d, J= 4.4Hz, IH),
6.27-6.49 (m, IH), 5.27-5.44 (m,
125 801
IH), 3.94-4.06 (m, IH), 3.71-3.83
F 0=S=0
1 (m, IH), 3.63 (br. s, 3H), 3.36 (s,
4H), 2.90 (br. s, 3H), 2.70 (br. s,
3H), 1.99-2.19 (m, IH), 0.86-0.98
(m, 6H).
^-NMR (CDCI3, 400 MHz) δ
7.86-8.05 (m, 3H), 7.28-7.69 (m,
4H), 7.16-7.27 (m, 5H), 6.85 (d, J =
9.2Hz, IH), 6.60 (dd, J = 5.2, 7.2Hz,
126 IH), 5.98-6.25 (m, IH), 4.31 (br. s, 799
IH), 3.65 (br. s, 5H), 3.39 (s, 5H),
Figure imgf000129_0001
2.97 (d, J = 3.2 Hz, 3H), 2.72 (br. s.,
3H), 1.90-2.49 (m, 2H), 1.63-1.79
(m, 2H).
^-NMR (CDCI3, 400 MHz) δ 7.96
(s, IH), 7.88 (d, J = 3.2Hz, 2H), 7.55
(s, IH), 7.38 (d, J = 17.6Hz, 2H),
7.04-7.18 (m, 5H), 6.76 (t, J =
8.4Hz, IH), 6.40-6.54 (m, 2H),
127 5.97-6.08 (m, IH), 5.18 (d, J = 801
8.0Hz, IH), 3.87 (t, J = 7.2Hz, IH),
Figure imgf000129_0002
3.61 (s, 3H), 3.38-3.58 (m, 2H),
3.32 (s, 3H), 2.91 (d, J = 5.2Hz, 3H),
2.72 (s, 3H), 2.03-2.18 (m, IH),
0.90 (dd, J = 19.2, 6.8Hz, 6H).
Example 40
Preparation of Compound 128
128
Figure imgf000130_0002
128
A mixture of 5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (50 mg, 0.08 mmol), and Et3N (11 mg, 0.12 mmol) in dichloromethane (1 mL) was stirred at room temperature under N2 protection. Then MsCI (11 mg, 0.09 mmol) was added and the solution was stirred at room temperature for overnight. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane : MeOH=15: l) to provde 5-(l l-fluoro-6- (methylsulfonamidomethyl)-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 35.7%). 1H- MR (400 MHz, DMSO-i¾) δ 8.55 (d, J= 4.8 Hz, 1H), 7.83 (s, 1H),
7.96-8.06 (m, 3H), 7.65-7.70 (m, 1H), 7.59-7.63 (m, 1H), 7.57 (t, J= 6.4 Hz, 1H), 7.37-7.44 (m, 3H), 7.24-7.30 (m, 1H), 7.10 (s, 1H), 6.91-6.97 (m, 1H), 6.77 (dd, J= 6.8 Hz, 4.4 Hz, 1H), 3.37 (dd, J= 14.0, 7.2 Hz, 2H), 3.29 (br s, 3H), 2.89 (s, 3H), 2.77-2.87 (m, 6H). MS (M+H)+: 722.
Example 41
Preparation of Compound 129 and 130
Figure imgf000131_0001
Figure imgf000131_0002
129 (Enantiomer 1 , peak 1 on SFC) 130 (Enantiomer 2, peak 2 on SFC)
A mixture of 5-(6-(aminomethyl)-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide (50 mg, 0.08 mmol), and pyridine (11 mg, 0.14 mmol) in dichloromethane (1 mL) was stirred at room temperature under N2 protection. Then acetyl chloride (11 mg, 0.14 mmol) was added and the solution was stirred at room temperature for 1.5 hours. Then the mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was washed with brine (30 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (dichloromethane : MeOH=10: l) to provde 5-(6- (acetamidomethyl)- 11 -fluoro-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (30 mg, yield: 56.3%). And after SFC separation, two enantiomers were obtained. Column: Chiralpak AD-3 50*4.6mm I D., 3um. Mobile phase: 60%ethanol(0.05% DEA) in C02. Flow rate:
3mL/min. Wavelength: 220 nm. Compound 129: RT= 0.449 min, Compound 130: RT= 1.264 minutes. Compound 129, enantiomer 1 (peak 1 on SFC), 1H- MR (CDC13, 400 MHz) 58.05 (s, 1H), 7.85-7.95 (m, 2H), 7.62 (s, 1H), 7.39-7.49 (m, 2H), 7.10-7.26 (m, 5H), 6.82 (t, J = 8.4 Hz, 1H), 6.60 (t, J= 5.2 Hz, 1H), 6.12 (d, J= 3.6 Hz, 1H), 5.96-6.04 (m, 1H), 3.52-3.65 (m, 2H), 3.38 (s, 3H), 2.93 (d, J= 4.4 Hz, 3H), 2.69-2.80 (m, 3H), 1.91 (s, 3H). MS (M+H)+: 686.
Compound 130, enantiomer 2 (peak 2 on SFC), 1H- MR (CDC13, 400 MHz) 58.05 (s, 1H), 7.85-7.95 (m, 2H), 7.62 (s, 1H), 7.39-7.49 (m, 2H), 7.10-7.26 (m, 5H), 6.82 (t, J = 8.4 Hz, 1H), 6.60 (t, J= 5.2 Hz, 1H), 6.12 (d, J= 3.6 Hz, 1H), 5.96-6.04 (m, 1H), 3.52-3.65 (m, 2H), 3.38 (s, 3H), 2.93 (d, J= 4.4 Hz, 3H), 2.69-2.80 (m, 3H), 1.91 (s, 3H). MS (M+H)+: 686.
Example 42
Preparation of Compound 131
Figure imgf000132_0001
131
Synthesis of 4-bro -2-(3-chloro-lH-indol-2-yl)phenol
Figure imgf000132_0002
To a solution of 4-bromo-2-(lH-indol-2-yl)phenol (100 mg, 0.35 mmol) in DMF (1 mL) was added NCS (46 mg, 0.35 mmol), it was allowed to stir at room temperature until LCMS showed the starting material was consumed completely. The reaction solution was extracted with EtOAc, and the combined organic layers were washed with H20 (3 x 10 mL), brine and dried over Na2S04. The solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 4-bromo-2-(3-chloro-lH-indol-2-yl)phenol (110 mg, yield: 98.2%). 1H- MR (CDC13, 400 MHz) δ 9.25 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.40-7.43 (m, 1H), 7.20-7.30 (m, 2H), 7.12 (t, J = 4.0 Hz, 1H), 6.86 (t, J = 6.0 Hz, 1H), 5.93 (s, 1H). MS (M+H)+: 322 / 324. Step 2 - Synthesis of 2-bromo-12-chloro-6-c clopropyl-6H-benzo[5, 6] [l,3]oxazino[3,4-a]indole
Figure imgf000133_0001
Cyclopropanecarbaldehyde (70 mg, 1.0 mmol) and PTSA (17 mg, 0.1 mmol) were added to a solution of 4-bromo-2-(3-chloro-lH-indol-2-yl)phenol (110 mg, 0.34 mmol) in toluene (2 mL). The mixture was allowed to stir at 110 °C for about 15 hours. The reaction solution was extracted by EtOAc, and the combined organic layers were washed with H20 (3 x 10 mL), brine and dried over Na2S04. The solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 2-bromo-12-chloro-6-cyclopropyl-6H- benzo[5,6][l,3]oxazino[3,4-a]indole (40 mg, yield: 31.3%). 1H- MR (CDC13, 400 MHz) δ 8.42 (m, 1H), 7.63 (t, J = 0.4 Hz, 1H), 7.30-7.35 (m, 2H), 7.15-7.24 (m, 2H), 6.93 (m, 1H), 5.62 (d, J = 0.8 Hz, 1H), 1.36-1.45 (m, 1H), 0.50-0.56 (m, 4H). MS (M+H)+: 374 / 376.
Step 3 - Synthesis of 12-chloro-6-cyclopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 6H-benzo[ 5, 6] [1,3 Joxazinof 3, 4-a ] indole
Figure imgf000133_0002
To a degassed solution of 2-bromo-12-chloro-6-cyclopropyl-6H- benzo[5,6][l,3]oxazino[3,4-a]indole (40 mg, 0.11 mmol) and pinacol diborane (56 mg, 0.22 mmol) in dry DMF (1.5 mL) were added Pd(dppf)Cl2 (10 mg) and KOAc (49 mg, 0.50 mmol) under N2. The mixture was heated to 90 °C and stirred for about 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting resulting residue was purified using column chromatography eluted with petroleum ether : EtOAc = 4 : 1 to provde 12-chloro- 6-cyclopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6H-benzo[5,6][l,3]oxazino[3,4- a]indole (40 mg, yield: 88.3%). MS (M+H)+: 422. Step 4 - Synthesis of 5-(12-chloro-6-cyclopropyl-6H-benzo[5, 6][l,3]oxazino[3,4-a]indo
(4fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-
(Compound 131)
Figure imgf000134_0001
A mixture of 12-chloro-6-cyclopropyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-6H-benzo[5,6][l,3]oxazino[3,4-a]indole (40 mg, 0.10 mmol), 5-bromo-2-(4-fluorophenyl)- N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (45 mg, 0.10 mmol), K3P04-3H20 (80 mg, 0.30 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 2 mL of DMF was heated in a sealed tube under microwave condition at 100 °C for 20 minutes, and then the mixture was purified using prep-HPLC to provide Compound 131 (35 mg, yield: 55. !%).¾- MR (CDCI3, 400 MHz) δ 8.39 (s, 1H), 7.96-7.93 (t, J= 8.0 Hz, 2H), 7.85 (s, 1H), 7.64 (d, J = 6.8 Hz, 2H), 7.40 (d, J= 4.4 Hz, 2H), 7.30 (d, J= 7.2 Hz, 1H), 7.23-7.20 (m, 4H), 5.94 (s, 1H), 5.77 (d, J= 7.2 Hz, 1H), 3,29 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H), 2.62 (s, 3H), 1.55-1.50 (m, 1H), 0.66-0.60 (m, 4H). MS (M+H)+: 670.
Example 43
Preparation of Compound 132
Figure imgf000134_0002
132
Figure imgf000134_0003
Pd / C (10 mg) was added to a solution of Compound 131 (20 mg, 0.03 mmol) in MeOH (5 mL). The mixture was allowed to stir under H2 atmosphere (50 psi) for about 15 hours. After filtrated and concentrated, the mixture was purified using prep-HPLC to provide Compound 132 (10 mg, yield: 52.6%). 1H- MR (CDC13, 400 MHz) δ 7.92-7.94 (m, 2H), 7.84 (s, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.63 (d, J= 10.8 Hz, 2H), 7.42 (d, J= 8.0 Hz, 1H), 7.31-7.34 (m, 1H), 7.11-7.24 (m, 5H), 6.85 (s, 1H), 5.94 (d, J= 4.8 Hz, 1H), 5.81 (d, J= 7.2 Hz, 1H), 3.16 (s, 3H), 2.98 (d, J= 5.2 Hz, 3H), 2.71 (s, 3H), 1.50-1.58 (m, 1H), 0.57-0.66 (m, 4H). MS (M+H)+: 636. Example 44
Preparation of Compound 133
Figure imgf000135_0001
133
Synthesis of 2-(lH-benzo[d]imidazol-2-yl)-4-chlorophenol
Figure imgf000135_0002
A mixture of benzene- 1,2-diamine (500 mg, 4.6 mmol), 5-chloro-2-methoxy- benzoic acid (1.3 g, 6.9 mmol) in PPA (30 mL) was allowed to stir at 200 °C for 5 hours. The mixture was poured to ice and neutralized with KOH. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04. The organic phase was concentrated to provide 2-(lH-benzo[d]imidazol-2-yl)-4-chlorophenol (300 mg, yield: 27%). 1H- MR (DMSO-i , 400 MHz) δ 8.20 (d, J = 2.5 Hz, 1H), 7.73-7.70 (m, 2H), 7.44 (dd, J = 8.8, 2.6 Hz, 1H), 7.34-7.32 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H). MS (M+H)+: 245.
Step 2 - Synthesis of 2-chloro-6H-benzo [ejbenzo [4,5]imidazo / 1 ,2-cJ '/ 1 ,3]oxazine
Figure imgf000135_0003
A mixture of 2-(lH-benzo[d]imidazol-2-yl)-4-chlorophenol (80 mg, 0.33 mmol), dibromo-methane (341 mg, 1.96 mmol), K2C03 (137 mg, 0.99 mmol) in DMF (6 mL) was allowed to stir at 80°C for 12 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide 2-chloro-6H-benzo[e]benzo[4,5]imidazo[l,2-c][l,3]oxazine (30 mg, yield: 36%). 1H- MR (Methanol^, 400 MHz) δ 8.07 (d, J = 2.1 Hz, 1H), 7.83-7.81 (m, 1H), 7.78-7.75 (m, 1H), 7.63 (dd, J = 8.8, 2.2 Hz, 1H), 7.54-7.52 (m, 2H), 7.30 (d, J = 8.8 Hz, 1H), 6.33 (s, 2H). MS (M+H)+: 257.
Step 3 - Synthesis of 5-(6H-benzo[e]benzo[4,5]imidazo[l,2-c] [l^joxazin-l-y^-l^- fluoropheny^-N-methyl-e-^-methylmethylsulfonamido^enzofuran-S-carboxamide (Compound 133)
Figure imgf000136_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzofuran-3-carboxamide (117 mg, 0.23 mmol) and 2-chloro-6H- benzo[e]benzo[4,5]imidazo[l,2-c][l,3]oxazine (60 mg, 0.23 mmol) in dioxane : H20 (2 mL : 0.5 mL) was added Pd2(dba)3 (21 mg, 0.02 mmol), X-Phos (22 mg, 0.05 mmol) and K3P04 (184 mg, 0.69 mmol) under N2. The mixture was heated to 100 °C and stirred for about 15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H20, brine, dried over Na2S04. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the product of Compound 133 (30 mg, yield: 22%).
1H- MR (DMSO-i¾ 400 MHz) δ 8.59 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 1.9 Hz, 1H), 8.08-8.05 (m, 3H), 7.77-7.72 (m, 2H), 7.69 (s, 1H), 7.63 (dd, J = 8.7, 2.0 Hz, 1H), 7.46 (t, J = 8.7 Hz, 2H), 7.37-7.30 (m, 3H), 6.38 (s, 2H), 3.21 (s, 3H), 3.05 (s, 3H), 2.87 (d, J = 4.4 Hz, 3H). MS
(M+H)+: 597. Compound 134-140, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Figure imgf000137_0001
Figure imgf000138_0001
Example 45
Preparation of Compound 141
Figure imgf000139_0001
141
Synthesis of 5-bromo-2-methoxynicotinamide
Figure imgf000139_0002
To a solution of 5-bromo-2-methoxynicotinic acid (5 g, 22 mmol) in dichloromethane (75 mL) was treated with Oxalyl dichloride (10 ml) by dropwise at 0 °C, then the mixture was stirred at R.T. for 4 hours. A mixture of Ice- H3.H20 was poured into the react solution within an ice-bath and stirred at 0 °C for more 10 min and filtered, the filter cake was dried to provide 5-bromo-2-methoxynicotinamide (4.7 g, yield: 94.4%). 1HNMR (400MHz, CDCI3) δ 8.45 (d, J= 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.78 (br, 2H), 3.94 (s, 3H). MS (M+H)+: 231 / 233.
Synthesis of methy -bromo-2-methoxynicotinimidate
Figure imgf000139_0003
To a solution of 5-bromo-2-methoxynicotinamide (4.7 g, 0.02 mol) in
dichloromethane (100 mL) was added Trimethyl-oxonium tetrafluoro borate (4.6 g, 0.02 mol) at room temperature. The mixture was stirred at room for 12 hours. The solvent was moved off and the resulting residue was washed with dichloromethane (50 mL * 2), then dry to provide methyl 5-bromo-2-methoxynicotinimidate (6.1 g, yield 91%). 1HNMR (400MHz, D20) δ 8.46 (m, 2H), 4.22 (s, 3H), 4.02 (s, 3H), 1.93 (s, 2H). MS (M+H)+: 333 / 335.
Step 3 - Synthesis of trans-2-(5-bromo-2-methoxypyridin-3-yl)-3a,4,5, 6, 7, 7a-hexahydro-lH- benzof d] imidazole
Figure imgf000140_0001
To a solution of methyl 5-bromo-2-methoxynicotinimidate (6.1 g, 18.5 mmol) in EtOH (100 mL) was added trans-Cyclohexane-1, 2-diamine (2.1 g, 18.5 mmol) at room temperature, the mixture was stirred at 80 °C for 12 hours. The solvent was removed and the resulting residue was washed with dichloro methane (50 mL * 2), then dry to provide trans-2-(5- bromo-2-methoxypyridin-3-yl)-3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazole (4 g, yield 70.2%). 1HNMR (400MHz, CDC13) δ 8.56 (d, J= 2.4 Hz, 1H), 8.43 (s, J= 2.4 Hz, 1H), 4.14 (s, 3H), 3.51-3.53 (m, 2H), 2.45-2.49 (m, 2H), 1.91-1.93 (m, 2H), 1.61-1.63 (m, 2H), 1.36-1.41 (m, 2H), 1.25 (s, 1H). MS (M+H)+: 310 / 312.
Step 4 - Synthesis of 2-(5-bromo-2-methoxypyridin-3-yl)-4,5, 6, 7-tetrahydro-lH- benzof d] imidazole
Figure imgf000140_0002
To a solution of Oxalyl dichloride (10 ml) in dichloromethane (10 mL), was treated with DMSO (2 mL) in dichloromethane (10 mL) by dropwise at -78 °C, the solution was stirred at -78 °C for another 10 min, then trans-2-(5-bromo-2-methoxypyridin-3-yl)- 3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazole (1 g, 3.3 mmol) was added in one portion under N2 protection. The react solution was stirred at -60 °C for 30 min, triethylamine is added over 5 min and the mixture was stirred at R.T. overnight. The resulting solution was treated with ice- cold 1 M hydrochloric acid solution (10 mL), the two phases are separated, the aqueous phase was extracted with dichloromethane (2 * 30 mL), and the combined organic phases was washed with pH 7 aqueous phosphate buffer (2 * 20 mL), then dried with anhydrous sodium sulfate and concentrated under reduced pressure to provide 2-(5-bromo-2-methoxypyridin-3-yl)-4, 5,6,7- tetrahydro-lH-benzo[d]imidazole (0.78 g, yield 78.8%) as a solid. 1HNMR (400MHz, DMSO) δ 14.5 (br, 1H), 8.78 (d, J= 2 Hz, 1H), 8.50 (d, J= 2 Hz, 1H), 4.04 (s, 3H), 3.15 (s, 4H), 2.66 (s, 4H). MS (M+H)+: 310 / 312. MS (M+H)+: 308 / 310. Step 5 - Synthesis of 5-bromo-3-(4,5, 6, 7-tetrahydro-lH-benzo[d]imidazol-2-yl)pyridin-2-ol
Figure imgf000141_0001
To a solution of 2-(5-bromo-2-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-lH- benzo[d] imidazole (0.8 g, 2.6 mmol) in HBr / AcOH (10 mL), was heated to 100 °C for 12 hours. The solvent was removed off and the resulting residue was washed with dichloromethane (2 * 20 mL), then dry to provide 5-bromo-3-(4,5,6,7-tetrahydro-lH-benzo[d]imidazol-2-yl)pyridin-2-ol (1 g, yield 100%) as a solid. 1HNMR (400MHz, DMSO) δ 13.87 (br, 2H), 8.40 (d, J= 2.7 Hz, 1H), 8.03(d, J= 2.7 Hz, 1H), 2.61 (s, 4H), 1.76 (s, 4H). MS (M+H)+: 294 / 296.
Step 6 - Synthesis of 2-bromo-8,9, 10, l l-tetrahydro-6H-benzo[4,5]imidazo[l,2-c]pyrido[3,2- e] [l,3]oxazine
Figure imgf000141_0002
To a solution of 5-bromo-3-(4,5,6,7-tetrahydro-lH-benzo[d]imidazol-2- yl)pyridin-2-ol (0.3 g, 1.02 mmol) and Cesium carbonate (0.663 g, 2.04 mmol) in DMF (10 mL), was heated to 100 °C. Then chloroiodomethane (215 mg, 1.22 mmol) was added by dropwise, the react mixture was stirred at 100 °C for 30 minutes. The solvent was removed off and the resulting residue was purified using flash column (petroleum ether: EtOAc 3 : 1) to provide 2- bromo-8,9, 10, 1 l-tetrahydro-6H-benzo[4,5]imidazo[l,2-c]pyrido[3,2-e][l,3]oxazine (50 mg, yield 16%) as a solid. 1HNMR (400MHz, CDC13): δ= 8.30 (d, J= 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 5.87 (s, 2H), 2.66-2.68 (m, 2H), 2.58-2.61 (m, 2H), 1.87-1.88 (m, 4H). MS (M+H)+: 306 / 308.
Step 7 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(8,9, 10, 11- tetrahydro-6H-benzof 4, 5 Jimidazof 1, 2-c Jpyridof 3, 2-e ][ 1, 3 ]oxazin-2-yl) benzofuran-3- carboxamide (Compound 141)
Figure imgf000142_0001
The procedure of Compound 141 (80 mg, yield: 44.4%) was similar to Example 1. 1HNMR (400MHz, CDC13) δ 8.82 (s, 1H), 8.55 (s, 1H), 8.04-8.08 (m, 2H), 7.93 (s, 1H), 7.59 (s, 1H), 7.45 (br, 1H), 7.16-7.20 (m, 2H), 6.07 (s, 2H), 3.32 (s, 3H), 3.04 (d, J= 4.8 Hz, 3H), 2.90 (s, 3H), 2.83 (s, 2H) 2.69 (s, 2H), 1.95-1.96 (m, 4H). MS (M+H)+: 602.
Example 46
Preparation of Compound 142
Figure imgf000142_0002
142
Step 1 - Synthesis of 2-(5-bromo-2-methoxyphenyl)imidazo[l,2-a]pyridine
Figure imgf000142_0003
To a mixture of 2-bromo-l-(5-bromo-2-methoxyphenyl)ethanone (500 mg, 1.6 mmol) in EtOH (5 mL), pyridin-2-amine (153 mg, 1.6 mmol) was added. The mixture was stirred at 80 °C for 12 hours, and then cooled to 25 °C. After filtrated, the solid was dried in vacuo to provide 2-(5-bromo-2-methoxyphenyl)imidazo[l,2-a] pyridine (30 mg, yield: 5%). 1H- MR (CDC13, 400 MHz) δ 8.54 (s, 1H), 8.18 (s, 1H), 8.12-8.13 (m, 1H), 7.62-7.64 (m, 1H), 7.37-7.40 (m, 1H), 7.16-7.21 (m, 1H), 6.86-6.88 (m, 1H), 6.76-6.79 (m, 1H), 3.98 (s, 3H). MS (M+H)+: 303 / 305.
Step 2 - Synthesis of 2-(5-bromo-2-methoxyphenyl)imidazo[l,2-a]pyridine-3-carbaldehyde
Figure imgf000143_0001
POCI3 (0.39 g, 2.5 mmol) was added to DMF (0.43 g, 6 mmol) by dropwise at 0
°C. Then 2-(5-bromo-2-methoxyphenyl)imidazo[l,2-a]pyridine (0.1 g, 0.33 mmol) in DMF (3 mL) was added. Then warmed to 25 °C and heated to 120 °C and stirred for 30 minutes and at 80 °C for 2 hours and then cooled to 25 °C. H20 (20 mL) was added and extracted with EtOAc (3 * 50 mL), washed by aq NaHC03 (3 * 50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 3 : 1) to provide 2-(5- bromo-2-methoxyphenyl)imidazo[l,2-a]pyridine-3-carbaldehyde (100 mg, yield: 90%). 1H- MR (CDC13, 400 MHz) δ 9.85 (s, 1H), 9.60 (s, 1H), 7.77-7.81 (m, 2H), 7.54-7.58 (m, 2H), 7.12-7.15 (m, 1H), 6.92-6.94 (m, 1H), 3.82 (s, 3H). MS (M+H)+: 331 / 333.
Step 3 - Synthesis of 2-(5-bromo-2-hydroxyphenyl)imidazo / 1 , 2-aJpyridine-3-carbaldehyde
Figure imgf000143_0002
2-(5-bromo-2-methoxyphenyl)imidazo[l,2-a]pyridine-3-carbaldehyde (0.1 g, 3 mmol) was dissolved in dichloromethane (0.5 mL) at -78 °C. BBr3 (1 mL) was added by dropwise stirred for 2 hours at that temperature. Then warmed to 25 °C and stirred for 10 hours. H20 (20 mL) was added by dropwise at -78 °C and extracted with EtOAc (3 * 50 mL), washed by aq NaHC03 (3 * 50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether : EtOAc = 3 : 1) to provide 2-(5-bromo-2- hydroxyphenyl)imidazo[l,2-a]pyridine-3-carbaldehyde (40 mg, yield: 48%). 1H- MR (CDC13, 400 MHz) δ 10.29 (s, 1H), 9.76 (s, 1H), 7.78-7.79 (m, 2H), 7.65-7.69 (m, 1H), 7.46-7.48 (m, 1H), 7.20-7.22 (m, 1H), 7.00-7.02 (m, 1H). MS (M+H)+: 317 / 319.
Step 4 - Synthesis of 4-bromo-2-(3-(hydroxymethyl)imidazo / 1 ,2-a]pyridin-2-yl)phenol
Figure imgf000143_0003
2-(5-bromo-2-hydroxyphenyl)imidazo[l,2-a]pyridine-3-carbaldehyde (0.19 g,
0.63 mmol) was dissolved in MeOH (2 mL) at 0 °C. NaBH4 (0.072 g, 1.9 mmol) was added portionwise. After addition, the mixture was stirred at 25 °C for 30 minutes, and then H20 (20 mL) was added by dropwise. Extracted with EtOAc (3 * 50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether : EtOAc = 3 : 1) to provide 4-bromo-2-(3-(hydroxymethyl)imidazo [l,2-a]pyridin-2-yl)phenol (150 mg, yield: 85%). 1H- MR (CDC13, 400 MHz) δ 8.33-8.35 (m, 1H), 7.72 (s, 1H), 7.62-7.64 (m, 1H), 7.31-7.37 (m, 2H), 6.92-7.01 (m, 2H), 5.20 (s, 2H). MS (M+H)+: 319 / 321. Step 5 - Synthesis of 2- e
Figure imgf000144_0001
4-bromo-2-(3-(hydroxymethyl)imidazo[l,2-a]pyridin-2-yl)phenol (0.2 g, 0.06 mmol) was dissolved in mesitylene (1 mL). The mixture was stirred at 170 °C for 6 hours, and then cooled to 25 °C. H20 (20 mL) was added and extracted with EtOAc (3 * 50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC
(petroleum ether : EtOAc= 1 : l) to provide 2-bromo-6H-chromeno[4',3':4,5]imidazo[l,2- a]pyridine (100 mg, yield: 53.0%). 1H- MR (CDC13, 400 MHz) δ 7.98-7.99 (m, 1H), 7.74-7.76 (m, 1H), 7.66-7.68 (m, 1H), 7.21-7.28 (m, 2H), 6.82-6.90 (m, 2H), 5.70 (s, 2H). MS (M+H)+: 301 / 303.
Step 6 - Synthesis of 5-(6H-chromeno [4' ,3' : 4,5]imidazo [ 1 ,2-a]pyridin-2-yl)-2-(4-fluorophenyl)- N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (Compound 142)
Figure imgf000144_0002
142
The procedure of Compound 142 (30 mg, yield: 45%) was similar to Example 1. 1H- MR (Methanol^, 400 MHz) δ 8.64-8.66 (m, 1H), 7.96-8.02 (m, 4H), 7.89 (s, 1H), 7.76 (s 1H), 7.71 (s, 1H), 7.51-7.58 (m, 2H), 7.28-7.32 (m, 2H), 7.17-7.19 (m, 1H), 5.89 (s, 2H), 3.23 (s, 3H), 2.94-2.97 (m, 6H). MS (M+H)+: 597. Compound 143, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Figure imgf000145_0003
Example 47
Preparation of Compound 144
Figure imgf000145_0001
144
Step 1 - Synthesis of 5-bromo-2-methoxynicotinic acid
Figure imgf000145_0002
To a solution of 2-methoxynicotinic acid (20 g, 130.60 mmol) in H20 (1500 mL), Br2 (20 mL, 375.45 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with water and dried to provide 5-bromo-2-methoxynicotinic acid (25 g, yield: 82%). 1H- MR (DMSO, 400 MHz) δ 13.33 (br s, 1H), 8.47 (d, J= 2.4 Hz, 1H), 8.21 (d, J= 2.4 Hz, 1H), 3.90 (s, 3H). MS (M+H)+: 232 / 234. Step 2 - Synthesis of 5-bromo-N,2-dimethoxy-N-methylnicotinamide
Figure imgf000146_0001
To a solution of 5-bromo-2-methoxynicotinic acid (15.0 g, 64.65 mmol) in anhydrous DMF (150 mL), HOBT (9.0 g, 66.61 mmol) and EDCI (25.0 g, 130.41 mmol) were added. The reaction mixture was stirred at room temperature for 2 hour. And then
Me HOMe.HCl (20.0 g, 205.04 mmol) and Et3N (60 mL, 415.06 mmol) was added to the mixture. The mixture was stirred at 20 °C overnight. The reaction mixture was concentrated in vacuo. Then H20 was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether : EtOAc = 2 : 1) to provide 5-bromo-N,2-dimethoxy-N-methylnicotinamide (16.5 g, yield: 92%). 1H- MR (CDC13, 400 MHz) δ 8.23 (d, J= 2.4 Hz, 1H), 7.68 (d, J= 2.4 Hz, 1H), 3.95 (s, 3H), 3.53 (s, 3H), 3.33 (s, 3H). MS (M+H)+: 275 / 277.
Step 3 - Synthesis of l-(5-brom -2-methoxypyridin-3-yl)ethanone
Figure imgf000146_0002
To a solution of 5-bromo-N,2-dimethoxy-N-methylnicotinamide (5.0 g, 18.18 mmol) in THF (50 mL), MeMgBr (10 mL, 30.0 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at 20 °C overnight. Then the reaction mixture was added to H4C1 solution. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with petroleum ether : EtOAc = 10 : 1) to provide l-(5-bromo-2-methoxypyridin-3-yl)ethanone (3.0 g, yield: 71%). 1H- MR (CDC13, 400 MHz) δ 8.33 (d, J= 2.4 Hz, 1H), 8.19 (d, J= 2.4 Hz, 1H), 4.03 (s, 3H), 2.63 (s, 3H). MS (M+H)+: 230 / 232
Step 4 - Synthesis of 2-bromo-l-(5-bromo-2-hydroxypyridin-3-yl)ethanone
Figure imgf000147_0001
To a solution of l-(5-bromo-2-methoxypyridin-3-yl)ethanone (2.0 g, 8.69 mmol) in HBr (20 mL, HO Ac solution), Br2 (1.4 g, 8.76 mmol) was added dropwise at room
temperature. The reaction mixture was stirred at room temperature for 5 hours. Then the reaction mixture was filtered to collect the HBr salt. The solid was suspended with Na2C03 solution, extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to provide 2-bromo-l-(5-bromo-2- hydroxypyridin-3-yl)ethanone (2.0 g, yield: 74%). 1H- MR (DMSO, 400 MHz) δ 12.83 (br s, 1H), 8.11-8.13 (m, 2H), 4.85 (s, 2H). MS (M+H)+: 295.
Step 5 - Synthesis of 5-bromo-3-(imidazo[l,2-a]pyridin-2-yl)pyridin-2-ol
Figure imgf000147_0002
A mixture of 2-bromo-l-(5-bromo-2-hydroxypyridin-3-yl)ethanone (300 mg, 1.02 mmol) and 2-aminopyridine (100 mg, 1.06 mmol) in EtOH (10 mL) was stirred at reflux overnight. The reaction mixture was cooled and filtered to provide 5-bromo-3-(imidazo[l,2- a]pyridin-2-yl)pyridin-2-ol (200 mg, yield: 67%). 1H- MR (DMSO, 400 MHz) δ 12.75 (br s, 1H), 9.02 (s, 1H), 8.94 (d, J= 6.8 Hz, 1H), 8.42 (d, J= 2.8 Hz, 1H), 7.89-7.96 (m, 3H), 7.45 (d, J= 4.8 Hz, 1H). MS (M+H)+: 290 / 292. Step 6 - Synthesis of 2-(5-bromo-2-chloropyridin-3-yl)imidazo[ 1, 2-a]pyridine-3-carbaldehyde
Figure imgf000147_0003
A solution of 5-bromo-3-(imidazo[l,2-a]pyridin-2-yl)pyridin-2-ol (500 mg, 1.72 mmol) in POCl3 (10 mL) was stirred at 100 °C overnight. Then DMF (10 mL) was added dropwise. The reaction mixture was stirred at 100 °C for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was suspended with water, and saturated aqueous NaHC03 solution was added until the solution was at pH 7. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with dichloromethane : MeOH = 50 : 1) to provide 2-(5-bromo-2-chloropyridin-3- yl)imidazo[l,2-a]pyridine-3-carbaldehyde (300 mg, yield: 51%). 1H- MR (CDC13, 400 MHz) δ 9.87 (s, 1H), 9.62 (d, J= 7.2 Hz, 1H), 8.61 (d, J= 2.4 Hz, 1H), 8.12 (d, J= 2.4 Hz, 1H), 7.84 (d, J= 9.2 Hz, 1H), 7.63-7.67 (m, 1H), 7.21-7.24 (m, 2H). MS (M+H)+: 336 / 338.
Synthesis of (2-(5-bromo-2-chloropyridin-3-yl)imidazo[ 1, 2-a]pyridin-3-yl)methanol
Figure imgf000148_0001
To a solution of 2-(5-bromo-2-chloropyridin-3-yl)imidazo[l,2-a]pyridine-3- carbaldehyde (100 mg, 0.29 mmol) in MeOH (5 mL), NaBH4 (20 mg, 0.53 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using PTLC (eluted with dichloromethane : MeOH = 30 : 1) to provide (2-(5-bromo-2-chloropyridin-3- yl)imidazo[l,2-a]pyridin-3-yl)methanol (30 mg, yield: 29%). 1H- MR (DMSO, 400 MHz) δ 8.66 (d, J= 2.4 Hz, 1H), 8.49 (d, J= 6.8 Hz, 1H), 8.25 (d, J= 2.4 Hz, 1H), 7.64 (d, J= 9.2 Hz, 1H), 7.35-7.40 (m, 1H), 7.03-7.07 (m, 1H), 5.33 (t, J= 5.2 Hz, 1H), 4.75 (d, J= 5.2 Hz, 2H). MS (M+H)+: 338 / 340.
Synthesis of 2-bromo-4-aza-6H-chromeno 4 ', 3 ': 4, 5 Jimidazof 1, 2 -a ] pyridine
Figure imgf000148_0002
To a solution of (2-(5-bromo-2-chloropyridin-3-yl)imidazo[l,2-a]pyridin-3- yl)methanol (20 mg, 0.06 mmol) in DMF (2 mL), K2C03 (20 mg, 0.14 mmol) was stirred at 100 °C overnight. The reaction mixture was concentrated in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using PTLC (eluted with dichloromethane : MeOH = 50 : 1) to provide 2-bromo-4-aza- 6H-chromeno[4',3':4,5]imidazo[l,2-a]pyridine (7 mg, yield: 39%). 1H- MR (CDC13, 400 MHz) δ 8.23 (d, J= 2.4 Hz, 1H), 8.13 (d, J= 2.4 Hz, 1H), 7.75 (d, J= 6.8 Hz, 1H), 7.66 (d, J= 9.2 Hz, 1H), 7.27-7.30 (m, 1H), 6.90-6.95 (m, 1H), 5.93 (s, 2H). MS (M+H)+: 302 / 304. Step 9 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-[methyl(methylsulfonyl)amino]-5-(6H pyrido[ 1",2 ": 1 ' 2 'Jimidazof 4 ' 5 ': 4, 5 Jpyranof 2, 3-b Jpyridin-2-yl)-l-benzofuran-3-carboxamide (Compound 144)
Figure imgf000149_0001
The procedure of Compound 144 (30 mg, yield: 45%) was similar to Example 1. 1H- MR (CDC13, 400 MHz) δ 8.21 (d, J= 2.0 Hz, 1H), 8.14 (d, J= 2.0 Hz, 1H), 7.94-7.98 (m, 2H), 7.83 (s, 1H), 7.77 (d, J= 6.8 Hz, 1H), 7.62-7.65 (m, 2H), 7.16-7.27 (m, 3H), 6.90-6.94 (m, 1H), 6.14 (br s, 1H), 5.96 (s, 2H), 3.22 (s, 3H), 3.03 (d, J= 4.8 Hz, 3H), 2.78 (s, 3H). MS (M+H)+: 598.
Example 48
Preparation of Compound 145
Figure imgf000149_0002
145
Step 1 - Synthesis of 4, 7-dibromo-3,4-dihydrobenzofbJoxepin-5(2H)-one
Figure imgf000149_0003
A mixture of compound 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (100 mg, 0.415 mmol) and CuBr2 (93 mg, 0.415 mmol) in ethyl acetate/CHCl3 (lmL/lmL) was stirred at 70-80 °C under N2 overnight. The mixture was then purified using prep-TLC (petroleum ether : ethyl acetate = 10: 1) to provide compound 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (58 mg, yield: 44.4%). MS (M+H)+: 319 / 321 / 323. Step 2 - Synthesis of 2-bromo-6 7-dihydrobenzo[ 2 ', 3 'Joxepinof 4 ' 5 ': 4, 5 Jimidazof 1, 2-a Jpyridine
Figure imgf000150_0001
A mixture of compound 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (330 mg, 1.031 mmol) and pyridin-2-amine (97 mg, 1.031 mmol) was stirred at 60 °C for 3 hours. The mixture was then purified using chromatography (petroleum ether : ethyl acetate = 3 : 1) to provide 2-bromo-6,7-dihydrobenzo[2',3']oxepino[4',5':4,5]imidazo[l,2-a]pyridine (40 mg, yield: 12.3%). 1H- MR (CDC13, 400 MHz) δ 8.54 (d, J= 2.8 Hz, 1H), 7.78 (d, J= 6.8 Hz, 1H), 7.58 (d, J= 9.2 Hz, 1H), 7.14-7.24 (m, 2H), 6.78-6.88 (m, 2H), 4.42 (d, J= 5.2 Hz, 2H), 3.21 (d, J = 5.2 Hz, 2H). MS (M+H)+: 315 / 317. Step 3 - Synthesis of 5-(6, 7-dihydrobenzo [2 3']oxepino [4 ',5' ': 4,5]imidazo / 1 ,2-a]pyridin-2-yl)-2- (4 luorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
(Compou
Figure imgf000150_0002
The procedure of compound 145 (50 mg, yield: 64.9%) was similar to that of Example 1. 1H- MR (DMSO-i¾ 400 MHz) δ 8.62 (s, 1H), 8.50 (d, J= 2.4 Hz, 1H), 8.36 (d, J = 6.8 Hz, 1H), 8.06-8.09 (m, 2H), 8.02 (s, 1H), 7.66 (t, J= 4.4 Hz, 2H), 7.48 (t, J= 8.8 Hz, 2H), 7.33-7.43 (m, 2H), 7.17 (d, J= 8.4 Hz, 1H), 7.03 (t, J= 6.8 Hz, 1H), 4.56 (t, J= 5.0 Hz, 2H), 3.44 (t, J= 5.0 Hz, 2H), 3.17 (s, 3H), 3.01 (s, 3H), 2.87 (d, J= 4.8 Hz, 3H). MS (M+H)+: 611. Example 49
Preparation of Compound 146
Figure imgf000151_0001
Step 1 - Synthesis of 3-(3- benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-l-ol
Figure imgf000151_0002
A mixture of compound 3-(benzyloxy)-6-chloro-2-iodopyridine (2.5 g, 7.2 mmol), prop-2-yn-l-ol (443 mg, 7.9 mmol), Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) and Cul (76 mg, 0.4 mmol) in Et3N (25 mL) was stirred at room temperature for 6 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (petroleum ether : ethyl acetate = 2 : 1) to provide the product of compound 3- (3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-l-ol (1.8 g, yield: 90%). 1H- MR (CDC13, 400 MHz) δ 7.42-7.33 (m, 5H), 7.17 (s, 2H), 5.18 (s, 2H), 4.54 (s, 2H). MS (M+H)+: 274 / 276. Step 2 - Synthesis of (2-(3-(benzyloxy)-6-chloropyridin-2-yl)pyrazolo[ 1, 5-a]pyridin-3- yljmethanol
Figure imgf000151_0003
A mixture of compound 3-(3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-l-ol (1.9 g, 6.9 mmol), 1-aminopyridinium iodide (2.3 g, 10.4 mmol) and DBU (2.2 g, 14 mmol) in MeCN (15 mL) was stirred at 80 °C for 2 hours. Water (15 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (petroleum ether : ethyl acetate = 1 : 1) to provide the product of compound (2-(3-(benzyloxy)-6- chloropyridin-2-yl)pyrazolo[l,5-a]pyridin-3-yl)methanol (1.2 g, yield: 47%). 1H- MR (CDC13, 400 MHz) δ 8.42 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H),
7.29-7.22 (m, 3H), 7.21-7.17 (m, 3H), 7.02 (t, J= 8.0 Hz, 1H), 6.76 (dt, J= 1.6, 8.0 Hz, 1H), 5.09 (s, 2H), 4.77 (d, J= 6.4 Hz, 2H). MS (M+H)+: 366 / 368.
Step 3 - Synthesis of 5-(5-(benzyloxy)-6-(3-(hydroxymethyl)pyrazolo / 1 ,5-a]pyridin-2-yl)pyridin- 2-yl)-2- -fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carbo
Figure imgf000152_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)benzofuran-3-carboxamide (452 mg, 0.90 mmol) and compound (2-(3-(benzyloxy)-6- chloropyridin-2-yl)pyrazolo[l,5-a]pyridin-3-yl)methanol (300 mg, 0.82 mmol) in dioxane/H20 (5 mL/1 mL) was added Pd2(dba)3 (90 mg, 0.1 mmol), X-Phos (95 mg, 0.2 mmol) and K3P04 (1.2 g, 2.4 mmol) under N2. After stirred at 100 °C overnight, the reaction mixture was cooled to room temperatureand filtered. The filtrate was washed with brine and dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (petroleum ether : ethyl acetate = 1 : 2) to provide the product of compound 5-(5-(benzyloxy)-6-(3- (hydroxymethyl)pyrazolo[l,5-a]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, yield: 53%). 1H- MR
(Methanol^, 400 MHz) δ 8.47 (d, J= 8.8 Hz, 1H), 8.00 (dd, J= 5.2, 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.68 (d, J= 9.2 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.30-7.24 (m, 7H), 7.16-7.11 (m, 1H), 7.13 (dt, J= 0.8, 6.8 Hz, 1H), 5.22 (s, 2H), 4.74 (s, 2H), 3.29 (s, 3H), 2.93 (s, 3H), 2.89 (s, 3H). MS (M+H)+: 706. Step 4 - Synthesis of 2-(4-fluorophenyl)-5-(5-hydroxy-6-(3-(hydroxymethyl)pyrazolof 1, 5- a]pyridin-2-yl)pyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonam
carboxamide
Figure imgf000153_0001
A mixture of compound 5-(5-(benzyloxy)-6-(3-(hydroxymethyl)pyrazolo[l,5- a]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (250 mg, 0.35 mmol) and Pd/C (20 mg) in MeOH (2 mL) was stirred at room temperature under H2 for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified using prep-TLC (EA : MeOH = 20 : 1) to provide the product of compound 2-(4-fluorophenyl)-5-(5-hydroxy-6- (3 -(hydroxymethyl)pyrazolo [ 1 , 5 -a]pyridin-2-yl)pyridin-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 46%). 1H- MR
(Methanol^, 400 MHz) δ 8.50 (d, J= 6.8 Hz, 1H), 7.98 (dd, J= 5.2, 8.4 Hz, 2H), 7.84 (s, 2H), 7.78 (d, J= 9.2 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.29-7.23 (m, 3H), 6.93 (t, J= 6.8 Hz, 1H), 4.77 (s, 2H), 3.26 (s, 3H), 2.93 (s, 3H), 2.90 (s, 3H). MS (M+H)+: 616.
Step 5 - Synthesis of 2-(4-fluorophenyl)-N-methyl-5-(l-aza-6H-chromeno[4',3':3,4]pyrazolo[l,5- a]pyridin-2- l -6- -meth lmeth lsul onamido benzo uran-3-carboxamide om ound 146)
Figure imgf000153_0002
A solution of DEAD (158 mg, 0.91 mmol) and PPh3 (341 mg, 1.3 mmol) in THF (1 mL) was added dropwise to a solution of compound 2-(4-fluorophenyl)-5-(5-hydroxy-6-(3- (hydroxymethyl)pyrazolo[l,5-a]pyridin-2-yl)pyridin-2-yl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.13 mmol) in THF (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated and the resulting residue was purified using prep-HPLC to provide the product of 146 (30 mg, yield: 39%). 1H- MR (DMSO, 400 MHz) δ 8.81 (d, J= 6.8 Hz, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.18 (d, J= 8.8 Hz, 1H), 8.07-8.03 (m, 3H), 7.98 (s, 1H), 7.46-7.42 (m, 5H), 7.04 (t, J = 6.8 Hz, 1H), 5.65 (s, 2H), 3.25 (s, 3H), 2.99 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H). MS (M+H) 598.
Example 50
Preparation of Compound 147
Figure imgf000154_0001
147
Synthesis of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl) benzofuran- 3-carboxylate
Figure imgf000154_0002
2,4-difluoro-l-iodobenzene (2.09 g, 8.72 mmol) and Pd(PPh3)4 (20 mg) were added into a solution of ethyl 6-amino-5-bromo-2-(tributylstannyl) benzofuran-3-carboxylate (5 g, 8.72 mmol, prepared from ethyl 6-amino-5-bromobenzofuran-3-carboxylate with LDA and Bu3SnCl) in toluene (10 mL) under N2, then the mixture was stirred at 60 °C overnight. The reaction mixture was cooled to room temperatureand filtered. The filtrate was washed with H20, brine, dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (petroleum ether : EtOAc = 6 : 1) to provide the product of ethyl 6-amino-5- bromo-2-(2,4-difluorophenyl)benzofuran- 3-carboxylate (310 mg, yield: 9%). 1H- MR (CDC13, 400 MHz) δ 8.10 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 6.95-7.01 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 4.37 (q, J= 7.6 Hz, 2H), 1.33 (t, J= 7.6 Hz, 3H). MS (M+H)+: 396 / 398. Step 2 - Synthesis of ethyl 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido) benzofuran-3- carboxylate
Figure imgf000154_0003
To a solution of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl) benzofuran-3- carboxylate (310 mg, 0.78 mmol) and pyridine (185 mg, 2.35 mmol) in dichloromethane (10 mL) was added dropwise methanesulfonyl chloride (179 mg, 1.56 mmol) at 0 °C, then the mixture was stirred at 25 °C overnight. 10% HCl (aq) was added, then the mixture was extracted with dichloromethane (30 mL * 3), dried over Na2S04, and concentrated to provide ethyl 5-bromo-2- (2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (350 mg, yield: 94%). 1H- MR (CDC13, 400 MHz) δ 8.32 (s, 1H), 7.91 (s, 1H), 7.64-7.90 (m, 1H), 7.06 (d, J= 3.0 Hz, 1H), 7.03 (d, J= 3.0 Hz, 1H), 6.88 (s, 1H), 4.38 (q, J= 7.2 Hz, 2H), 3.02 (s, 3H), 1.33 (t, J= 7.6 Hz, 3H). MS (M+H)+: 474 / 476.
Step 3 - Synthesis of 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido) benzofuran-3- carboxylic acid
Figure imgf000155_0001
To a solution of ethyl 5-bromo-2-(2,4-difluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylate (653 mg, 1.38 mmol) in 1,4-Dioxane (10 mL) and H20 (1 mL) was added LiOH (289 mg, 6.88 mmol), then the mixture was stirred at 110°C. After 3 hours, 10% HCl (aq) was added until pH reach 4. The mixture was extracted with
EtOAc. The organic layer was dried over Na2S04 and concentrated to provide 5-bromo-2-(2,4- difluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (440 mg, yield: 65 %). 1H- MR (CDCI3, 400 MHz) δ 8.38 (s, 1H), 7.94 (s, 1H), 7.66-7.94 (m, 1H), 7.08 (d, J= 3.0 Hz, 1H), 6.91 (s, 1H), 3.04 (s, 3H). MS (M+H)+: 446 / 448.
Step 4 - Synthesis of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(methylsulfonamido) benzofuran-3-carboxamide
Figure imgf000155_0002
A solution of 5-bromo-2-(2,4-difluorophenyl)-6-(methylsulfonamido)benzofuran- 3-carboxylic acid (440 mg, 0.99 mmol), HOBT (199 mg, 1.48 mmol) and EDCI (283 mg, 1.48 mmol) in dry DMF (10 mL) was stirred at 25 °C. After 2 hours, Et3N (299 mg, 2.96 mmol) and Me H2 (200 mg, 2.96 mmol) was added to the mixture and then stirred overnight. The solvent was removed by vacuum, the mixture was washed with H20 (20 mL) and extract with EtOAc (40 mL * 3), dried over Na2S04, After concentrated, the resulting residue was purified using column chromatography (dichloromethane : EtOAc = 2 : 1) to provide 5-bromo-2-(2,4- difluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 88%). 1H- MR (DMSO- 6, 400 MHz) δ 9.61 (s, 1H), 8.19 (d, J= 3.6 Hz, 1H), 7.97 (s, 1H), 7.80-7.86 (m, 1H), 7.73 (s, 1H), 7.44-7.50 (m, 1H), 7.27-7.31 (m, 1H), 3.02 (s, 3H), 2.75 (d, J = 4.8 Hz, 3H). MS (M+H)+: 459 / 461.
Step 5 - Synthesis of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000156_0001
To a solution of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (653 mg, 1.38 mmol), K2C03 (406 mg, 2.94 mmol) in DMF (10 mL) was added Mel (519 mg, 3.66 mmol), then the mixture was stirred at 80°C. After 3 hours, the solvent was removed by vacuum, the mixture was washed with H20 (20 mL) and extract with dichloromethane (50 mL * 3), dried over Na2S04 and concentrated to provide 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran- 3-carboxamide (118 mg, yield: 25%). 1H- MR (CDC13, 400 MHz) 8.24 (s, 1H), 7.69-7.75 (m, 2H), 7.05-7.10 (m, 1H), 6.98-7.03 (m, 1H), 5.64 (d, J= 3.0 Hz, 1H), 3.09 (s, 3H), 2.97 (s, 3H), 2.95 (s, 3H). MS (M+H)+: 473 / 475.
Step 6 - Synthesis of 2-(2,4-difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5- tetramethyl-1, 3, 2
Figure imgf000156_0002
To a degassed solution of 5-bromo-2-(2,4-difluorophenyl)-N-methyl-6- (N- methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, 0.85 mmol), (Bpin)2 (1 g, 4.23 mmol), KOAc (249 mg, 2.54 mmol) in 1,4-Dioxane (5 mL) and H20 (1 mL) was added Pd(dppf)Cl2 (5 mg), then the mixture was stirred at 130°C. After 3 hours, the solvent was removed by vacuum, and the mixture was washed with H20 (20 mL), extract with
dichloromethane (50 mL * 3), dried over Na2S04. After concentrated, the resulting residue was purified using column chromatography (petroleum ether : EtOAc = 2 : 1) to provide 2-(2,4- difluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide (240 mg, yield: 54%). 1H- MR (CDC13, 400 MHz) 8.26 (s, 1H), 7.73 (d, J= 6.8 Hz, 1H), 7.56 (s, 1H), 7.05 (t, J= 6.8 Hz, 1H), 6.96 (q, J= 6.8 Hz, 1H), 5.96 (s, 1H), 3.33 (s, 3H), 2.97 (s, 3H), 2.93 (s, 3H), 1.20 (s, 12H). MS (M+H)+: 521. Step 7 - Synthesis of 2-(2,4-difluorophenyl)-5-(l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4- aJindol-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxam (Compound 147)
Figure imgf000157_0001
The procedure of Compound 147 (30 mg, yield: 25%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 8.12 (s, 1H), 7.76-7.81 (m, 1H), 7.70 (s, 1H),
7.48-7.52 (m, 2H), 7.23-7.46 (m, 2H), 7.19-7.24 (m, 2H), 7.71 (t, J= 7.2 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.83 (s, 2H), 5.75 (d, J= 7.2 Hz, 1H), 3.39 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 633.
Compounds 148 -149, depicted in the table below, were prepared using
method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H) +
Figure imgf000158_0001
Example 51
Preparation of Compound 150
Figure imgf000158_0002
Step 1 - Synthesis of methyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3- carboxylate
Figure imgf000158_0003
MsCI (4.8 g, 41.2 mmol) was added to a solution of methyl 6-amino- 5-bromo-2- (4-fluorophenyl) benzofuran-3-carboxylate (5.0 g, 13.4 mmol) and pyridine (5.4 g, 68.7mL) in dry dichloromethane (50 mL) at 0 °C. After stirred overnight at room temperature, the mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography to provde methyl 5-bromo-2-(4-fluorophenyl)-6- (methylsulfonamido) benzofuran- 3-carboxylate (5.3 g, yield: 83%). 1H- MR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.99-8.03 (m, 2H), 7.83 (s, 1H), 7.11-7.16 (m, 2H), 6.82 (br s, 1H), 3.90 (s, 3H), 2.96 (s, 3H). MS (M+H)+: 442 /444.
Step 2 - Synthesis of methyl 5-bromo-2-(4-fluorophenyl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxylate
Figure imgf000159_0001
The procedure of methyl 5-bromo-2-(4-fluorophenyl)-6- (N- methylmethylsulfonamido) benzofuran-3-carboxylate (5 g, yield: 93%) was similar to step 5 of Example 3. 1H- MR (400 MHz, CDC13) δ 8.32 (s, 1H), 8.05-8.09 (m, 2H), 7.72 (s, 1H), 7.17-7.22 (m, 2H), 3.96 (s, 3H), 3.35 (s, 3H), 3.10 (s, 3H). MS (M+H)+: 456 /458.
Step 3 - Synthesis of methyl 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)-5- (4,4,5,5- tetramethyl-1, 3, -dioxaborolan-2-yl)benzofuran-3-carboxylate
Figure imgf000159_0002
To a N2 degassed solution of methyl 5-bromo-2-(4-fluorophenyl)-6- (N- methylmethylsulfonamido)benzofuran-3-carboxylate (4.0 g, 8.8 mmol), KOAc (2.5 g, 26.3 mmol) and dis(pinacolato)diboron (6.7 g, 26.3 mmol) in dioxane (150 mL), Pd(dppf)Cl2 (600 mg, 0.88 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours, and then filtered through a Celite pad. The filtrate was concentrated in vacuo, and the resulting residue was purified using column chromatography (petroleum ether : EtOAc = 15 : 1) to provide methyl 2- (4-fluorophenyl)-6-(N-methylmethylsulfonamido) -5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxylate (2.6 g, yield: 60 %). 1H- MR (CDC13, 400 MHz) δ 8.47 (s, 1H), 8.05-8.06 (m, 2H), 7.60 (s, 1H),7.18-725 (m, 2H), 4.00 (s, 3H), 3.38 (s, 3H), 2.97 (s, 3H), 1.39 (s, 12H). MS (M+H)+: 504.
Step 4 - Synthesis of methyl 5-(l l-fluoro-6H-pyrido [2' , 3' : 5, 6] ' [l,3]oxazino[3,4-a]indo l-2-yl)-2- ( 4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate ( ompound 150)
Figure imgf000160_0001
The procedure of Compound 150 (2.6 g, yield: 53%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 8.15 (s, 1H), 8.00-8.04 (m, 2H), 7.61 (s, 1H), 7.43-7.44 (m5 2H), 7.12-7.18 (m, 4H), 7.03 (d, J= 8.8 Hz, 1H), 6.75-6.79 (m, 1H), 5.92 (s, 3.86 (s, 3H), 3.31 (s, 1H), 2.67 (s, 3H). MS (M+H)+: 616.
Example 52
Preparation of Compound 151
Figure imgf000160_0002
151
Step 1 - Synthesis o/5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid
Figure imgf000160_0003
To a solution of methyl 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino [3,4- a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (60 mg, 0.10 mmol) in dioxane / H20 (11 mL / 5 mL) was added LiOH-H20 (12.3 mg, 0.30 mol), and the mixture was stirred at 100 °C for 2 hours. After concentrated, the resulting residue was dissolved in H20, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solvent was removed by distillation to provide 5-(l l-fluoro-6H-pyrido[2',3':5,6] [l,3]oxazino[3,4- a]indol-2-yl)-2- (4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (41 mg, yield: 70%). 1H- MR (DMSO- 6, 400 MHz) δ 13.36 (s, 1H), 8.26 (s, 1H), 8.13-8.16 (m, 2H), 8.09 (s, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.42-7.46 (m, 2H), 7.25-7.27 (m, 1H), 7.09 (s, 1H), 6.92-6.96 (m, 1H), 6.28 (s, 2H), 3.30 (s, 3H), 2.98 (d, 3H). MS (M+H)+: 602. Step 2 - Synthesis of 5-(ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a] indol- 2-yl)-2-(4- fluorophenyl)-N-(2-hydroxyethyl)-6-(N-methylmethylsulfonamido
(Compound 151
Figure imgf000161_0001
The procedure of Compound 151 (48 mg, yield: 73%) was similar to step 2 of Example 8. 1H- MR (CDC13, 400 MHz) 8.09 (s, 1H), 7.98-8.02 (m, 2H), 7.68 (s, 1H),
7.48-7.54 (m, 2H), 7.19-7.25 (m, 4H), 7.12 (d, J= 8.4 Hz, 1H), 6.83-6.88 (m, 1H), 6.38 (s, 1H), 6.01 (s, 2H), 3.82 (t, J= 4.4 Hz, 2H), 3.64 (t, J= 4.4 Hz, 2H), 3.39 (s, 3H), 2.75 (s, 3H). MS (M+H)+: 645. Compounds 152-158, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents.
Compound MS
Structure NMR
No (M+H) +
Figure imgf000162_0001
Figure imgf000163_0001
Example 53
Preparation of Compound 159
Figure imgf000163_0002
159
Step 1 - Synthesis ofN-(5-(ll-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 2-yl)-2-(4- fluorophenyl)-3-(hydrazinecarbonyl)benzofuran-6-yl)-N-methylmethanesulfonamide
Figure imgf000163_0003
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a] indol-2-yl)- 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (50 mg, 0.08 mmol) in THF (10 mL) was added CDI (172 mg, 0.67 mmol). After 1 hour, H2 H2 H20 (12 mg, 0.25 mmol) was added to the reaction mixture. Then the mixture was stirred at 25 °C for 2 hours. After the solvent was removed by vacuum, the resulting residue was purified using prep- TLC (dichloromethane : MeOH = 10 : 1) to provide N-(5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-3-
(hydrazinecarbonyl)benzofuran-6-yl)-N-methylmethanesulfonamide (30 mg, yield: 59%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.95-7.98 (m, 2H), 7.69 (s, 1H), 7.50 (s, 2H), 7.19-7.24 (m, 4H), 7.11-7.15 (m, 2H), 6.83-6.85 (m, 1H), 6.01 (s, 2H), 4.14 (s, 2H), 3.37 (s, 3H), 2.75 (s, 3H). MS (M+H)+: 616.
Step 2 - Synthesis ofN-(5-(ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol- 2-yl)-2-(4- fluorophenyl)-3-(l , 3,4-oxadiazol-2-yl)benzofuran-6-yl)-N-methylmethanesulfonamide
(Compound 159
Figure imgf000164_0001
To a solution of N-(5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino [3,4-a]indol-2- yl)-2-(4-fluorophenyl)-3-(hydrazinecarbonyl)benzofuran-6-yl)-N-methylmethanesulfonamide (20 mg, 0.03 mmol) and Et3N (1 mL) in MeCN (5 mL) was added ethyl formimidate (6 mg, 0.05 mmol). Then the mixture was stirred at 110 °C for 2 hours. After the solvent was removed by vacuum, the resulting residue was purified using prep-HPLC to provide Compound 159 (10 mg, yield: 40%). 1H- MR (CDC13, 400 MHz) δ 9.01 (s, 1H), 8.35 (s, 1H), 8.10 (t, J= 2.8 Hz, 2H), 7.89 (s, 1H), 7.48 (t, J= 2.8 Hz, 2H), 7.15-7.23 (m, 4H), 7.07 (s, 1H), 6.78 (t, J= 2.8 Hz, 1H), 5.98 (s, 2H), 3.29 (s, 3H), 2.89 (s, 3H). MS (M+H)+: 626.
Example 54
Preparation of Compound 160
Figure imgf000165_0001
160
Step 1 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophen -6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000165_0002
5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (200 mg, 0.33 mmol), HOBT (50 mg, 0.37 mmol) and EDCI (140 mg, 0.73 mmol) were dissolved in dry DMF (5 mL). The resulting solution was stirred for 2 hours. And then H4C1 (100 mg, 1.87 mmol) and Et3N (0.5 mL) were added to the mixture. The mixture was stirred at room temperature overnight. Then H20 was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using column chromatography (dichloromethane : MeOH = 40 : 1) to provide 5- ( 11 -fluoro-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, yield: 90%). 1H- MR (CDC13, 400 MHz) δ 8.14 (s, 1H), 7.98-8.03 (m, 2H), 7.69 (s, 1H), 7.48-7.54 (m, 2H), 7.19-7.24 (m, 4H), 7.12 (d, J= 8.4 Hz, 1H), 6.83-6.88 (m, 1H), 6.01 (s, 2H), 5.70-5.86 (m, 2H), 3.39 (s, 3H), 2.74 (s, 3H). MS (M+H)+: 601.
Step 2 - Synthesis of (Z)-N-((dimethylamino)methylene)-5-(l l-fluoro-6H-pyrido[2',3' : 5, 6] [ 1 ,3] oxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3- carboxamide
Figure imgf000165_0003
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.13 mmol) in DMF-DMA (2 mL) was stirred at 120 °C for 2 hour. The reaction mixture was concentrated in vacuo and the resulting residue was used to the next step without further purification. 1H- MR (CDC13, 400 MHz) δ 8.66 (s, 2H), 8.10-8.15 (m, 2H), 7.63 (s, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.10-7.24 (m, 5H), 6.82-6.87 (m, 1H), 6.00 (s, 2H), 3.38 (s, 3H), 3.16 (s, 3H), 3.08 (s, 3H), 2.78 (s, 3H). MS (M+H)+: 656.
Step 3 - Synthesis ofN-(5-(ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-3-(lH-l,2,4-triazol-5-yl)benzofuran-6-yl)-N-methylmethanesulfonamide
(Compou
Figure imgf000166_0001
To a solution of (Z)-N-((dimethylamino)methylene)-5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (80 mg, 0.12 mmol) in HO Ac (2 mL) was added Hydrazine hydrate (0.1 mL). The reaction mixture was stirred at 120 °C for 3 hour. The reaction mixture was concentrated in vacuo and the resulting residue was purified using prep- HPLC to provide compound 160 (40 mg, yield: 52%). 1H- MR (CDC13, 400 MHz) δ 13.20 (br s, 1H), 8.52 (s, 1H), 7.94-7.98 (m, 2H), 7.92 (s, 1H), 7.54 (s, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.31-7.34 (m, 2H), 7.08-7.14 (m, 1H), 7.01-7.05 (m, 2H), 6.96 (d, J= 8.4 Hz, 1H), 6.67-6.72 (m, 1H), 5.71 (s, 2H), 3.38 (s, 3H), 2.80 (s, 3H). MS (M+H)+: 625.
Example 55
Preparation of Compound 161
Figure imgf000167_0001
161
Step 1 - Synthesis of (Z)-N-(l-(dimethylamino)ethylidene)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide
Figure imgf000167_0002
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.17 mmol) in DMA-DMA (2 mL) was stirred at 120 °C for 2 hour. The reaction mixture was concentrated in vacuo and the resulting residue was used to the next step without further purification.
Step 2 - Synthesis ofN-(5-(ll-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-3-(3-methyl-lH-l,2,4-triazol-5-yl)benzofuran-6-yl)-N-methylm
(Compou
Figure imgf000167_0003
To a solution of (Z)-N-(l-(dimethylamino)ethylidene)-5-(l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (110 mg, 0.16 mmol) in HO Ac (2 mL) was added Hydrazine hydrate (0.15 mL). The reaction mixture was stirred at 120 °C for 3 hour. The reaction mixture was concentrated in vacuo and the resulting residue was purified using prep-HPLC to provide compound 161 (50 mg, yield: 47%). 1H- MR (CDC13, 400 MHz) δ 11.86 (br s, 1H), 8.21 (s, 1H), 8.01 (br s, 2H), 7.61 (s, 1H), 7.45 (d, J= 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.17 (s, 2H), 7.04-7.08 (m, 3H), 6.78-6.83 (m, 1H), 5.90 (s, 2H), 3.36 (s, 3H), 2.76 (s, 3H), 2.35 (s, 3H). MS (M+H)+: 639.
Example 56
Preparation of Compound 162
Figure imgf000168_0001
Step 1 - Synthesis of 2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl) benzofuran-3-carboxamide
Figure imgf000168_0002
To a degassed solution of 5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (500 mg, 1.44 mmol), KOAc (423 mg, 4.31 mmol) and (BPin)2 (730 mg, 2.87 mmol) in 1,4-dioxane (8 mL) was added Pd(dppf)Cl2 (30 mg) under N2 protection. The mixture was stirred at 140 °C for 6 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 3 : 1) to provide 2-(4-fluorophenyl)-N- methyl-5 -(4,4, 5 , 5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)benzofuran-3 -carboxamide (500 mg, yield: 88%). 1H- MR (CDC13, 400 MHz) δ 8.19 (s, 1H), 7.96-8.00 (m, 2H), 7.77-7.79 (dd, J = 8.4 Hz, 1H), 7.48 (d, J= 7.6 Hz, 1H), 7.11-7.16 (m, 2H), 5.95 (s, 1H), 3.02-3.04 (d, J= 4.8 Hz, 3H), 1.35 (s, 12H). MS (M+H)+: 396.
Step 2 - Synthesis of5-(l l-fluoro-6H-pyrido[2',3':5, 6Jfl,3Joxazino[3,4-aJindol- 2-yl)-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (Compound 162)
Figure imgf000169_0001
The procedure of Compound 162 (10 mg, yield: 10.5%) was similar to step 6 of Example 1. 1H- MR (DMSO-i¾, 400 MHz) δ 8.56 (d, J= 4.4 Hz, 1H), 8.31 (s, 1H), 8.20 (d, J = 10.0 Hz, 1H), 7.95-7.99 (m, 3H), 7.76 (d, J= 8.8 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.35-7.39 (t, J= 8.8 Hz, 2H), 7.20 (s, 2H), 6.89-6.93 (dd, J= 10 Hz, 1H), 6.22 (s, 2H), 2.86 (d, J= 4.4 Hz, 3H). MS (M+H)+: 508.
Example 57
Preparation of Compound 163
Figure imgf000169_0002
Step 1 - Synthesis of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2- l benzo uran-3-carboxamide
Figure imgf000169_0003
To a degassed solution of 6-amino-5-bromo-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (8 g, 22.03 mmol), KOAc (4.32 g, 44.06 mmol) and (BPin)2 (27.97 g, 110.14 mmol) in 1,4-dioxane (100 mL) was added Pd(dppf)Cl2 (0.8 g) under N2 protection. The mixture was stirred at 140 °C for 6 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 3 : 1) to provide 6-amino-2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzofuran-3-carboxamide (6 g, yield: 66%). 1H- MR (CDC13, 400 MHz) δ 7.90-7.95 (m, 3H), 7.10 (t, J= 8.8 Hz, 2H), 6.67 (s, 1H), 5.98 (s, 1H), 3.00 (d, J= 4.4 Hz, 3H), 1.23 (s, 12H). MS (M+H)+: 411. Step 2 - Synthesis of 6-amino-5-(ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a] indol-2-yl)- 2-(4-fluoro henyl)-N-methylbenzofuran-3-carboxamide (Compound 163)
Figure imgf000170_0001
The procedure of Compound 163 (2.4 g, yield: 63%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 7.94 (s, 1H), 7.87-7.90 (m, 2H), 6.65 (d, J= 8.8 Hz, 1H), 7.51 (t, J= 8.8 Hz, 1H), 7.24 (d, J= 7.6 Hz, 1H), 7.11-7.21 (m, 3H), 6.84-6.90 (m, 2H), 6.00 (s, 1H), 5.90 (s, 2H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 523.
Example 58
Preparation of Compound 164
Figure imgf000170_0002
164
To a solution of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.38 mmol), ethyl hydrazinecarboxylate (42 mg, 0.40 mmol) and trimethoxymethane (204 mg, 1.92 mmol) in 10 mL of methanol was added PTSA (6 mg, 0.04 mmol) and the mixture was heated at 100 °C for 6 hours. Then the solution was cooled to room temperature and to this mixture sodium methanolate was added before this reaction mixture was heated at reflux for another 16 hours. The pH of the reaction system was adjusted to 1 with concentrated HCl and then the mixture was filtered to get a yellow solid. Finally the desired Compound 164 (40 mg, yield: 18%) was obtained by the prep-HPLC. 1H- MR (Methanol-^, 400 MHz) δ 7.80-8.01 (m, 5H), 7.57 (s, 2H), 7.06-7.30 (m, 5H), 6.78-6.82 (m, 1H), 6.05 (s, 2H), 2.97 (s, 3H). MS (M+H)+: 591.
Example 59
Preparation of Compound 165
Figure imgf000171_0001
165
Step 1 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4-a]indol- 2-yl)-2-(4- fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide
Figure imgf000171_0002
To a mixture of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (500 mg, 0.96 mmol), Cul (182 mg, 0.96 mmol), KI (238 mg, 1.44 mmol) in acetonitrile (5 mL) was added t-BuONO (168 mg, 1.44 mmol) at 0 °C under N2 protection. The mixture was stirred at 80 °C for 4 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The crude product was purified using column chromatography (petroleum ether : EtOAc = 1 : 1) to provide 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (170 mg, yield: 28%). 1H- MR (CDC13, 400 MHz) δ 8.15 (s, 1H), 7.94-8.00 (m, 3H), 7.47 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.37 (s, 1H), 7.20 (t, J= 8.8 Hz, 5H), 6.80-6.87 (m, 1H), 6.02 (s, 2H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 634.
Step 2 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol- 2-yl)-2-(4- fluorophenyl)-N-methyl-6-(l-methyl-lH-pyrazol-5-yl)benzofuran-3-carboxamide (Compound 165)
Figure imgf000172_0001
165
To a degassed solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (100 mg, 0.16 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-pyrazole (100 mg, 0.48 mmol) and K3P04.3H20 (60 mg, 0.45 mmol) in DMF (2 mL) was added Pd(dppf)Cl2 (20 mg) under N2 protection. The reaction mixture was stirred at 100 °C for 16 hours. The mixture was filtered through a celite pad, and the resulting residue was concentrated to provide crude product. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 1 : 2) to provide the product of Compound 165 (15 mg, yield: 16%). 1H- MR (CDC13, 400 MHz) δ 8.12 (s, 1H), 7.95 (dd, J= 8.4, 6.0 Hz, 2H), 7.51 (s, 1H), 7.42 (s, 1H), 7.15 (t, J= 8.8 Hz, 5H), 7.02 (d, J= 8.0 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 6.78 (t, J= 8.8 Hz, 1H), 6.24 (s, 1H), 5.96 (s, 1H), 5.88 (s, 2H), 3.38 (s, 3H), 3.00 (d, J= 5.2 Hz, 3H). MS (M+H)+: 588.
Compounds 166-167, depicted in the table below, were prepared using
method described above and substituting the appropriate reactants and/or reagents.
Figure imgf000172_0002
Example 60
Preparation of Compound 168
Figure imgf000173_0001
4-chlorobutanoyl chloride (670 mg, 4.76 mmol) was added dropwise to a 0 °C solution of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3- carboxylate and Et3N (1.0 mL) in CH2C12 (10 mL) under N2 atmosphere. The resulting reaction was allowed to stir at room temperature for 16 hours, then the reaction mixture was concentrated in vacuo. The resulting resulting residue was dissolved in CH3CN (10 mL), and then K2C03 (658 mg, 4.76 mmol) and KI (263 mg, 1.59 mmol) was added and the mixture was heated to reflux and allowed to stir at this temperature for 16 hours. After being cooled to room temperature, the mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography (eluted with petroleum ether : EtOAc = 2: 1) to provide ethyl 5-bromo-2-(4- fluorophenyl)-6-(2-oxopyrrolidin-l-yl)benzofuran-3 -carboxylate (280 mg, yield: 40%). 1H- MR (CDC13, 400 MHz) δ 8.32 (s, 1H), 8.04-8.07 (m, 2H), 7.48 (s, 1H), 7.17-7.21 (m, 2H), 4.42-4.43 (m, 2H), 3.82-3.86 (m, 2H), 2.61-2.65 (m, 2H), 2.27-2.31 (m, 2H), 1.40-1.44 (m, 3H). MS (M+H)+: 446 / 448.
Step 2 - Synthesis of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-l-yl)benzofuran-3- car boxy lie acid
Figure imgf000174_0001
A solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-l- yl)benzofuran-3-carboxylate (2.5 g, 5.8 mmol) and LiOH (0.5 g, 21.0 mmol) in dioxane (30 mL) and water (10 mL) was allowed to stir at 90 °C for 1 hour. The mixture was cooled to room temperature and extracted with dichloromethane, the organic extract was washed with brine, dried over Na2S04 and concentrated to provide 5-bromo- 2-(4-fluorophenyl)-6-(2-oxopyrrolidin- l-yl)benzofuran-3-carboxylic acid (2.2 g, yield: 91%). 1H- MR (CDC13, 400 MHz) δ 8.08 (s, 1H), 7.81-7.84 (m, 2H), 7.34 (s, 1H), 6.89-6.93 (m, 2H), 3.79-3.82 (m, 2H), 2.66-2.70 (m, 2H), 2.26-2.31 (m, 2H). MS (M+H)+: 418 / 420.
Step 3 - Synthesis of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran- 3-carboxamide
Figure imgf000174_0002
A solution of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-l- yl)benzofuran-3- carboxylic acid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg, 1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for 1 hour. Then Et3N (0.2 mL) and CH3 H2 (HC1 salt, 100 mg, 1.48 mmol) was added to the mixture, and the reaction was allowed to stir for about 15 hours. After being concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated in vacuo and the resulting resulting residue was purified using column
chromatography (eluted with petroleum ether : EtOAc = 1 : 1) to provide 5-bromo-2-(4- fluorophenyl-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (220 mg, yield: 73%), which was also prepared from 6-amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran- 3-carboxamide and 4-chlorobutanoyl chloride using the method described in step 1 above. 1H- MR (CDC13, 400 MHz) δ 7.94 (s, 1H), 7.82-7.86 (m, 2H), 7.32 (s, 1H), 7.09-7.14 (m, 2H), 6.29 (s, 1H), 3.75-3.78 (m, 2H), 2.97 (d, J= 4.8 Hz, 3H), 2.56-2.60 (m, 2H), 2.24-2.26 (m, 2H). MS (M+H)+: 431 / 433.
Step 4 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-l-yl)-5-(4, 4,5,5- tetramethyl-1, 3, -dioxaborolan-2-yl) benzofuran-3-carboxamide
Figure imgf000175_0001
To a solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-l- yl)benzofuran-3-carboxamide (500 mg, 1.16 mmol) and (Bpin)2 (900 mg, 3.54 mmol) in THF (15 mL), KOAc (400 mg, 4.08 mmol), Pd(dtbpf)Cl2 (80 mg, 0.12 mmol) were added under N2 protection. The mixture was heated at 70 °C for 1 hour. The mixture was added
dichloromethane and MeOH. The mixture was filtered through a Celit pad. The filtrate was dried and concentrated in vacuo. The resulting residue was purified using column
chromatography (dichloromethane : MeOH = 80 : 1) to provide 2-(4-fluorophenyl)-N-methyl-6- (2-oxopyrrolidin- 1 -yl)-5-(4,4, 5, 5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)benzofuran-3 - carboxamide (230 mg, yield: 41.5%). 1H- MR (CDC13, 400 MHz) δ 8.03-8.07 (m, 3H),
7.12-7.18 (m, 2H), 7.04 (s, 1H), 6.17 (br s, 1H), 4.06 (t, J= 7.2 Hz, 2H), 3.05 (d, J= 4.8 Hz, 3H), 2.92 (t, J= 8.0 Hz, 2H), 2.27-2.35 (m, 2H), 1.36 (s, 12H). MS (M+H)+: 479.
Step 5 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophen l)-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (Compound 168)
Figure imgf000175_0002
168
The procedure of Compound 168 (30 mg, yield: 45%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 7.97 (s, 1H), 7.89-7.93 (m, 2H), 7.44 (s, 1H), 7.40-7.42 (m, 2H), 7.11-7.19 (m, 4H), 7.04-7.07 (m, 1H), 6.77-6.82 (m, 1H), 5.92 (s, 2H), 5.85 (br s, 1H), 3.83 (t, J= 7.2 Hz, 2H), 2.95 (d, J= 4.8 Hz, 3H), 2.26 (t, J= 8.0 Hz, 2H), 2.01-2.06 (m, 2H). MS (M+H)+: 591.
Method II for preparation of Compound 168
Step 1 - Synthesis of 1 l-fluoro-2-(trimethylstannyl)-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4- a] indole
Figure imgf000176_0001
To a degassed solution of 2-chloro-l l-fluoro-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (3.0 g, 10.92 mmol) in Toluene (80 mL), (Me3Sn)2 (5.4 g, 16.40 mmol) and Pd(DTBPF)Cl2 (250 mg, 0.41 mmol) were added. The reaction mixture was stirred at 100 °C for 3.5 hours. The reaction mixture was filtered through a Celit pad. The filtrate was concentrated in vacuo and purified using aluminum oxide column chromatography (petroleum ether : EtOAc = 30: 1) to provide l l-fluoro-2-(trimethylstannyl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (3.7 g, yield 84 %). 1H- MR (CDC13, 400 MHz) δ 7.35-7.31 (m, 2H), 7.26-7.16 (m, 2H), 7.08 (d, J= 8.4 Hz, 1H), 6.84 (dd, J= 8.4 Hz, 1H), 5.91 (s, 2H), 0.45-0.31 (m, 9H).
Step 2 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophen l)-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (Compound 168)
Figure imgf000176_0002
To a solution of 1 l-fluoro-2-(trimethylstannyl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (60 mg, 0.14 mmol), 5-bromo-2-(4-fluorophenyl)-N- methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (50 mg, 0.11 mmol) in DMF (4 mL), Pd(PPh3)4 was added. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered through a Celit pad. The filtrate was concentrated in vacuo. The resulting residue was suspended in water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provide 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (20 mg, yield:
29.2%). 1H- MR (CDC13, 400 MHz) δ 7.97 (s, 1H), 7.89-7.93 (m, 2H), 7.44 (s, 1H), 7.40-7.42 (m, 2H), 7.1 1-7.19 (m, 4H), 7.05 (d, J = 8.8 Hz, 1H), 6.77-6.82 (m, 1H), 5.92 (s, 2H), 5.85 (br s, 1H), 3.83 (t, J = 7.2 Hz, 2H), 2.95 (d, J = 4.8 Hz, 3H), 2.26 (t, J = 8.4 Hz, 2H), 2.00-2.06 (m, 2H). MS (M+H)+: 591. Compounds 169-170, depicted in the table below, were prepared using method II described above and substituting the appropriate reagents and/or reactants.
Figure imgf000177_0001
Example 61
Preparation of Compound 171
Figure imgf000178_0001
171
Step 1 - Synthesis of 1 l-fluoro-2-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-6H- benzof 5, 6] [1,3 Joxazinof 3, 4-a] indole
Figure imgf000178_0002
The procedure of 1 l-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6H- benzo[5,6][l,3]oxazino[3,4-a]indole was similar to step 4 of Example 3, using 2-chloro-l 1- fluoro-6H-benzo[5,6][l,3]oxazino[3,4-a]indole described in Example 4. MS (M+H)+: 366. Step 2 - Synthesis of 5-(l l-fluoro-6H-benzo[5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(2-oxopyrrolidin-l-yl)benzofuran-3-carboxamide (Compound 171)
Figure imgf000178_0003
171
The procedure of Compound 171 was similar to step 5 of Example 3 using 11- fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6H-benzo[5,6][l,3]oxazino[3,4-a]indole and 5 -bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxopyrrolidin- 1 -yl)benzofuran-3 -carboxamide described in Example 60. 1H- MR (CDC13, 400 MHz) δ 7.93-7.97 (m, 2H), 7.86 (s, 1H), 7.77-7.78 (m, 1H), 7.51 (s, 1H), 7.31-7.34 (m, 1H), 7.08-7.22 (m, 5H), 6.91 (s, 1H), 6.80-6.85 (m, 1H), 5.93 (s, 3H), 3.32-3.35 (m, 2H), 2.99-3.00 (m, 3H), 2.45-2.49 (m, 2H), 1.88-1.96 (m, 2H). MS (M+H)+: 590. Example 62
Preparation of Compound 172
Figure imgf000179_0001
172
Step 1 - Synthesis of 2-chloroethyl (5-bromo-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-y I) carbamate
Figure imgf000179_0002
2-chloroethyl carbonochloridate (189 mg, 0.83 mmol) was added to a solution of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (200 mg, 0.55 mmol) and C5H5N (131 mg) in CH2C12 (3 mL), and then the mixture was stirred at room temperature under N2 for 12 hours. The mixture was concentrated in vacuo. The resulting residue was extracted with EtOAc and concentrated to obtain the ethyl 2-chloroethyl (5-bromo-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)carbamate (158 mg, yield: 61%). 1H- MR (CDC13, 400 MHz) δ 8.38 (s, 1H), 8.04 (s, 1H), 7.87-7.91 (m, 2H),7.38 (s, 1H), 7.19-7.21 (m, 2H), 5.79 (s, 1H), 4.46-4.49 (m, 2H), 3.76-3.79 (m, 2H), 2.99 (d, J= 4.8 Hz, 3H). MS (M+H)+: 469 / 471.
Step 2 - Synthesis of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran- 3-carboxami
Figure imgf000179_0003
2-chloroethyl (5-bromo-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6- yl)carbamate (1.00 g, 2.10 mmol) was added to a mixture of KI (0.40 g, 2.10 mmol) and K2C03 (0.75 g, 6.30 mmol) in DMF (20 mL) and the mixture was stirred under N2 protection at 110 °C for 2 hours. After concentrated in vacuo, the resulting residue was washed with water and EtOAc to provide 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3- carboxamide (408 mg, yield: 45%). 1H- MR (CDC13, 400 MHz) δ 7.58 (s, 1H), 7.51 (m, 2H), 7.19 (s, 1H), 7.11-7.13 (d, J= 8.0 Hz, 1H), 6.83-6.88 (m, 1H), 4.37-7.41 (m, 2H), 4.12-4.14 (m, 2H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 433 / 435. Step 3 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluoro henyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (Compound 172)
Figure imgf000180_0001
172
Pd2(dba)3 (10 mg, 0.01 mmol) and X-Phos (11 mg, 0.02 mmol) was added to the mixture of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3- carboxamide (100 mg, 0.23 mmol), 1 l-fluoro-2-(trimethylstannyl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (140 mg, 0.35 mmol) in dioxane / H20 (4 mL / 0.2 mL) under N2. Then the reaction mixture was heated to 100 °C for 1 hour and filtered. The resulting residue was extracted with EtOAc. The combined organic phase was dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether : EtOAc = 1 : 2) to provide 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3 -carboxamide (32 mg, yield:
24%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.94-7.98 (m, 2H), 7.58 (s, 1H), 7.51 (m, 2H), 7.19-7.23 (m, 4H), 7.11-7.13 (d, J= 8.0 Hz, 1H), 6.83-6.88 (m, 1H), 6.12 (s, 1H), 6.00 (s, 2H), 4.37-7.41 (m, 2H), 4.12-4.14 (m, 2H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 593.
Example 63
Preparation of Compound 173
Figure imgf000180_0002
173 Step 1 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)-5-(4,4,5,5- tetramethyl-1, -dioxaborolan-2-yl)benzofuran-3-carboxamide
Figure imgf000181_0001
To a N2 degassed solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(2- oxooxazolidin-3-yl)benzofuran-3-carboxamide (500 mg, 1.2 mmol), KOAc (352 mg, 3.6 mmol) and dis(pinacolato)diboron (913 mg, 3.6 mmol) in THF (10 mL), Pd(dppf)Cl2 (67 mg, 0.12 mmol) was added. The reaction mixture was stirred at 100 °C for 1 hour, and then filtered through a celite pad. The filtrate was concentrated in vacuo, and the resulting residue was purified using column chromatography (petroleum ether : EtOAc = 15 : 1) to provide 2-(4-fluorophenyl)-N- methyl-6-(2-oxooxazolidin-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (397 mg, yield: 69 %). 1H- MR (CDC13, 400 MHz) δ 7.58 (s, 1H), 7.50-7.53 (m, 3H), 7.19 (s, 1H), 7.11-7.13 (d, J= 8.0 Hz, 1H), 6.83-6.88 (m, 1H), 4.39 (t, J= 4.4 Hz, 2H), 4.13 (t, J= 4.4 Hz, 2H), 3.00 (d, J= 4.8 Hz, 3H), 1.39 (s, 12H). MS (M+H)+: 481. Step 2 - Synthesis of 5-(l l-fluoro-6H-pyrimido[4 ',5 ': 5 , 6] '[1 ,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophen l)-N-methyl-6-(2-oxooxazolidin-3-yl)benzofuran-3-carboxamide (Compound 173)
Figure imgf000181_0002
173
Pd2(dba)3 (14 mg, 0.015 mmol) and X-Phos (14 mg, 0.03 mmol) was added to the mixture of 2-(4-fluorophenyl)-N-methyl-6-(2-oxooxazolidin-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide (73 mg, 0.15 mmol), 2-chloro-l l-fluoro-6H- pyrimido[4',5':5,6][l,3]oxazino[3,4-a]indole (50 mg, 0.18 mmol) and Κ3Ρ04·3Η20 (121 mg, 0.45 mmol) in dioxane / H20 (3 mL / 0.5 mL) under N2. Then the reaction mixture was heated to 100 °C for 1 hour and filtered. The mixture was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using chromatography ( petroleum ether : EtOAc = 1 : 2) to provde 5-(l 1- fluoro-6H-pyrimido [4', 5 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(2- oxooxazolidin-3-yl)benzofuran-3-carboxamide (43 mg, yield: 42%). 1H- MR (CDC13, 400 MHz) δ 8.63 (s, IH), 8.55 (s, IH), 8.00-8.04 (m, 2H), 7.56 (s, IH), 7.46 (s, IH), 7.32-7.35 (m, IH), 7.15-7.20 (m, 3H), 6.87-6.91 (m, IH), 6.03 (s, 2H), 5.97-6.00 (m, IH), 4.54 (t, 2H), 4.24 (t, 2H), 3.06 (d, J= 4.8Hz, 3H). MS (M+H)+: 594.
Compound 174, depicted in the table below, was prepared using the method described above and substituting the appropriate reagents and/or reactants.
Figure imgf000182_0002
Example 64
Preparation of Compound 175
Figure imgf000182_0001
175
Step 1 - Synthesis of 6-(3-chloropropylsulfonamido)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide
Figure imgf000183_0001
To a solution of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2C12 (2 mL) was added 3-chloropropane-l-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0 °C. The reaction mixture was stirred at 12 °C for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
Step 2 - Synthesis of 6-(l ', l-dioxidoisothiazolidin-2-yl)-5-(l l-fluoro-6H- pyridof 2 ', 3 ':5, 6][ 1, 3 Joxazino f 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (Compound 175)
Figure imgf000183_0002
A solution of 6-(3-chloropropylsulfonamido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (90 mg, 0.15 mmol) and K2C03 (63 mg, 0.45 mmol) in CH3CN (3 mL) was refluxed for 16 hours. The reaction mixture was added water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provide compound 175 (20 mg, yield: 20%). 1H- MR (CDC13, 400 MHz) δ 7.98 (s, 1H), 7.89-7.92 (m, 2H), 7.83 (s, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.39 (d, J= 8.8 Hz, 1H), 7.10-7.19 (m, 4H), 7.04-7.06 (m, 1H), 6.76-6.81 (m, 1H), 5.93 (s, 2H), 5.88-5.90 (br s, 1H), 3.63-3.66 (m, 2H), 3.07-3.11 (m, 2H), 2.93 (d, J= 4.8 Hz, 3H), 2.25-2.29 (m, 2H). MS (M+H)+: 627. Example 65
Preparation of Compound 176
Figure imgf000184_0001
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (50 mg, 0.08 mmol), azetidin-2- one (17 mg, 0.23 mmol) and K2C03 (22 mg, 0.16 mmol) in 1 mL of 1,4-dioxane was added Cul (10 mg) and N,N -dimethylcyclohexane-l,2-diamine (10 mg) in seal tube. The mixture was heated at 100 °C for 10 hours, concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated to provide compound 176 (10 mg, yield: 22%) through the prep-TLC. 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.89 (d, J = 5.6 Hz, 2H), 7.79 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.17-7.10 (m, 3H), 7.05 (d, J = 8 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 5.94 (s, 2H), 5.85 (d, J = 4.0 Hz, 1H), 3.25 (t, J = 4.4 Hz, 2H), 2.92 (d, J = 4.8 Hz, 3H), 2.89 ((t, J = 4.4 Hz, 2H). MS (M+H)+: 577.
Example 66
Preparation of Compound 177
Figure imgf000184_0002
177 Step 1 - Synthesis of 6-(3-(2-chloroethyl)ureido)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide
Figure imgf000185_0001
To a solution of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg, 0.19 mmol) in THF, l-chloro-2-isocyanatoethane (60 mg, 0.57 mmol) was added at 80 °C. Then the reaction mixture was stirred at room temperature overnight. The mixture was extracted with EtOAc, washed with brine, dried and concentrated to provde 6-(3-(2-chloroethyl)ureido)-5-(l 1-fluoro- 6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (80 mg, yield: 66.5%) without further purification. MS (M+H)+: 628.
Step 2 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] ' [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(2-oxoimidazolidin-l-yl)benzofuran-3-carboxamide
Figure imgf000185_0002
To a solution of 6-(3-(2-chloroethyl)ureido)-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (80 mg, 0.13 mmol) in CH3CN (2 mL), K2CO3 (50 mg, 0.36 mmol) was stirred reflux overnight. The reaction mixture was concentrated in vacuo. The resulting residue was suspended with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The crude product was purified using PTLC (eluted with
dichloromethane : MeOH = 50 : 1) to provide compound 177 (20 mg, yield: 26.6%). 1H- MR (DMSO- e, 400 MHz) δ 8.56 (d, J= 4.8 Hz, 1H), 8.02 (dd, J = 8.8Hz, J2 = 5.6 Hz, 2H), 7.81 (s, 1H), 7.77 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.57 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.41 (t, J= 8.8 Hz, 2H), 7.23-7.28 (m, 1H), 7.10 (s, 1H), 6.94 (dd, Ji = J2 = 8.0 Hz, 1H), 6.54 (s, 1H), 6.25 (s, 2H), 3.84 (t, J= 8.4 Hz, 2H), 3.32 (t, J= 8.4 Hz, 2H), 2.83 (s, 3H). MS (M+H)+: 592.
Example 67
Preparation of Compound 178
Figure imgf000186_0001
Step 1 - Synthesis of l-(2-chloroethyl)-3-methylurea
<_ CH3NH2 I!
H H
To a solution of l-chloro-2-isocyanatoethane (5 g, 47 mmol) in THF (120 mL) was added 2M CH3 H2 (38 mL) in THF at 0 °C. The reaction mixture was stirred at room temperature overnight, concentrated in vacuo to provide l-(2-chloroethyl)-3-methylurea (6 g, yield: 92%) and used to the next step without purified. 1H- MR (CDC13, 400 MHz) δ 5.48 (s, 1H), 5.21 (s, 1H), 3.56-3.59 (m, 2H), 3.47-3.52 (m, 2H), 2.74 (s, 3H). MS (M+H)+: 137.
Step 2 - Synthesis of l-methylimidazolidin-2-one
?\ NaH ""NH
-NAN^CI
H H / 0
To a solution of l-(2-chloroethyl)-3-methylurea (3 g, 22 mmol) was dissolved in THF (80 mL) and to the resulting solution was added NaH (2.2 g, 55 mmol). The reaction mixture was stirred at room temperature under N2 for 18 hours, quenched with MeOH, filtrated, the filtrate was dried with Na2S04, concentrated in vacuo to provide l-methylimidazolidin-2-one (1.5 g, yield: 68%). MS (M+H)+: 101.
Step 3 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(3-methyl-2-oxoimidazolidin-l-yl)benzofuran-3-carboxamide
(Compound 178)
Figure imgf000187_0001
178
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (200 mg, 0.3 mmol), 1- methylimidazolidin-2-one (63 mg, 0.6 mmol) and CS2CO3 (206 mg, 0.6 mmol) in 1, 4-dioxane (5 mL) was added (lR,2R)-N1,N2-dimethylcyclohexane-l,2-diamine (20 mg) and Cul (20 mg) under nitrogen. The reaction mixture was heated at 100 °C overnight in seal tube, concentrated in vacuo to remove 1, 4-dioxane and purified to provide compound 178 (20 mg, yield: 10%) through the prep-HPLC. 1H- MR (CDC13, 400 MHz) δ 7.90-7.95 (m, 3H), 7.49 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.04-7.14 (m, 4H), 7.76-7.81 (m, 1H), 6.76-6.81 (m, 1H), 5.91 (s, 2H), 5.85 (brs, 1H), 3.62-3.66 (m, 2H), 3.26-3.30 (m, 2H), 2.94 (d, J = 4.8 Hz, 3H), 2.68 (s, 3H). MS (M+H)+: 606.
Example 68
Preparation of Compound 179
Figure imgf000187_0002
Step 1 - Synthesis of 6-(3-(2-chloroacetyl)ureido)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide
Figure imgf000187_0003
To a solution of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.38 mmol) in THF (15 mL) was added a solution of 2-chloroacetyl isocyanate (100 mg, 0.78 mmol) in THF (1 mL) dropwise under nitrogen. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the resulting residue was obtained 6-(3-(2- chloroacetyl)ureido)-5 -( 11 -fluoro-6H-pyrido [2*, 3 * : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (203 mg, yield: 81 %) without further purification. MS (M+H)+: 642.
Step 2 - Synthesis of 6-(2,4-dioxoimidazolidin-l-yl)-5-(ll-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (Compound 179)
Figure imgf000188_0001
To a solution of 6-(3-(2-chloroacetyl)ureido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (140 mg, 0.22 mmol) in DMF (10 mL) was added NaH (26 mg, 0.65 mmol) at 0 °C The mixture was stirred at 0 °C for 30 minutes. The reaction was quenched with saturated aqueous NH4C1, and the solvent was removed under reduced pressure. The resulting residue was diluted with water and extracted CH2C12 / MeOH (10 : 1). The organic layers were washed with brine, dried over Na2S04, and concentrated to provide the crude. The crude was purified using prep-HPLC to obtained compound 179 (65 mg yield: 50%). 1H-NMR (CDC13, 400 MHz) δ 8.08 (s, 1H), 7.95 (t, J = 7.2 Hz, 2H), 7.63 (s, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.20 (s, 1H), 7.07 (d, J = 6.4 Hz, 2H), 6.84 (t, J = 8.8 Hz, 1H), 6.55 (d, J = 4.4 Hz, 1H), 5.92 (s, 2H), 4.32 (s, 2H), 3.00 (d, J = 4.8 Hz, 3H). MS (M+H)+: 606.
Example 69
Preparation of Compound 180
Figure imgf000188_0002
Figure imgf000189_0001
To a degassed solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3] oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (150 mg, 0.24 mmol) and Zn(CN)2 (28 mg, 0.24 mmol) in DMSO (3.0 mL) were added Pd(PPh3)4 (20 mg) under N2. The mixture was heated at 100 °C for 3 hours. The reaction mixture was cooled to room temperature and added water. Then the suspension was filtered, the collection was purified using the prep-HPLC to provide compound 180 (50 mg, yield: 40% ). 1H- MR (DMSO, 400 MHz) δ 8.60 (s, 1H), 8.42 (s, 1H), 8.10 (s, 1H), 8.00 (t, J = 4.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (s, 1H), 6.91 (t, J = 8.8 Hz, 1H), 6.27 (s, 2H). 2.82 (s, 3H). MS (M+H)+: 533.
Example 70
Preparation of Compound 181
Figure imgf000189_0002
A solution of 6-cyano-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol- 2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.09 mmol) and Raney-Ni (10 mg) in dichloromethane / MeOH (10 mL, V / V= 3 : 1) was hydrogenated at room
temperature under hydrogen for 10 hours. After filtered, the filtrate was concentrated to provide the crude product. The crude product was purified using the prep-HPLC to provide compound 181 (10 mg, yield: 20%). 1H-NMR (DMSO, 400 MHz) δ 8.55 (d, J = 5.2 Hz, 1H), 8.04 (t, J = 7.6 Hz, 2H), 7.99 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H), 7.31 (s, 1H), 7.29 (m, 1H), 6.95 (t, J = 8.8 Hz, 1H), 6.29 (s, 2H), 4.18 (s, 2H), 2.85 (d, J = 4.4 Hz, 3H). MS (M+H)+: 537.
Example 71
Preparation of Compound 182
Figure imgf000190_0001
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino [3,4-a]indol-2-yl)-
2-(4-fluorophenyl)-6-iodo-N-methylbenzofuran-3-carboxamide (100 mg, 0.15 mmol) and Et3N (36 mg, 0.36 mmol) in DMSO (5 mL) and MeOH (2 mL) was added Pd(dppf)Cl2 (10 mg). The reaction mixture was stirred under CO atmosphere (30 psi) at 80 °C for 10 hours, concentrated and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated to provide the compound 182 (30 mg, yield: 36%) through the prep-
HPLC. 1H- MR (DMSO, 400 MHz) δ 8.56 (d, J= 4.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.93 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 6.97 (s, 1H), 6.92 (t, J = 8.8 Hz, 1H), 6.24 (s, 2H), 5.73 (s, 1H), 3.58 (s, 3H), 2.83 (d, J = 4.5 Hz, 3H). MS (M+H)+: 566.
Example 72
Preparation of Compound 183
Figure imgf000190_0002
183 Step 1 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-carboxylic acid
Figure imgf000191_0001
182
The procedure of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-
2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-carboxylic acid (30 mg, yield: 45%) was similar to step 1 of Example 38. MS (M+H)+: 552.
Step 2 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N3-methylbenzofuran-3, 6-dicarboxamide (Compound 183)
Figure imgf000191_0002
183
To a degassed solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-carboxylic acid (50 mg, 0.09 mmol), EDCI (25 mg, 0.13 mmol), HOBT (20 mg, 0.13 mmol), H4C1 (24 mg, 0.45 mmol) and Et3N (45 mg, 0.45 mmol) in THF (3 mL) was stirred at room temperature for 2 hours under N2. The reaction mixture was extracted with EtOAc and washed with water, brine and dried over Na2S04. After concentrated, the crude product was purified using prep-HPLC to provide compound 183 (20 mg, yield: 40%). 1H- MR (DMSO, 400 MHz) δ 8.50 (d, J = 5.2 Hz, 1H), 7.98-7.99 (m, 2H), 7.92 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 7.18-7.21 (m, 1H), 7.05 (s, 1H), 6.89 (t, J = 9.2 Hz, 1H), 6.20 (s, 2H), 2.80 (d, J = 4.8 Hz, 3H). MS (M+H)+: 551.
Example 73
Preparation of Compound 184
Figure imgf000192_0001
184
Step 1 - Synthesis of 2,2-difluoroethyl 4-methylbenzenesulfonate
F OH F OTS
To a solution of compound 2,2-difluoroethanol (1 g, 12.2 mmol) in CH2C12 (15 mL) was added TsCI (3.5 g, 18.3 mmol) at 0 °C. The mixture was stirred at room temperature overnight. Then aqueous HCl was added to the mixture to adjusted the mixture to pH<7 and the mixture was separated. The aqueous phase was extracted with EtOAc and the combined organic phases was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether : EtOAc = 15 : 1) to provde 2,2-difluoroethyl 4-methylbenzenesulfonate. (2.5 g, yield: 86.8%). 1H- MR (CDC13, 400 MHz) δ 7.78 (d, J= 8.0 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 5.75- 6.04 (m, 1H), 4.10-4.18 (m, 2H), 2.44 (s, 3H). MS (M+H)+: 267. Step 2 - Synthesis of 5-bromo-6-(N-(2, 2-difluoroethyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofura -3-carboxamide
Figure imgf000192_0002
A mixture of compound 2,2-difluoroethyl 4-methylbenzenesulfonate (0.3 g, 1.25 mmol), 5-bromo-6-(N-(2,2-difluoroethyl)methylsulfonamido)-2- (4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (0.55 g, 1.25 mmol), K2C03 (0.35 g, 2.5 mmol) and KI (0.25 g, 0.15 mmol) in DMF (10 mL) was stirred at 80 °C under reflux for 2 hours. The mixture was concentrated in vacuo and the resulting residue was washed by H20 and filtered to provde 5- bromo-6-(N-(2,2-difluoroethyl) methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (440 mg, yield: 70.2%). 1H- MR (CDC13, 400 MHz) δ 8.18 (s, 1H), 7.86-7.89 (m, 2H), 7.66-7.72 (m, 1H), 7.18-7.22 (m, 2H), 5.92-6.23 (m, 1H), 5.78 (s, 1H), 4.12-4.32 (m, 1H), 3.71-3.89 (m, 1H), 3.09 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H). MS (M+H)+: 505 / 507.
Step 3 - Synthesis of 6-(N-(2,2-difluoroethyl)methylsulfonamido)-2-(4-fluorop
(4,4, 5, 5-tetrameth -l, 3, 2-dioxaborolan-2-yl) benzofuran-3-carboxamide
Figure imgf000193_0001
To a solution of 5-bromo-6-(N-(2,2-difluoroethyl)methylsulfonamido)-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (2 g, 4 mmol), (Bpin)2 (3 g, 6 mmol) and KOAc (1.2 g, 6 mmol) in dioxane / H20 (100 / 10 mL) was added Pd(dppf)Cl2 (0.4 g, 0.3 mmol) under N2. The mixture was stirred at 80 °C under reflux for 4 hours. Then it was filtered and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ether : EtOAc = 4 : 1) to provde 6-(N-(2,2-difluoroethyl)methylsulfonamido)-2-(4- fluorophenyl)-N-methyl-5-(4,4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (1.63 g, yield: 74.0%). 1H- MR (CDC13, 400 MHz) δ 8.32 (s, 1H), 7.93 (m, 2H), 7.60 (s, 1H), 7.17 (t, J= 8.4 Hz, 2H), 5.92-5.98 (m, 1H), 4.20-4.31 (m, 1H), 3.77 (br s, 1H), 3.02 (d, J= 4.8 Hz, 3H), 2.98 (s, 3H), 1.36 (s, 12H). MS (M+H)+: 553.
Step 4 - Synthesis of 6-(N-(2,2-difluoroethyl)methylsulfonamido)-5-(l l-fluoro-6H- pyridof 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide Compound 184)
Figure imgf000193_0002
The procedure of Compound 184 (150 mg, yield: 62.5%) was similar to step 6 of Example 1. 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.91-7.95 (m, 2H), 7.73 (s, 1H), 7.50 (s, 2H), 7.16-7.23 (m, 4H), 7.09-7.11 (m, 1H), 6.82-6.86 (m, 1H), 5.86- 6.23 (m, 4H), 4.05-4.16 (m, 2H), 2.97 (d, J = 4.8 Hz, 3H), 2.86 (s, 3H). MS (M+H)+: 665.
Compounds 185-204, depicted in the table below, were prepared using the method described above and substituting the appropriate reactants and/or reagents. For some compounds, such as Compound 204, mesylation and alkylation were conducted as the last two steps using compound 163.
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Example 74
Preparation of Compound 205
Figure imgf000199_0002
205
Step 1 - Synthesis of 5-bromo-6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methylbenzofuran- -carboxamide
Figure imgf000199_0003
A solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (0.55 g, 1.25 mmol), l-chloro-4-
(chloromethyl)benzene (0.24 g, 1.5 mmol), K2C03 (0.35 g, 2.5 mmol) and KI (0.25 g, 0.15 mmol) in DMF (10 mL) was stirred at 80 °C for 2 hours. The mixture was concentrated in vacuo and the resulting residue was washed by H20 and filtered to provde the white solid 5-bromo-6-(N-(4- chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide without further purification. 1H- MR (CDC13, 400 MHz) δ 8.14 (s, 1H), 7.81-7.84 (m, 2H), 7.15-7.25 (m, 7H), 5.79 (br s, 1H), 5.15 (d, J= 7.4 Hz, 1H), 4.55 (d, J= 7.4 Hz, 1H), 3.10 (s, 3H), 2.96 (d, J= 4.8 Hz, 3H). MS (M+H)+: 565 / 567.
Step 2 - Synthesis of 6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5- (4,4, 5, 5 -tetramethyl- 1 ' , 3, 2-dioxaborolan-2-yl) benzofuran-3-carboxamide
Figure imgf000200_0001
To a solution of 5-bromo-6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4- fluorophenyl)-N-methylbenzofuran-3-carboxamide (0.71 g, 1.25 mmol), (Bpin)2 (0.95 g, 3.75 mmol) and KOAc (0.37 g, 3.75 mmol) in dioxane / H20 (25 mL / 3 mL) was added Pd(dppf)Cl2 (0.14 g, 0.19 mmol) under N2. The mixture was stirred at 100 °C under reflux for 8 hours. Then it was filtered and extracted with EtOAc. The combined organic phases was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ether :EtO Ac = 4: 1) to provde 6-(N-(4- chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide. 1H- MR (CDC13, 400 MHz) δ 8.27 (s, 1H), 7.85-7.88 (m, 2H), 7.19 (br s, 5H), 7.13 (t, J= 8.0 Hz, 2H), 5.95 (s, 1H), 4.81-5.08 (m, 2H), 2.97-2.99 (m, 6H), 1.39 (s, 12H). MS (M+H)+: 613.
Step 3 - Synthesis of 6-(N-(4-chlorobenzyl)methylsulfonamido)-5-(l l-fluoro-6H- pyrido[ 2 ', 3 ':5, 6][ 1, 3 Joxazinof 3, 4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide
Figure imgf000200_0002
To a solution of 6-(N-(4-chlorobenzyl)methylsulfonamido)-2-(4-fluorophenyl)-N- methyl-5-(4,4,5,54etramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (0.15 g, 0.25 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (0.09 g, 0.33 mmol) and Κ3Ρ04·3Η20 (0.15 g, 0.56 mmol) in dioxane / H20 (6 mL / 12 drops) was added Pd2(dba)3 (12 mg, 0.013 mmol) and X-Phos (12 mg, 0.026 mmol) under N2. The mixture was stirred at 100 °C under reflux for 2 hours. Then it was filtered and extracted with EtOAc. The combined organic phases was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ethenEtOAc = 2: 1) to provde 6-(N-(4-chlorobenzyl)methylsulfonamido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 Joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide. 1H- MR (CDC13, 400 MHz) δ 7.90 (s, 1H), 7.82-7.86 (m, 2H), 7.39 (s, 2H), 7.04-7.19 (m, 10H), 6.76-6.80 (m, 1H), 5.95 (s, 2H), 5.86 (s, 1H), 4.66-4.78 (m, 2H), 2.89 (d, J = 4.0 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 725.
Step 4 - Synthesis of 5-(l l-fluoro-6H-pyrido[2',3':5, 6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) benzyl)methylsulfonamido)benzofuran-3-carboxamide
Figure imgf000201_0001
To a solution of 6-(N-(4-chlorobenzyl)methylsulfonamido)-5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 joxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (0.12 g, 0.17 mmol), (Bpin)2 (0.11 g, 0.42 mmol) and KOAc (0.049 g, 0.5 mmol) in dioxane / H20 (6 mL / 12 d) was added Pd2(dba)3 (0.016 g, 0.02 mmol) and X-Phos (0.016 g, 0.03 mmol) under N2. The mixture was stirred at 110 °C under reflux for 2 hours. Then it was filtered and extracted with EtOAc. The combined organic phases was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using flash gel chromatography (petroleum ethenEtOAc = 1 : 1) to provde 5-(l l-fluoro-6H- pyrido[2^3^5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide. 1H- MR (CDC13, 400 MHz) δ 7.91-7.96 (m, 3H), 7.66-7.68 (m, 2H), 7.46-7.47 (m, 2H), 7.27 (s, 1H), 7.15-7.21 (m, 6H), 7.09-7.11 (m, 1H),6.77~6.87 (m, 1H), 6.01 (s, 2H), 5.89 (s, 1H), 4.67-4.88 (m, 2H), 2.97 (d, J= 4.0 Hz, 3H), 2.81 (s, 3H), 1.28 (s, 12H). MS (M+H)+: 817.
Step 5 - Synthesis of (4-((N-(5-(l l-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2- (4fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)methyl) phenyl) boronic acid (Compound 205)
Figure imgf000202_0001
A solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2- (4-fluorophenyl)-N-methyl-6-(N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)methylsulfonamido)benzofuran-3-carboxamide (0.12 g, 0.15 mmol) and NaI04 (0.16 g, 0.74 mmol) in THF / H20 (12 mL / 4 mL) was stirred at room temperature for 24 hours. The mixture was filtered and extracted by EtOAc. The combined organic phases was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-HPLC to provde Compound 205. 1H- MR (Methanol-^, 400 MHz) δ 8.00 (s, 2H), 7.77-7.79 (m, 2H), 7.53-7.66 (m, 1H), 7.51-7.52 (m, 1H), 7.22-7.44 (m, 6H), 7.11-7.14 (m,
1H), 6.99-7.01 (m, 1H), 6.91-6.93 (m, 1H), 6.82-6.86 (m, 1H), 6.14 (s, 2H), 4.84-4.86 (m, 1H), 4.50-4.58 (m, 1H), 3.17-3.20 (m, 3H), 2.93 (s, 3H). MS (M+H)+: 735.
Figure imgf000202_0002
A mixture of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.814 mmol) and ethyl glyoxalate (323 μΐ, 1.627 mmol) was heated at 1 15°C for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature, concentrated under vacuum then applied onto 2-EP column (30mm x 250mm) eluted with 30% IPA/C02. This resulted in 108 mg (18.5 %) of ethyl 2-(l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3^5,6][l,3]oxazino[3,4-a]indol-12-yl)- 2-hydroxyacetate (Compound 206) as a white solid. LC-MS (ES, m/z) C36H3oF2N408S: 716; Found: 717 [M+H]+.
Example 76
Preparation of Compound 207
Figure imgf000203_0001
207
A mixture of ethyl 2-(l l-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N- methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2',3^5,6][l,3]oxazino[3,4-a]indol-12-yl)
2- hydroxyacetate (233 mg, 0.325 mmol) and lithium hydroxide (54.5 mg, 2.276 mmol) in THF (1 ml), water (0.5 ml) and MeOH (0.5 ml) was stirred at romm temperature over night, then concentrated under vacuum. The resulting residue was purified using EP column (30mm x 250mm), 60% IPA/C02. This resulted in 128 mg (57.2 %) of 2-(l l-fluoro-2-(2-(4-fluorophenyl)
3- (methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H- pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetic acid (Compound 207) as a white solid. LC-MS (ES, m/z) C34H26F2N408S : 688; Found: 689 [M+H]+.
Example 77
Preparation of Compound 208
Figure imgf000204_0001
208
To a solution of 5-(l l-fluoro-6H-pyrido[2*,3*:5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.163 mmol) in THF (2 mL) at -78°C under N2 added n-butyllithium (0.203 ml, 0.325 mmol). After 10 mins, ethyl chloroformate (61.8 mg, 0.569 mmol) was added to the reaction mixture. And the reaction mixture was warmed to room temperature and stirred overnight under N2. The reaction mixture was quenched with 5 ml water extracted with 3x10 mL ethyl acetate. The organic layers were combined, washed with 2x5 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum. . Silica gel chromatography eluted with ethyl acetate/hexane (20-100%) resulted in 38 mg (34 %) of Ethyl (5-(l l-fluoro-6H-pyrido[2',3':5,6] [l,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran- 3-carbonyl)(methyl)carbamate (Compound 208) as a white solid. LC-MS (ES, m/z)
C35H28F2N407S : 686; Found: 687 [M+H]+.
Example 78
Preparation of Compound 209
Figure imgf000204_0002
209
A mixture of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2- (4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (260 mg, 0.423 mmol) and methyl oxalyl chloride (311 mg, 2.54 mmol) in CC14 (6 ml) was heated under reflux for 5 hours. The reaction was concentrated under vacuum. The resulting residue was purified using silica gel column eluted with ethyl acetate/hexane 20-100%. This resulted in 58 mg (17.6 %) of methyl 2-(5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamido)-2- oxoacetate (Compound 209) as a white solid. LC-MS (ES, m/z) C35H26F2N4O8S : 700; Found: 701 [M+H]+.
Example 79
Preparation of Compound 210
Figure imgf000205_0001
Figure imgf000205_0002
To a solution of 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indol-2-yl)- 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, 0.81 mmol) in dichloromethane (2 ml) was added acetyl chloride (174 μΐ, 2.44 mmol) and ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (495 μΐ, 2.44 mmol). The resulting mixture was stirred at room temperature overnight. Concentrated in vacuo and added Et3N (5 ml) Silica gel chromatography (eluted with 0-5% MeOH / dichloromethane) to provide N-acetyl-5- ( 11 -fluoro-6H-pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6- (N-methylmethylsulfonamido)benzofuran-3-carboxamide (500 mg, yield: 94%) MS (M+H)+: 657.
Example 80
Preparation of Compound 211
Figure imgf000206_0001
211
Step 1 - Synthesis of 5-(l l-fluoro-6H-pyrido[2 3 ':5 , 6) '[1 ,3]oxazino[3 ' ,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide
Figure imgf000206_0002
To a mixture of 6-amino-5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1000 mg, 1.914 mmol) and pyridine (1.548 mL, 19.14 mmol) in dichloromethane (30 mL), methylsulfonyl chloride (0.741 mL, 9.57 mmol) was added dropwise at 0 °C. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was quenched with NaHC03 and 20 mL dichloromethane was added. Solid crushed out, the mixture was filtered and washed with water. The crude solid was dried under vaccum and gave the crude product 5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6- (methylsulfonamido)benzofuran-3-carboxamide (1 100 mg, 96 % yield).
Step 2 - Synthesis of gave 5-(l l-fluoro-6H-pyrido[2 ',3 ': 5, 6) '[1 ,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-(2-morpholinoethyl)methylsulfonamido)benzofuran-3-carboxam
Figure imgf000206_0003
To a microwave tube was added 5-(l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.167 mmol), 4-(2-iodoethyl)morpholin-4-ium chloride (139 mg, 0.500 mmol), K2C03 (57.5 mg, 0.416 mmol) and DMF (4 mL). The mixture was heated at 150 °C for lh. The reaction was cooled down and the DMF solution was loaded to the CI 8 column directly through a filter, and purified using ISCO (0 to 100% water/acetonitrile) and gave 5-(l l-fluoro-6H- pyrido [2*, 3 * : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-(2- morpholinoethyl)methylsulfonamido)benzofuran-3-carboxamide (Compound 211, 25 mg, 21% yield). MS (M+H)+: 714.
Example 81
Preparation of Compound 2
Figure imgf000207_0001
Synthesis of ethyl 3- 4-fluorophenyl)-3-oxopropanoate
Figure imgf000207_0002
Diethyl carbonate (130 g, 1.1 mol) was dissolved in a suspension ofNaH (60% in oil, 50.2 g, 1.3 mol) in anhydrous tetrahydrofuran (1.5 L), and then l-(4-fluorophenyl)ethanone (150 g, 1.09 mol) was added dropwise at 70 °C. The resulting mixture was stirred at 70 °C for 3 hours. After the reaction mixture was cooled to room temperature and poured into HCl (1 N). The mixture was extracted with EtOAc, the organic phase was dried with anhydrous NaS04 and concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with petroleum ether / EtOAc = 50 / 1) to provide ethyl 3-(4-fluorophenyl)-3-oxopropanoate (217 g, yield: 95%). 1H-NMR (CDC13, 400 MHz) δ 7.92-7.97 (m, 2H), 7.07-7.13 (m, 2H), 4.14-4.20 (m, 2H), 3.93 (s, 2H), 1.22 (d, J= 7.2 Hz, 3H). MS (M+H)+: 211. Step 2 - Synthesis of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate
Figure imgf000207_0003
A solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (130 g, 0.6 mol), 4- bromophenol (311 g, 1.8 mol) and FeCl3-6H20 (19.5 g, 0.09 mol) in DCE (700 mL) was heated to reflux, and then 2-(tert-butylperoxy)-2-methylpropane (193 g, 1.32 mol) was added dropwise under nitrogen. After 6 hours of refluxing, the mixture was cooled to RT, quenched with saturated NaHS03 and extracted with dichloromethane. The organic phases were washed with water, brine and dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / dichloromethane = 15 / 1) to provide the crude product, which was crystallized from cold MeOH to provde ethyl 5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (37 g, yield: 14.3%) as solid. 1H- MR (CDC13, 400 MHz) δ 8.12 (s, 1H), 7.97-8.01 (m, 2H), 7.37 (d, J= 4.0 Hz, 1H), 7.32 (d, J= 8.0 Hz, 1H), 7.11 (t, J= 8.0 Hz, 2H), 4.32-4.38 (m, 2H), 1.36 (t, J= 8.0 Hz, 3H). MS (M+H)+: 363 / 365.
Step 3 - Synthesis of eth l 5-bromo-2-(4-fluorophen -6-nitrobenzofuran-3-carboxylate
Figure imgf000208_0001
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (50 g,
137.6 mmol) in CHC13 (500 mL), fuming HN03 (50 mL) was added dropwise at -15 °C and the mixture was stirred for 0.5 hour. The reaction mixture was poured into ice water and extracted with CH2C12. The organic layer was washed with a.q. sat. NaHC03 and brine, after removed the most of solvent, the resulting residue was crystallized with petroleum ether / dichloromethane = 20 / 1 to provide product of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (35 g, yield: 66%). 1H- MR (CDC13, 400 MHz) δ 8.36 (s, 1H), 8.02-8.04 (m, 3H), 7.13-7.18 (m, 2H), 4.36-4.41 (m, 2H), 1.37 (t, J= 4.0 Hz, 3H). MS (M+H)+: 408 / 410.
Step 4 - Synthesis of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate
Figure imgf000208_0002
A mixture of ethyl 5-bromo-2-(4-fluorophenyl)-6-nitrobenzofuran-3-carboxylate (52 g, 127 mmol), iron filings (21.3 g, 382.2 mmol) and H4C1 (41 g, 764.4 mmol) in MeOH / THF / H20 (2 / 2 / 1, 500 mL) was stirred at reflux for 3 hour. After filtered and concentrated, the resulting residue was purified using column chromatography (petroleum ether / EtOAc / dichloromethane = 20 : 1 : 20) to provide ethyl 6-amino-5-bromo-2-(4-fluorophenyl) benzofuran-3-carboxylate (40 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.01 (s, 1H), 7.94-7.98 (m, 2H), 7.08 (t, J= 8.0 Hz, 2H), 6.83 (s, 1H), 4.32-4.36 (m, 2H), 4.18 (s, 2H), 1.35 (t, J= 8.0 Hz, 3H). MS (M+H)+: 378 / 380.
Step 5 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid eth l ester
Figure imgf000209_0001
MsCI (31.7 g, 277.5 mmol) was added to a solution of ethyl 6-amino-5-bromo-2- (4-fluorophenyl)benzofuran-3-carboxylate (35 g, 92.5 mmol) and pyridine (60 mL) in
dichloromethane (300 mL) at 0 °C. After stirred overnight at room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo, the resulting residue was purified using crystallized with EtOAc to provde the pure product of ethyl 5-bromo-2-(4-fluorophenyl)-6- (methylsulfonamido)benzofuran-3-carboxylate (35 g, yield: 82%). 1H- MR (CDC13, 400 MHz) δ 8.27 (s, 1H), 8.01-8.05 (m, 2H), 7.87 (s, 1H), 7.15-7.19 (m, 2H), 6.87 (s, 1H), 4.38-4.43 (m, 2H), 3.00 (s, 3H), 1.40 (t, J= 40 Hz, 3H). MS (M+H)+: 456 / 458.
Step 6 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid
Figure imgf000209_0002
To a solution of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3-carboxylate (53 g, 0.23 mol) in dioxane / H20 (5 / 1, 600 mL) was added
LiOH-H20 (25 g, 1.17 mol), and the mixture was stirred at 100 °C for 3 hours. After
concentrated, the resulting residue was dissolved in H20, 1 N HCl was added until pH reached 3, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solvent was removed to provide the product of 5-bromo-2-(4- fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (48 g, yield: 96%). 1H- MR (DMSO- e, 400 MHz) δ 13.49 (s, 1H), 9.67 (s, 1H), 8.30 (s, 1H), 8.12-8.17 (m, 2H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H). MS (M+H)+: 428 / 430. Step 7 - Synthesis of 5-Bromo-2-(4-fluoro-phenyl)-6-methanesulfonylamino-benzofuran-3- carboxylic acid methylamide
Figure imgf000210_0001
A solution of 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido) benzofuran-3- carboxylic acid (33 g, 77 mmol), HOBT (15.6 g, 115.5 mmol) and EDCI (22.2 g, 115.5 mmol) in DMF (250 mL) was stirred at room temperature. After 2 hours, Et3N (50 mL) and CH3 H2 (HC1 salt, 17.7 g, 231 mmol) was added to the mixture, and the mixture was stirred overnight. After the solvent was removed, H20 was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with H20, brine and concentrated in vacuo. The resulting residue was washed with EtOAc to provide the product of 5-bromo-2-(4-fluorophenyl)-N- methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, yield: 94%). 1H- MR (DMSO- ck, 400 MHz) δ 9.55 (br s, 1H), 8.46-8.48 (m, 1H), 8.12-8.17 (m, 2H), 7.96 (s, 1H), 7.87 (s, 1H), 7.45-7.50 (m, 2H), 3.16 (s, 3H), 2.93 (d, J= 8.4 Hz, 3H). MS (M+H)+: 441 / 443.
Step 8 - Synthesis of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido benzofuran-3-carboxamide
Figure imgf000210_0002
CH3I (31.6 g, 223 mmol) was added to a mixture of 5-bromo-2-(4-fluorophenyl)- N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (32 g, 74 mmol), K2C03 (25.6 g, 186 mmol) and KI (246 mg, 1.5 mmol) in DMF (150 mL) under N2 protection. The mixture was stirred at 80-90 °C overnight. After concentrated in vacuo, the resulting residue was washed with water (200 mL) and EtOAc (200 mL) to provide the product of 5-bromo-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (31.5 g, 94%). 1H- MR (CDCI3, 400 MHz) δ 8.16 (s, 1H), 7.88-7.92 (m, 2H), 7.70 (s, 1H), 7.18-7.23 (m, 2H), 5.78 (br s, 1H), 3.34 (s, 3H), 3.09 (s, 3H), 3.00 (d, J= 4.8 Hz, 3H). MS (M+H)+: 455 / 457. Step 9 - Synthesis of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4, 4, 5, 5- tetramethyl-1 -dioxaborolan-2-yl)benzofuran-3-carboxamide
Figure imgf000211_0001
a degassed solution of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (1.0 g, 2.2 mmol) and pinacol diborane (2.79 g, 11.0 mmol) in 1,4-Dioxane (25 mL) was added KOAc (647 mg, 6.6 mmol) under N2 and stirred for 4 hours at room temperature. Then Pd(dppf)Cl2 (60 mg) was added, and the mixture was stirred for another 30 minutes. Then the mixture was put into a pre-heated oil-bath at 130 °C and stirred for another 1 hour under N2. The reaction mixture was cooled to room
temperatureand concentrated and extracted with EtOAc. The organic layers were washed with brine, dried over Na2S04. After concentrated, the crude product of the boronic ester was purified using column chromatography (petroleum ether / EtOAc = 5 / 1 to 2 / 1) to obtain 2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzofuran-3-carboxamide as white solid (700 mg, yield: 64%). 1H- MR (CDCI3, 400 ΜΗζ) δ 8.17 (s, 1H), 7.87-7.91 (m, 2H), 7.52 (s, 1H), 7.11 (t, 7= 7.6 Hz, 2H), 5.81 (d, 7= 2.8 Hz, 1H), 3.30 (s, 3H), 2.97 (d, 7= 5.2 Hz, 3H), 2.90 (s, 3H), 1.31 (s, 12H). MS (M+H)+: 503.
Step 10 - Synthesis of tert-butyl 4-fluoro-lH-indole-l -car boxy late
Figure imgf000211_0002
To a solution of 4-fluoro-lH-indole (5 g, 0.11 mol) and DMAP (150 mg, 3%Wt) in THF (50 mL) was added (Boc)20 (8.5 g, 0.04 mol) dropwise. The mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo, and the resulting residue was purified using column chromatography (pure petroleum ether) to provide tert-butyl 4-fluoro- lH-indole-l-carboxylate (8.3 g, yield: 96%). 1H- MR (CDC13, 400 MHz) δ 7.92 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 3.6 Hz, 1H), 7.23 (m, 1H), 6.90 (m, 1H), 6.66 (d, J= 3.6 Hz, 1H), 1.67 (s, 9H). MS (M+H)+: 236.
Step 11 - Synthesis of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid
Figure imgf000212_0001
To a solution of diisopropylamine (7.5 mL, 0.11 mol) in THF (35 mL) at 0 °C was added «-BuLi (21 mL, 0.055 mol) dropwise. The mixture was stirred at 0 °C for 40 minutes. Then the mixture was cooled to -78 °C. Tert-butyl 4-fluoro-lH-indole-l-carboxylate (5 g, 0.02 mol) in THF (13 mL) was added dropwise slowly. After addition, the mixture was stirred at -78 °C for 2 hours. Then triisopropyl borate (3.29 g, 0.03 mol) was added. The mixture was stirred at -78 °C for another 40 minutes. The reaction was monitored using TLC. When the reaction was completed, the mixture was adjusted to pH = 6 with 1 N HC1. After extracted with EtOAc (25 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The obtained solid was recrystallized with EtOAc and petroleum ether to provide (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (4.5 g, yield: 76.7%, which might be unstable at high temp, work up, store in fridge). 1H- MR (CDC13, 400 MHz) δ 7.77 (d, J= 8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Step 12 - Synthesis of 6-chloro-2-iodopyridin-3-ol
Figure imgf000212_0002
6-chloropyridin-3-ol (5.0 g, 38.6 mmol) was dissolved in water (50 mL) and placed under an N2 atmosphere. Na2C03 (8.2 g, 77.4 mmol) was added followed by iodine (9.8 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into 1M Na2S203 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04 and concentrated to provide the product of 6-chloro-2- iodopyridin-3-ol (7.0 g, yield: 70.9%). 1H- MR (CDC13, 400 MHz) δ 7.17 (d, J= 8.4 Hz, 1H), 7.06 (d, J= 8.4 Hz, 1H). MS (M+H)+: 256 / 258.
Step 13 - Synthesis of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol
Figure imgf000213_0001
A mixture of (l-(tert-butoxycarbonyl)-4-fluoro-lH-indol-2-yl)boronic acid (5 g, 18.0 mmol), 6-chloro-2-iodopyridin-3-ol (3.82 g, 15.0 mol) and NaHC03 (3.78 g, 45.0 mol) in 1, 4-dioxane (76 mL) and water (7 mL) was stirred at room temperature for 15 minutes. Then Pd(PPh3)2Cl2 (527 mg, 0.75 mmol) was added under nitrogen atmosphere, and the mixture was heated at 100 °C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), filtered and concentrated in vacuo. The resulting residue was diluted with H20 (60 mL) and EtOAc (30 mL), and the layer was separated, the aqueous layer was extracted with EtOAc (3*30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether / EtOAc = 20 / 1 ~ 3 / 1) to provide 6-chloro-2- (4-fluoro-lH-indol-2-yl)pyridin-3-ol (3 g, yield: 76.5%). 1H- MR (MeOD, 400 MHz) δ 7.36 (s, 1H), 7.23-7.27 (m, 2H), 7.03-7.11 (m, 2H), 6.63-6.68 (m, 1H). MS (M+H)+: 263 / 265.
Ste 14 - Synthesis of 2-chloro-ll-fluoro-6H-pyrido[2',3':5, 6][l,3]oxazino[3,4-a]indole
Figure imgf000213_0002
A solution of 6-chloro-2-(4-fluoro-lH-indol-2-yl)pyridin-3-ol (2 g, 7.6 mmol) and Cs2C03 (7.46 g, 22.89 mmol) in DMF (100 mL) was stirred at 100 °C (internal temperature) for 15 min, and then chloroiodomethane (2.85 g, 15.3 mmol) in DMF (2 mL) was added dropwise. After the reaction was completed, the mixture was filtered and concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EA=10: l) to provde 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4-a]indole (1.8 g, yield: 86.1%). 1H- MR (DMSO-i¾, 400 MHz) δ 7.64 (d, J= 8.8 Hz, 1H), 7.39-7.46 (m, 2H), 7.21-7.25 (m, 1H), 7.06 (s, 1H), 6.88-6.92 (m, 1H), 6.18 (s, 2H). MS (M+H)+: 275 / 277. Step 15 - Synthesis of5-(ll-fluoro-6H-pyrido[2 3':5, 6][l,3]oxazino[3,4-a]indol-2-yl)-2-(4- fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxam
Figure imgf000214_0001
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-3- carboxamide (100 mg, 0.199 mmol), 2-chloro-l l-fluoro-6H-pyrido[2',3':5,6][l,3]oxazino[3,4- a]indole (56 mg, 0.199 mmol) and Κ3Ρ04·3Η20 (159 mg, 0.597 mmol) in dioxane / H20 (0.8 mL / 0.2 mL) was added Pd2(dba)3 (9 mg, 0.01 mmol) and X-Phos (9 mg, 0.02 mmol) under N2. The mixture was heated at 80 °C for 1 hour. The mixture was then diluted with water (30 mL) and extracted with EtOAc (15 mL x 3). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether / EtOAc = 1 : 1.5) to provde the pure product of 5-(l l-fluoro-6H- pyrido [2', 3 ' : 5 , 6] [ 1 , 3 ]oxazino [3 ,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N- methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, 48.8%). 1H- MR (CDC13, 400 MHz) δ: 7.99 (s, 1H), 7.93-7.96 (m, 2H), 7.65 (s, 1H), 7.45-7.50 (m, 2H), 7.17-7.21 (m, 4H), 7.10 (d, J= 8.0 Hz, 1H), 6.81-6.85 (m, 1H), 5.98 (s, 3H), 3.35 (s, 3H), 2.98 (d, J= 4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 615.
Example 82
Measuring Compound Inhibitory Potency
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. ViROLOGiCAL METHODS 201 (2003); Steven S. Carroll et al, Inhibition of Hepatitis C Virus RNA Replication by 2 '-Modified Nucleoside Analogs, 278(14) J. BIOLOGICAL CHEMISTRY 11979 (2003). However, the underlying principles are common to all of these determinations, and are outlined below.
Stable neomycin phosphotransferase encoding replicons-harboring cell lines were used, so all cell lines were maintained under G418 selection prior to the assay. Potency was deteremined using a cell ELISA assay with an antibody to the replicons encoded NS3/4a protease. See Caterina Trozzi et al, In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor, 77(6) J. Virol. 3669
(2003). To initiate an assay, 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 formate for manual operation, or a 384-well plate format for automated assay. Replicon cells and compound were incubated for 96 hours. At the end of the assay, cells were washed free of media and compound, and the cells were then lysed. RNA was quantified indirectly through detection of replicon-encoded NS3/4A protein levels, through an ELISA-based assay with an antibody specific for NS3/4A. IC50 determinations were calculated as a percentage of a DMSO control by fitting the data to a four-parameter fit function and the data obtained is provided in the table below.
Data for selected compounds of the present invention was obtained for genotypes la and lb using this method and is provided in the table below: la lb la lb
Compound# Compound#
IC5o (nM) IC5o (nM) IC5o (nM) IC5o (nM)
1 2.4 4.8 107 1.5 0.7
2 1.6 2.7 108 14 2.4
3 2.0 3.7 109 2.0 2.1
4 0.7 1.3 110 3.0 4.8
5 1.0 2.0 111 4.5 4.3
6 1.5 2.3 112 20 23
7 2.4 1.6 113 32 29
8 1.6 2.1 114 7.3 18 9 1.1 1.9 115 8.9 19
10 1.6 2.4 116 53 9.4
11 2.1 1.8 117 74 7.5
12 1.6 1.7 118 19 4.0
13 2.0 2.2 119 17 5.1
14 3.0 6.2 120 4.3 2.1
15 9.1 9.9 121 3.0 7.5
16 2.1 2.3 122 5.1 5.2
17 4.0 3.9 123 3.4 3.6
18 9.2 5.4 124 19 4.5
19 19 21 125 5.1 3.4
20 6.7 6.9 126 2.7 1.4
21 14 13 127 3.5 1.6
22 3.5 1.9 128 2.6 0.9
23 0.9 1.2 129 1.7 2.1
24 3.0 5.1 130 3.0 3.0
25 1.0 1.8 131 79 50
26 1.1 1.2 132 4.8 7.9
27 2.9 6.1 133 2.6 3.2
28 2.1 4.5 134 4.0 2.9
29 4.8 8.0 135 2.4 2.4
30 1.0 2.1 136 3.5 2.9
31 7.2 6.5 137 44 7.9
32 5.7 19 138 62 19
33 0.9 1.2 139 1.9 1.9
34 1.4 3.3 140 7.9 5.9
35 2.5 4.7 141 2.4 2.4
36 1.7 7.1 142 4.1 4.0
37 3.4 5.9 143 15 8.0
38 3.2 5.8 144 2.9 1.9
39 2.4 1.8 145 5.3 2.7 40 2.0 2.2 146 225 37
41 2.4 5.0 147 9.0 6.9
42 3.1 4.5 148 2.8 4.6
43 2.4 3.9 149 1.2 2.2
44 2.8 2.4 150 38 30
45 9.2 11 151 4.3 5.9
46 1.5 2.1 152 14 15
47 1.2 1.8 153 2.5 4.9
48 2.2 2.6 154 2.7 2.2
49 0.6 1.7 155 7.0 17
50 15 4.6 156 2.3 2.9
51 17 33 157 7.6 11
52 1.7 2.7 158 42 24
53 8.0 7.9 159 11 22
54 69 39 160 19 16
55 57 49 161 32 54
56 13 12 162 29 18
57 11 13 163 1.1 2.2
58 13 8.7 164 1.7 1.0
59 2.5 4.2 165 27 9.7
60 69 31 166 69 27
61 6.5 11 167 21 17
62 12 3.4 168 3.3 2.8
63 92 83 169 14 5.0
64 71 44 170 54 13
65 11 19 171 12 4.7
66 49 59 172 2.2 2.1
67 9.2 10 173 8.4 2.1
68 60 19 174 13 4.7
69 57 45 175 5.3 3.1
70 71 18 176 7.9 8.8 71 13 4.5 177 4.6 4.0
72 52 9 178 133 28
73 625 36 179 32 7.4
74 15 25 180 3.0 5.3
75 2.8 2.6 181 13 14
76 4.5 5.8 182 24 23
77 10 1 1 183 2.0 7.1
78 5.7 3.5 184 8.4 6.5
79 10 1 1 185 7.9 16
80 18 15 186 4.4 7.6
81 36 22 187 7.5 9.4
82 15 1 1 188 3.8 3.7
83 15 12 189 2.9 4.4
84 26 16 190 2.8 3.8
85 13 7.7 191 1.7 2.2
86 17 12 192 4.6 7.1
87 3 3.3 193 1.3 1.7
88 2.7 2.6 194 1.9 2.3
89 1.1 0.9 195 2.1 4.1
90 5.5 2.4 196 1.8 3.6
91 3.3 7.4 197 2.6 4.4
92 4.2 6.5 198 2.0 5.6
93 4.4 6.0 199 4.7 5.9
94 2.3 5.6 200 14 22
95 3.2 5.3 201 2.6 5.5
96 4.1 5.1 202 2.8 8.8
97 2.9 4.4 203 2.9 8.9
98 3.9 6.3 204 8.1 19
99 1.9 4.6 205 14 15
100 3.3 3.6 206 15 23
101 5.8 8.7 207 3.3 2.1 102 3.9 4.3 208 42 122
103 3.3 6.9 209 0.6 2.6
104 2.4 4.8 210 2.1 4.2
105 1.4 0.9 211 6.5 12
106 5.5 2.4
Uses of the Tetracyclic Heterocycle Compounds
The Tetracyclic Heterocycle Compounds are useful in human and veterinary medicine for treating or preventing a viral infection in a patient. In one embodiment, the
Tetracyclic Heterocycle Compounds can be inhibitors of viral replication. In another
embodiment, the Tetracyclic Heterocycle Compounds can be inhibitors of HCV replication. Accordingly, the Tetracyclic Heterocycle Compounds are useful for treating viral infections, such as HCV. In accordance with the invention, the Tetracyclic Heterocycle Compounds can be administered to a patient in need of treatment or prevention of a viral infection.
Accordingly, in one embodiment, the invention provides methods for treating a viral infection in a patient comprising administering to the patient an effective amount of at least one Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof. Treatment or Prevention of a Flaviviridae Virus
The Tetracyclic Heterocycle Compounds can be useful for treating or preventing a viral infection caused by the Flaviviridae family of viruses. Examples of Flaviviridae aredengue 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.
In one embodiment, the Flaviviridae infection being treated is hepatitis C virus infection.
Treatment or Prevention of HCV Infection
The Tetracyclic Heterocycle Compounds are useful in the inhibition of HCV (e.g., HCV NS5B), 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. For example, the Tetracyclic Heterocycle 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.
In one embodiment, the hepatitis C infection is acute hepatitis C. In another embodiment, the hepatitis C infection is chronic hepatitis C.
Accordingly, in one embodiment, 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 Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof. In a specific embodiment, the amount administered is effective to treat or prevent infection by HCV in the patient. In another specific embodiment, the amount administered is effective to inhibit HCV viral replication and/or viral production in the patient.
The Tetracyclic Heterocycle Compounds are also useful in the preparation and execution of screening assays for antiviral compounds. For example the Tetracyclic Heterocycle Compounds are useful for identifying resistant HCV replicon cell lines harboring mutations within NS5A, which are excellent screening tools for more powerful antiviral compounds.
Furthermore, the Tetracyclic Heterocycle Compounds are useful in establishing or determining the binding site of other antivirals to the HCV replicase.
The 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 1^: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. Additional 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 sequenced in the NS-5 region (see Simmonds et al. Gen Virol, 75(Pt 5): 1053-1061 (1994)).
Combination Therapy In another embodiment, the present methods for treating or preventing HCV infection can further comprise the administration of one or more additional therapeutic agents which are not Tetracyclic Heterocycle Compounds.
In one embodiment, the additional therapeutic agent is an antiviral agent.
In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.
Accordingly, in one embodiment, the present invention provides methods for treating a viral infection in a patient, the method comprising administering to the patient: (i) at least one Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Tetracyclic Heterocycle
Compound, wherein the amounts administered are together effective to treat or prevent a viral infection.
When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, 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). Thus, for non-limiting illustration purposes, a
Tetracyclic Heterocycle 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).
In one embodiment, the at least one Tetracyclic Heterocycle Compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
In another embodiment, the at least one Tetracyclic Heterocycle 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.
In another embodiment, the at least one Tetracyclic Heterocycle 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.
In still another embodiment, the at least one Tetracyclic Heterocycle 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.
In one embodiment, the at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, 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.
In one embodiment, the viral infection is HCV infection.
The at least one Tetracyclic Heterocycle 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.
In one embodiment, the administration of at least one Tetracyclic Heterocycle 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.
In one embodiment, the additional therapeutic agent is a viral protease inhibitor.
In another embodiment, the additional therapeutic agent is a viral replication inhibitor.
In another embodiment, the additional therapeutic agent is an HCV NS3 protease inhibitor. In still another embodiment, the additional therapeutic agent is an HCV NS5B polymerase inhibitor.
In another embodiment, the additional therapeutic agent is a nucleoside inhibitor. In another embodiment, the additional therapeutic agent is an interferon.
In yet another embodiment, the additional therapeutic agent is an HCV replicase inhibitor.
In another embodiment, the additional therapeutic agent is an antisense agent. In another embodiment, the additional therapeutic agent is a therapeutic vaccine. In a further embodiment, the additional therapeutic agent is a virion production inhibitor.
In another embodiment, the additional therapeutic agent is an antibody therapy. In another embodiment, the additional therapeutic agent is an HCV NS2 inhibitor. In still another embodiment, the additional therapeutic agent is an HCV NS4A inhibitor.
In another embodiment, the additional therapeutic agent is an HCV NS4B inhibitor.
In another embodiment, the additional therapeutic agent is an HCV NS5A inhibitor
In yet another embodiment, the additional therapeutic agent is an HCV NS3 helicase inhibitor.
In another embodiment, the additional therapeutic agent is an HCV IRES inhibitor. In another embodiment, the additional therapeutic agent is an HCV p7 inhibitor. In a further embodiment, the additional therapeutic agent is an HCV entry inhibitor.
In another embodiment, the additional therapeutic agent is an HCV assembly inhibitor.
In one embodiment, the additional therapeutic agents comprise a viral protease inhibitor and a viral polymerase inhibitor.
In still another embodiment, the additional therapeutic agents comprise a viral protease inhibitor and an immunomodulatory agent.
In yet another embodiment, the additional therapeutic agents comprise a polymerase inhibitor and an immunomodulatory agent. In another embodiment, the additional therapeutic agents comprise a viral protease inhibitor and a nucleoside.
In another embodiment, the additional therapeutic agents comprise an immunomodulatory agent and a nucleoside.
In one embodiment, the additional therapeutic agents comprise an HCV protease inhibitor and an HCV polymerase inhibitor.
In another embodiment, the additional therapeutic agents comprise a nucleoside and an HCV NS5A inhibitor.
In another embodiment, the additional therapeutic agents comprise a viral protease inhibitor, an immunomodulatory agent and a nucleoside.
In a further embodiment, the additional therapeutic agents comprise a viral protease inhibitor, a viral polymerase inhibitor and an immunomodulatory agent.
In another embodiment, 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 (Pharmasset), RG7128 (Roche/Pharmasset), GS-7977 (Gilead), PSI-938 (Pharmasset), PSI-879 (Pharmasset), PSI-661 (Pharmasset), PF-868554/filibuvir (Pfizer), VCH-759/VX-759 (ViroChem Pharma/Vertex), HCV-371 (Wyeth/VirroPharma), HCV-796 (Wyeth/ViroPharma), IDX-184 (Idenix), IDX-375 (Idenix), NM-283 (Idenix/Novartis), GL-60667 (Genelabs), JTK-109 (Japan Tobacco), PSI-6130 (Pharmasset), R1479 (Roche), R-1626 (Roche), R-7128 (Roche), MK-0608 (Isis/Merck), INX- 8014 (Inhibitex), INX-8018 (Inhibitex), INX-189 (Inhibitex), GS 9190 (Gilead), A-848837 (Abbott), ABT-333 (Abbott), ABT-072 (Abbott), A-837093 (Abbott), BI-207127 (Boehringer- Ingelheim), BILB-1941 (Boehringer-Ingelheim), MK-3281 (Merck), VCH-222/VX-222
(ViroChem/Vertex), VCH-916 (ViroChem), VCH-716(ViroChem), GSK-71185 (Glaxo
SmithKline), ANA598 (Anadys), GSK-625433 (Glaxo SmithKline), XTL-2125 (XTL
Biopharmaceuticals), and those disclosed in Ni et ah, Current Opinion in Drug Discovery and Development, 7(4}:446 (2004); Tan et al, Nature Reviews, 1:867 (2002); and Beaulieu et al, Current Opinion in Investigational Drugs, 5:838 (2004).
Other 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 09/032116, WO 09/032123, WO
09/032124 and WO 09/032125. Interferons useful in the present compositions and methods include, but are not limited to, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1 and petroleum etherG- interferon alpha conjugates. "PEG-interferon alpha conjugates" are interferon alpha molecules covalently attached to a petroleum etherG molecule. Illustrative petroleum etherG-interferon alpha conjugates include interferon alpha-2a (Roferon™, Hoffman La-Roche, Nutley, New Jersey) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name
Pegasys™), interferon alpha-2b (Intron™, from Schering-Plough Corporation) in the form of pegylated interferon alpha-2b (e.g., as sold under the trade name petroleum etherG-Intron™ from Schering-Plough Corporation), interferon alpha-2b-XL (e.g., as sold under the trade name petroleum etherG-Intron™), interferon alpha-2c (Berofor Alpha™, Boehringer Ingelheim, Ingelheim, Germany), petroleum etherG-interferon lambda (Bristol-Myers Squibb and
ZymoGenetics), interferon alfa-2b alpha fusion polypeptides, interferon fused with the human blood protein albumin (Albuferon™, Human Genome Sciences), Omega Interferon (Intarcia), Locteron controlled release interferon (Biolex/OctoPlus), Biomed-510 (omega interferon), Peg- IL-29 (ZymoGenetics), Locteron CR (Octoplus), R-7025 (Roche), IFN-a-2b-XL (Flame- Technologies), belerofon (Nautilus) and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen™, Amgen, Thousand Oaks, California).
Antibody therapy agents useful in the present compositions and methods include, but are not limited to, antibodies specific to IL-10 (such as those disclosed in US Patent
Publication No. US2005/0101770, humanized 12G8, a humanized monoclonal antibody against human IL-10, plasmids containing the nucleic acids encoding the humanized 12G8 light and heavy chains were deposited with the American Type Culture Collection (ATCC) as deposit numbers PTA-5923 and PTA-5922, respectively), and the like).
Examples of viral protease inhbitors useful in the present compositions and methods include, but are not limited to, an HCV protease inhibitor.
HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, those disclosed in U. S. Patent Nos. 7,494,988, 7,485,625, 7,449,447, 7,442,695, 7,425,576, 7,342,041, 7,253, 160, 7,244,721, 7,205,330, 7, 192,957, 7, 186,747, 7, 173,057, 7, 169,760, 7,012,066, 6,914, 122, 6,91 1,428, 6,894,072, 6,846,802, 6,838,475,
6,800,434, 6,767,991, 5,017,380, 4,933,443, 4,812,561 and 4,634,697; U.S. Patent Publication Nos. US20020068702, US20020160962, US200501 19168, US20050176648, US20050209164, US20050249702 and US20070042968; and International Publication Nos. WO 03/006490, WO 03/087092, WO 04/092161 and WO 08/124148.
Additional HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, VX-950 (Telaprevir, Vertex), VX-500 (Vertex), VX-813 (Vertex), VBY-376 (Virobay), BI-201335 (Boehringer Ingelheim), TMC-435 (Medivir/Tibotec), ABT-450 (Abbott/Enanta), TMC-435350 (Medivir), RG7227 (Danoprevir, InterMune/Roche), ethyl acetate-058 (Abbott/Enanta), ethyl acetate-063 (Abbott/Enanta), GS-9256 (Gilead), IDX- 320 (Idenix), ACH-1625 (Achillion), ACH-2684 (Achillion), GS-9132 (Gilead/ Achillion), ACH- 1095 (Gilead/ Achillon), IDX-136 (Idenix), IDX-316 (Idenix), ITMN-8356 (InterMune), ITMN- 8347 (InterMune), ITMN-8096 (InterMune), ITMN-7587 (InterMune), BMS-650032 (Bristol- Myers Squibb), VX-985 (Vertex) and PHX1766 (Phenomix).
Further examples of HCV protease inhbitors 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, 37(25): 8906-8914 (1998); Llinas- Brunet et al. , Bioorg Med Chem Lett, 8(13): 1713-1718 (1998); Martin et al , Biochemistry,
37(33): 11459-11468 (1998); Dimasi et al, J Virol, 7100): 7461-7469 (1997); Martin et al, Protein Eng, J0(5):607-614 (1997); Elzouki et al, JHepat, 270):42-48 (1997); BioWorld Today, 9(217V4 (November 10, 1998); U.S. Patent Publication Nos. US2005/0249702 and US
2007/0274951; and International Publication Nos. WO 98/14181, WO 98/17679, WO 98/17679, WO 98/22496 and WO 99/07734 and WO 05/087731.
Further examples of HCV protease inhibitors useful in the present compositions and methods include, but are not limited to, the following compounds:
Figure imgf000226_0001
226
Figure imgf000227_0001
227
Figure imgf000228_0001
Figure imgf000229_0001
and pharmaceutically acceptable salts thereof.
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), viramidine, A-831 (Arrow Therapeutics), EDP-239 (Enanta), ACH-2928 (Achillion), GS-5885 (Gilead); an antisense agent or a therapeutic vaccine. Viral entry inhibitors useful as second additional therapeutic agents in the present compositions and methods include, but are not limited to, PRO-206 (Progenies), REP-9C (REPICor), SP-30 (Samaritan Pharmaceuticals) and ITX-5061 (iTherx).
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 as second additional therapeutic agents in the present compositions and methods include, but are not limited to, AZD2836 (Astra Zeneca), ACH-1095 (Achillion) and ACH-806 (Achillion).
HCV NS5A inhibitors useful in the present compositions and methods include, but are not limited to, ACH-2928 (Achillon), AZD-7295 (Astra Zeneca), A-832 (Arrow
Therpeutics), PPI-461 (Presidio), PPI-1301 (Presidio), GS-5885 (Gilead) and BMS-790052 (Bristol-Myers Squibb).
HCV replicase inhibitors 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 (Globeimmune), TG-4040 (Transgene), GNI-103 (GENimmune), Hepavaxx C (ViRex Medical), ChronVac-C (Inovio/Tripep), PeviPROTM (Pevion Biotect), HCV/MF59 (Chiron/Novartis), MBL-HCV1 (MassBiologics), GI-5005 (Globeimmune), CT-011 (CureTech/Teva) and Civacir (NABI).
Examples of further additional therapeutic agents useful in the present
compositions and methods include, but are not limited to, Ritonavir (Abbott), TT033
(Benitec/Tacere Bio/Pfizer), Sirna-034 (Sirna Therapeutics), GNI-104 (GENimmune), GI-5005 (Globeimmune), IDX-102 (Idenix), Levovirin™ (ICN Pharmaceuticals, Costa Mesa, California); Humax (Genmab), ITX-2155 (Ithrex/Novartis), PRO 206 (Progenies), HepaCide-I
(NanoVirocides), MX3235 (Migenix), SCY-635 (Scynexis); KPE02003002 (Kemin Pharma), Lenocta (VioQuest Pharmaceuticals), IET - Interferon Enhancing Therapy (Transition
Therapeutics), Zadaxin (SciClone Pharma), VP 50406™ (Viropharma, Incorporated, Exton, Pennsylvania); Taribavirin (Valeant Pharmaceuticals); Nitazoxanide (Romark); Debio 025 (Debiopharm); GS-9450 (Gilead); PF-4878691 (Pfizer); ANA773 (Anadys); SCV-07 (SciClone Pharmaceuticals); NIM-881 (Novartis); ISIS 14803™ (ISIS Pharmaceuticals, Carlsbad,
California); Heptazyme™ (Ribozyme Pharmaceuticals, Boulder, Colorado); Thymosin™ (SciClone Pharmaceuticals, San Mateo, California); Maxamine (Maxim Pharmaceuticals, San Diego, California); NKB-122 (JenKen Bioscience Inc., North Carolina); Alinia (Romark Laboratories), INFORM-1 (a combination of R7128 and ITMN-191); and mycophenolate mofetil (Hoffman-LaRoche, Nutley, New Jersey).
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. When administered in combination, the Tetracyclic Heterocycle 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. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.
Generally, a total daily dosage of the at least one Tetracyclic Heterocycle
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. In one embodiment, the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, 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.
In one embodiment, when the additional therapeutic agent is INTRON-A interferon alpha 2b (commercially available from Schering-Plough Corp.), this agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW for 24 weeks or 48 weeks for first time treatment.
In another embodiment, when the additional therapeutic agent is petroleum etherG-INTRON interferon alpha 2b pegylated (commercially available from Schering-Plough 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.
In another embodiment, 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)/TIW for at least 48 to 52 weeks, or alternatively 6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks.
In still another embodiment, when the additional therapeutic agent is petroleum etherGASUS 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.
In yet another embodiment, when the additional therapeutic agent is 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.
In a further embodiment, when the additional therapeutic agent is Ribavirin (commercially available as REBETOL ribavirin from Schering-Plough 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.
In one embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In still another embodiment, 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.
In another embodiment, 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.
In another embodiment, 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.
In one 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 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.
In one embodiment, 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 administered with ribavirin.
In one embodiment, 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. In another embodiment, 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.
In still another embodiment, one or more compounds of the present invention are administered with ribavirin, interferon and a viral protease inhibitor.
In another embodiment, one or more compounds of the present invention are administered with ribavirin, interferon and an HCV protease inhibitor.
In another embodiment, one or more compounds of the present invention are administered with ribavirin, interferon and boceprevir or telaprevir.
In a further embodiment, one or more compounds of the present invention are administered with ribavirin, interferon and an HCV polymerase inhibitor.
In another embodiment, one or more compounds of the present invention are administered with pegylated-interferon alpha and ribavirin.
Compositions and Administration
Due to their activity, the Tetracyclic Heterocycle Compounds are useful in veterinary and human medicine. As described above, the Tetracyclic Heterocycle Compounds are useful for treating or preventing HCV infection in a patient in need thereof.
When administered to a patient, the Tetracyclic Heterocycle 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 Tetracyclic Heterocycle Compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, 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. For example, for oral administration in the form of tablets or capsules, 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.
Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the 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 administration. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
For preparing suppositories, 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.
Additionally, the 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. In one embodiment, the one or more Tetracyclic Heterocycle Compounds are administered orally.
In another embodiment, the one or more Tetracyclic Heterocycle Compounds are administered intravenously.
In one embodiment, a pharmaceutical preparation comprising at least one
Tetracyclic Heterocycle Compound is in unit dosage form. In such 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 Tetracyclic Heterocycle 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 Tetracyclic Heterocycle Compound(s) by weight or volume.
The quantity of Tetracyclic Heterocycle 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.
For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.
The amount and frequency of administration of the Tetracyclic Heterocycle Compounds will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Generally, a total daily dosage of the Tetracyclic Heterocycle 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. In one embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 2000 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 2000 mg/day, administered in a single dose or in 2-4 divided doses.
The 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 Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Tetracyclic Heterocycle Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat HCV infection.
In one embodiment, the present invention provides compositions comprising a Compound of Formula (I) and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides compositions comprising a Compound of Formula (I), a pharmaceutically acceptable carrier, and a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti- infective agents.
In another embodiment, the present invention provides compositions comprising a Compound of Formula (I), a pharmaceutically acceptable carrier, and wto additional therapeutic agents, each of which are independently selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
Kits
In one aspect, the present invention provides a kit comprising a therapeutically effective amount of at least one Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.
In another aspect the present invention provides a kit comprising an amount of at least one Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug 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. In one embodiment, the one or more Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in separate containers.
The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.
A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.

Claims

A compound having the formula:
Figure imgf000239_0001
(I)
or a pharmaceutically acceptable salt thereof,
wherein:
Q is:
Figure imgf000239_0002
A is phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered monocyclic cycloalkyl or 5 to 7-membered heterocycloalkyl, each of which can be optionally substituted with up to four R5 groups;
V is N or -C(R4)-;
W is N or -CH-;
X is -(CHR8)n-0-, -C(0)-0-,
Y1 is N or -C(R5)-;
Y2 is N or -C(R5)-;
Z is N, -C(R5)- or -C(O)-, such that when Z is -C(O)-, then the endocyclic double bond depicted in formula (Q2) between Z and Y1 is understood to be a single bond;
R1 represents up to 4 optional ring substituents, which can be the same or different, and are independently selected from halo, Ci-C6 alkyl, Ci-C6 haloalkyl, phenyl, 3 to 7- membered monocyclic cycloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 haloalkyl) and -CN;
R2 is -C(0)N(R6)(R7) or -C(0)0-(Ci-C6 alkyl);
R3 is H, 4- to 6-membered heterocycloalkyl, 5 or 6-membered heteroaryl, -N(RU)2, halo, -CN, -N(RU)2, -C(0)0-(Ci-C6 alkyl) or -N(R9)-S(0)n-R10, wherein said 5 or 6- membered heterocycloalkyl can optionally have one of its ring carbon atoms replaced with a carbonyl group;
R4 is selected from H, halo, C1-C5 alkyl, 3 to 7-membered monocyclic cycloalkyl, Ci-C6 haloalkyl, -0-(Ci-C6 alkyl), -C(OH)-C(0)ORu and -0-(Ci-C6 haloalkyl);
each occurrence of R5 is independently selected from H, halo, C1-C5 alkyl, C1-C5 haloalkyl, -0-(Ci-C6 alkyl), -0-(Ci-C6 haloalkyl) and -CN, wherein said C1-C5 alkyl group can be optionally substituted with -OH or -N(RU)2;
R6 and R7 are each independently selected from hydrogen, -C(0)Rn, -C(0)ORu, -C(0)C(0)ORu, Ci-C6 alkyl, Ci-C6 hydroxyalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl;
each occurrence of R8 is independently selected from H, halo, -OH, C1-C5 alkyl, Ci-C6 hydroxyalkyl, phenyl, 5 or 6-membered monocyclic heteroaryl, -N(RU)2, C1-C5 haloalkyl, -(C1-C3 alkylene)p-(3 to 7-membered monocyclic cycloalkyl), -(C1-C3 alkylene)p-0-(Ci-C6 alkyl), -(C1-C3 alkylene)p-N(Rn)2, -(C1-C3 alkylene)-NHC(0)-(Ci-C6 alkyl), -(C1-C3 alkylene)- OC(0)(Ci-C6 alkyl)NHC(0)0-(Ci-C6 alkyl), -(C1-C3 alkylene)-OC(0)-(3 to 7-membered monocyclic heterocycloalkyl), -(C1-C3 alkylene)-NHC(0)(3 to 7-membered monocyclic heterocycloalkyl), -CH(0-(d-C6 alkyl))2, -0-(Ci-C6 haloalkyl), -C(0)ORu, -C(0)N(Rn)2, - CH2OC(0)CH(NH2)-(Ci-C6 alkyl), -NHS(0)2-(Ci-C6 alkyl), -CH2NHCH(R11)C(0)OR11, -NR11- (C1-C3 alkylene)-N(Ru)2, -NRn-(Ci-C3 alkylene)-(3 to 7-membered monocyclic
heterocycloalkyl), -NRu-(Ci-C6 hydroxyalkyl) and -CN, or two R8 groups and the common carbon atom to which they are attached, can join to form a spirocyclic ring selected from 3 to 7- membered monocyclic cycloalkyl and 3 to 7-membered monocyclic heterocycloalkyl;
R9 is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 hydroxyalkyl, benzyl, -
(C1-C3 alkylene)-(3 to 7-membered monocyclic cycloalkyl) and 3 to 7-membered monocyclic cycloalkyl, wherein said C1-C5 alkyl group can be optionally substituted with a group selected from -N(Ru)2, -OR11, -COOH, -C(0)N(Rn)2, -S(0)2N(Rn)2 and 3 to 7-membered monocyclic heterocycloalkyl and wherein the phenyl moiety of said benzyl group can be optionally substituted with a boronic acid group;
R10 is selected from H, C1-C5 alkyl, C1-C5 haloalkyl, phenyl, 3 to 7-membered monocyclic cycloalkyl, 3 to 7-membered monocyclic heterocycloalkyl and 5 or 6-membered monocyclic heteroaryl, wherein said Ci-C6 alkyl group can be optionally substituted with a group selected from -N(RU)2, -OR11, -COOH, -C(0)N(Rn)2, and -S(0)2N(Rn)2;
each occurrence of R11 is independently selected from H, Ci-C6 alkyl, and 3 to 7- membered monocyclic cycloalkyl;
each occurrence of n is 1, 2 or 3; and
each occurrence of p is 0 or 1.
2. The compound of claim 1, wherein R2 is -C(0) H-(Ci-C6 alkyl). 3. The compound of claim 1 or 2, wherein R9 and R10 are each independently
Ci-C6 alkyl.
4. The compound of any of claims 1-3, wherein each occurrence of R1 is halo. 5. The compound of any of claims 1-4, wherein Q is Ql, A is phenyl, W is N, and each occurrence of Y is CH.
6. The compound of claim 1 having the formula:
Figure imgf000241_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein:
L is N or -CH-;
V is N or -C(R4)-;
X is -(CHR8)n-0- or -C(0)-0-;
R1 is H, halo or Ci-C6 alkyl;
R4 is H or halo;
R5 represents a single and optional halo substituent; R is H, Ci-C6 alkyl or 3 to 7-membered cycloalkyl;
R9 and R10 are each Ci-C6 alkyl; and
n is 1 or 2.
7. The compound of claim 6, wherein
V is N or -C(R4)-;
R1 is F;
R4 is H or CI;
R5 represents a single and optional F substituent;
R8 is H, methyl or cyclopropyl; and
R9 and R10 are each methyl.
8. The compound of claim 7, wherein L and V are each -CH- and X is
-CH2-0-.
The com ound of claim 1 having the formula:
Figure imgf000242_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein:
V is N or -CH-;
Y1 is N or -C(R5)-;
Y2 is N or -CH-;
Rla is H or F;
R3 is -N(CH3)S(0)2CH3 or:
Figure imgf000242_0002
R5 is H or -0-(Ci-C6 alkyl);
R5a and R5b are each independently H or F; and
each occurrence of R8 is H, or both R8 groups, together with the common carbon atom to which they are attached, join to form a 4- to 6-membered monocyclic heterocycloalkyl group.
10. The compound of claim 1, being any one of the compounds numbered 1- 211 in the above specification, or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) an effective amount of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition of claim 11, further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
13. The pharmaceutical composition of claim 12, wherein the second therapeutic agent is selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
14. A use of the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for inhibiting HCV NS5B activity or for preventing and/or treating infection by HCV in a patient in need thereof.
15. A method of treating a patient infected with HCV, the method comprising administering to the patient the compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in an amount effective to prevent and/or treat infection by HCV in the patient.
16. The method of claim 15, further comprising administering to said patient an effective amount of at least one second therapeutic agent selected from the group consisting of HCV NS3 and NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013034048A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
WO2014123795A2 (en) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123793A1 (en) * 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014123794A1 (en) 2013-02-07 2014-08-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c
WO2014205594A1 (en) * 2013-06-24 2014-12-31 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for treatment of viral diseases
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016196932A1 (en) * 2015-06-04 2016-12-08 Merck Sharp & Dohme Corp. Process for preparing substituted tetracyclic heterocycle compounds
KR102547771B1 (en) * 2015-11-09 2023-06-26 고려대학교 산학협력단 4-substituted-2-(5-substituted-1H-indol-2-yl)phenol derivatives, method for preparing the same and pharmaceutical composition for inhibiting cell proliferation and migration comprising the same
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CN111285844B (en) * 2020-02-24 2022-08-12 河南师范大学 Benzothiophene substituted amide compounds with biological activity and synthesis method and application thereof

Citations (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4634697A (en) 1983-10-04 1987-01-06 Shionogi & Co., Ltd. Carboxyalkenamidocephalosporins
US4812561A (en) 1986-07-02 1989-03-14 Shionogi & Co., Ltd. Crystalline hydrate of oral cephalosporin and its composition
US5017380A (en) 1986-07-02 1991-05-21 Shionogi & Co., Ltd. Gelatin hard capsule containing crystalline hydrate of oral cephalosporin
WO1998014181A1 (en) 1996-09-30 1998-04-09 Regents Of The University Of California Treatment and prevention of hepatic disorders
WO1998017679A1 (en) 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease
WO1998022496A2 (en) 1996-11-18 1998-05-28 F. Hoffmann-La Roche Ag Antiviral peptide derivatives
WO1999007734A2 (en) 1997-08-11 1999-02-18 Boehringer Ingelheim (Canada) Ltd. Hepatitis c inhibitor peptide analogues
US20020068702A1 (en) 2000-07-21 2002-06-06 Marguerita Lim-Wilby Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
US20020160962A1 (en) 2000-07-21 2002-10-31 Saksena Anil K. Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
WO2003006490A1 (en) 2001-07-11 2003-01-23 Vertex Pharmaceuticals Incorporated Bridged bicyclic serine protease inhibitors
WO2003087092A2 (en) 2002-04-11 2003-10-23 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease
WO2004041201A2 (en) * 2002-11-01 2004-05-21 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
US6767991B1 (en) 1997-08-11 2004-07-27 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptides
US6800434B2 (en) 2000-07-21 2004-10-05 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
WO2004092161A1 (en) 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hcv ns3-ns4a protease
US6838475B2 (en) 2000-07-21 2005-01-04 Schering Corporation Imidazolidinones as NS3-serine protease inhibitors of hepatitis C virus
US6846802B2 (en) 2000-04-05 2005-01-25 Schering Corporation Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising N-cyclic P2 moieties
US20050101770A1 (en) 2003-11-10 2005-05-12 Presta Leonard G. Interleukin-10 antibodies
US6894072B2 (en) 2002-01-23 2005-05-17 Schering Corporation Compounds as NS3-serine protease inhibitors of hepatitis C virus
US20050119168A1 (en) 2003-09-26 2005-06-02 Schering Corporation Macrocyclic inhibitors of hepatitis C virus NS3-serine protease
US6911428B2 (en) 2000-12-12 2005-06-28 Schering Corporation Diaryl peptides as NS3-serine protease inhibitors of hepatitis C virus
US6914122B2 (en) 2000-04-19 2005-07-05 Schering Corporation Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties
US20050209164A1 (en) 2004-02-27 2005-09-22 Schering Corporation Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease
WO2005087731A1 (en) 2004-02-27 2005-09-22 Schering Corporation Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease
US20050249702A1 (en) 2004-05-06 2005-11-10 Schering Corporation (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease
WO2006019832A1 (en) 2004-07-22 2006-02-23 Ptc Therapeutics, Inc. Thienopyridines for treating hepatitis c
WO2006019831A1 (en) 2004-07-14 2006-02-23 Ptc Therapeutics, Inc. Methods for treating hepatitis c
US7012066B2 (en) 2000-07-21 2006-03-14 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US7173057B2 (en) 2004-02-27 2007-02-06 Schering Corporation Ketoamides with cyclic P4'S as inhibitors of NS3 protease of hepatitis C virus
US7186747B2 (en) 2004-02-27 2007-03-06 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
US7192957B2 (en) 2004-02-27 2007-03-20 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
US7205330B2 (en) 2004-02-27 2007-04-17 Schering Corporation Inhibitors of hepatitis C virus NS3 protease
US7244721B2 (en) 2000-07-21 2007-07-17 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US7253160B2 (en) 2003-11-20 2007-08-07 Schering Corporation Depeptidized inhibitors of hepatitis C virus NS3 protease
US20070274951A1 (en) 2006-02-09 2007-11-29 Xiao Tong Combinations comprising HCV protease inhibitor(s) and HCV polymerase inhibitor(s), and methods of treatment related thereto
US7342041B2 (en) 2004-02-27 2008-03-11 Schering Corporation 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease
WO2008083351A2 (en) 2006-12-29 2008-07-10 Genifuel Corporation Controlled growth environments for algae cultivation
WO2008082484A1 (en) 2006-12-22 2008-07-10 Schering Corporation 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
WO2008082488A1 (en) 2006-12-22 2008-07-10 Schering Corporation 4, 5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
WO2008124148A2 (en) 2007-04-10 2008-10-16 Schering Corporation Sulfur compounds as inhiibitors of hepatitis c virus ns3 serine protease
US7449447B2 (en) 2003-08-26 2008-11-11 Schering Corporation Peptidomimetic NS3-serine protease inhibitors of hepatitis C virus
WO2008136815A2 (en) 2006-12-22 2008-11-13 Schering Corporation 5, 6-ring annulated indole derivatives and use thereof
US7476686B2 (en) 2002-11-19 2009-01-13 Achillion Pharmaceuticals, Inc. Substituted aryl thioureas and related compounds; inhibitors of viral replication
US20090022688A1 (en) 2003-04-11 2009-01-22 Farmer Luc J Inhibitors of serine protease, particularly hcv ns3-ns4a protease
US7485625B2 (en) 2003-12-11 2009-02-03 Schering Corporation Inhibitors of hepatitis C virus NS3/NS4a serine protease
US7494988B2 (en) 2000-04-03 2009-02-24 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease
WO2009032116A1 (en) 2007-08-29 2009-03-12 Schering Corporation 2, 3-substituted indole derivatives for treating viral infections
WO2009032124A1 (en) 2007-08-29 2009-03-12 Schering Corporation Substituted indole derivatives and methods of use thereof
WO2009032123A2 (en) 2007-08-29 2009-03-12 Schering Corporation Tetracyclic indole derivatives and their use for treating or preventing viral infections
WO2009032125A1 (en) 2007-08-29 2009-03-12 Schering Corporation 2,3-substituted azaindole derivatives for treating viral infections
US20090081636A1 (en) 2005-04-11 2009-03-26 Mingjun Huang Pharmaceutical compositions for and methods of inhibiting HCV replication
WO2011106992A1 (en) * 2010-03-02 2011-09-09 Merck Sharp & Dohme Corp. Inhibitors of hepatitis c virus ns5b polymerase

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6428571B1 (en) 1996-01-22 2002-08-06 Scimed Life Systems, Inc. Self-sealing PTFE vascular graft and manufacturing methods
WO2009101022A1 (en) 2008-02-14 2009-08-20 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
US8048887B2 (en) * 2008-09-11 2011-11-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US7994171B2 (en) * 2008-09-11 2011-08-09 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
AR080185A1 (en) 2010-02-19 2012-03-21 Glaxo Group Ltd DERIVATIVES OF BORONIC AND BENZOFURAN ACID, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USE OF THE SAME IN THE TREATMENT AND / OR PREVENTION OF VIRAL INFECTIONS, IN PARTICULAR BY HEPATITIS C (HCV) VIRUSES.
US8324212B2 (en) 2010-02-25 2012-12-04 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
JP2014511875A (en) 2011-04-13 2014-05-19 メルク・シャープ・アンド・ドーム・コーポレーション 2'-cyano-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
EP2697242B1 (en) 2011-04-13 2018-10-03 Merck Sharp & Dohme Corp. 2'-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
JP2014515023A (en) 2011-04-13 2014-06-26 メルク・シャープ・アンド・ドーム・コーポレーション 2'-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
WO2013033901A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Heterocyclic-substituted benzofuran derivatives and methods of use thereof for the treatment of viral diseases
WO2013033899A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases

Patent Citations (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4634697A (en) 1983-10-04 1987-01-06 Shionogi & Co., Ltd. Carboxyalkenamidocephalosporins
US4812561A (en) 1986-07-02 1989-03-14 Shionogi & Co., Ltd. Crystalline hydrate of oral cephalosporin and its composition
US4933443A (en) 1986-07-02 1990-06-12 Shionogi & Co., Ltd. Method for preparing crystalline hydrate of oral celphalosporin and its composition
US5017380A (en) 1986-07-02 1991-05-21 Shionogi & Co., Ltd. Gelatin hard capsule containing crystalline hydrate of oral cephalosporin
WO1998014181A1 (en) 1996-09-30 1998-04-09 Regents Of The University Of California Treatment and prevention of hepatic disorders
WO1998017679A1 (en) 1996-10-18 1998-04-30 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease
WO1998022496A2 (en) 1996-11-18 1998-05-28 F. Hoffmann-La Roche Ag Antiviral peptide derivatives
US6767991B1 (en) 1997-08-11 2004-07-27 Boehringer Ingelheim (Canada) Ltd. Hepatitis C inhibitor peptides
WO1999007734A2 (en) 1997-08-11 1999-02-18 Boehringer Ingelheim (Canada) Ltd. Hepatitis c inhibitor peptide analogues
US7494988B2 (en) 2000-04-03 2009-02-24 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease
US6846802B2 (en) 2000-04-05 2005-01-25 Schering Corporation Macrocyclic NS3-serine protease inhibitors of hepatitis C virus comprising N-cyclic P2 moieties
US6914122B2 (en) 2000-04-19 2005-07-05 Schering Corporation Macrocyclic NS-3 serine protease inhibitors of hepatitis C virus comprising alkyl and aryl alanine P2 moieties
US7012066B2 (en) 2000-07-21 2006-03-14 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US7169760B2 (en) 2000-07-21 2007-01-30 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US6800434B2 (en) 2000-07-21 2004-10-05 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US20050176648A1 (en) 2000-07-21 2005-08-11 Schering-Plough Corporation Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
US6838475B2 (en) 2000-07-21 2005-01-04 Schering Corporation Imidazolidinones as NS3-serine protease inhibitors of hepatitis C virus
US7244721B2 (en) 2000-07-21 2007-07-17 Schering Corporation Peptides as NS3-serine protease inhibitors of hepatitis C virus
US20020160962A1 (en) 2000-07-21 2002-10-31 Saksena Anil K. Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
US20020068702A1 (en) 2000-07-21 2002-06-06 Marguerita Lim-Wilby Novel peptides as NS3-serine protease inhibitors of hepatitis C virus
US6911428B2 (en) 2000-12-12 2005-06-28 Schering Corporation Diaryl peptides as NS3-serine protease inhibitors of hepatitis C virus
WO2003006490A1 (en) 2001-07-11 2003-01-23 Vertex Pharmaceuticals Incorporated Bridged bicyclic serine protease inhibitors
US6894072B2 (en) 2002-01-23 2005-05-17 Schering Corporation Compounds as NS3-serine protease inhibitors of hepatitis C virus
WO2003087092A2 (en) 2002-04-11 2003-10-23 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease
US7273885B2 (en) 2002-04-11 2007-09-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
WO2004041201A2 (en) * 2002-11-01 2004-05-21 Viropharma Incorporated Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases
US7476686B2 (en) 2002-11-19 2009-01-13 Achillion Pharmaceuticals, Inc. Substituted aryl thioureas and related compounds; inhibitors of viral replication
WO2004092161A1 (en) 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hcv ns3-ns4a protease
US20090022688A1 (en) 2003-04-11 2009-01-22 Farmer Luc J Inhibitors of serine protease, particularly hcv ns3-ns4a protease
US7449447B2 (en) 2003-08-26 2008-11-11 Schering Corporation Peptidomimetic NS3-serine protease inhibitors of hepatitis C virus
US20050119168A1 (en) 2003-09-26 2005-06-02 Schering Corporation Macrocyclic inhibitors of hepatitis C virus NS3-serine protease
US20050101770A1 (en) 2003-11-10 2005-05-12 Presta Leonard G. Interleukin-10 antibodies
US7442695B2 (en) 2003-11-20 2008-10-28 Schering Corporation Depeptidized inhibitors of hepatitis C virus NS3 protease
US7253160B2 (en) 2003-11-20 2007-08-07 Schering Corporation Depeptidized inhibitors of hepatitis C virus NS3 protease
US7485625B2 (en) 2003-12-11 2009-02-03 Schering Corporation Inhibitors of hepatitis C virus NS3/NS4a serine protease
US7205330B2 (en) 2004-02-27 2007-04-17 Schering Corporation Inhibitors of hepatitis C virus NS3 protease
US7192957B2 (en) 2004-02-27 2007-03-20 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
US7186747B2 (en) 2004-02-27 2007-03-06 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
US20070042968A1 (en) 2004-02-27 2007-02-22 Schering Corporation Sulfur compounds as inhibitors of Hepatitis C virus NS3 serine protease
US20050209164A1 (en) 2004-02-27 2005-09-22 Schering Corporation Cyclobutenedione-containing compounds as inhibitors of hepatitis C virus NS3 serine protease
US7342041B2 (en) 2004-02-27 2008-03-11 Schering Corporation 3,4-(cyclopentyl)-fused proline compounds as inhibitors of hepatitis C virus NS3 serine protease
US7173057B2 (en) 2004-02-27 2007-02-06 Schering Corporation Ketoamides with cyclic P4'S as inhibitors of NS3 protease of hepatitis C virus
WO2005087731A1 (en) 2004-02-27 2005-09-22 Schering Corporation Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease
US7425576B2 (en) 2004-02-27 2008-09-16 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
US20050249702A1 (en) 2004-05-06 2005-11-10 Schering Corporation (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as inhibitor of hepatitis C virus NS3/NS4a serine protease
WO2006019831A1 (en) 2004-07-14 2006-02-23 Ptc Therapeutics, Inc. Methods for treating hepatitis c
WO2006019832A1 (en) 2004-07-22 2006-02-23 Ptc Therapeutics, Inc. Thienopyridines for treating hepatitis c
US20090081636A1 (en) 2005-04-11 2009-03-26 Mingjun Huang Pharmaceutical compositions for and methods of inhibiting HCV replication
US20070274951A1 (en) 2006-02-09 2007-11-29 Xiao Tong Combinations comprising HCV protease inhibitor(s) and HCV polymerase inhibitor(s), and methods of treatment related thereto
WO2008082484A1 (en) 2006-12-22 2008-07-10 Schering Corporation 4,5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
WO2008136815A2 (en) 2006-12-22 2008-11-13 Schering Corporation 5, 6-ring annulated indole derivatives and use thereof
WO2008082488A1 (en) 2006-12-22 2008-07-10 Schering Corporation 4, 5-ring annulated indole derivatives for treating or preventing of hcv and related viral infections
WO2008083351A2 (en) 2006-12-29 2008-07-10 Genifuel Corporation Controlled growth environments for algae cultivation
WO2008124148A2 (en) 2007-04-10 2008-10-16 Schering Corporation Sulfur compounds as inhiibitors of hepatitis c virus ns3 serine protease
WO2009032116A1 (en) 2007-08-29 2009-03-12 Schering Corporation 2, 3-substituted indole derivatives for treating viral infections
WO2009032124A1 (en) 2007-08-29 2009-03-12 Schering Corporation Substituted indole derivatives and methods of use thereof
WO2009032123A2 (en) 2007-08-29 2009-03-12 Schering Corporation Tetracyclic indole derivatives and their use for treating or preventing viral infections
WO2009032125A1 (en) 2007-08-29 2009-03-12 Schering Corporation 2,3-substituted azaindole derivatives for treating viral infections
WO2011106992A1 (en) * 2010-03-02 2011-09-09 Merck Sharp & Dohme Corp. Inhibitors of hepatitis c virus ns5b polymerase

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"The Orange Book", FOOD & DRUG ADMINISTRATION
A. L. BINGHAM ET AL., CHERN. COMMUN., 2001, pages 603 - 604
ANDERSON ET AL.: "The Practice of Medicinal Chemistry", 1996, ACADEMIC PRESS
BEAULIEU ET AL., CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 5, 2004, pages 838
BEHRENS ET AL., EMBO J., vol. 15, no. 1, 1996, pages 12 - 22
BIOWORLD TODAY, vol. 9, no. 217, 10 November 1998 (1998-11-10), pages 4
CARROLL ET AL., J. BIOL. CHERN., vol. 278, no. 14, 2003, pages 11979 - 84
CATERINA TROZZI ET AL.: "In Vitro Selection and Characterization of Hepatitis C Virus Serine Protease Variants Resistant to an Active-Site Peptide Inhibitor", J. VIROL., vol. 77, no. 6, 2003, pages 3669, XP002273984, DOI: doi:10.1128/JVI.77.6.3669-3679.2003
DIMASI ET AL., J VIROL, vol. 71, no. 10, 1997, pages 7461 - 7469
E. C. VAN TONDE ET AL., AAPS PHARMSCITECHOURS, vol. 5, no. 1, 2004
ELZOUKI ET AL., JHEPAT, vol. 27, no. 1, 1997, pages 42 - 48
GREENE; WUTS: "Protecting Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
HOLLAND ET AL., PATHOLOGY, vol. 30, no. 2, 1998, pages 192 - 195
INGALLINELLA ET AL., BIOCHEMISTRY, vol. 37, no. 25, 1998, pages 8906 - 8914
JAN M. VROLIJK ET AL.: "A replicons-based bioassay for the measurement of interferons in patients with chronic hepatitis C", J. V O OG CA METHODS, vol. 110, 2003, pages 201
LAMBALLERIE ET AL., J GEN VIROL, vol. 78, no. 1, 1997, pages 45 - 51
LANDRO ET AL., BIOCHEMISTRY, vol. 36, no. 31, 1997, pages 9340 - 9348
LLINAS-BRUNET ET AL., BIOORG MED CHEM LETT, vol. 8, no. 13, 1998, pages 1713 - 1718
M. CAIRA ET AL., J. PHARMACEUTICAL SCI, vol. 93, no. 3, 2004, pages 601 - 611
MARTIN ET AL., BIOCHEMISTRY, vol. 37, no. 33, 1998, pages 1459 - 11468
MARTIN ET AL., PROTEIN ENG, vol. 10, no. 5, 1997, pages 607 - 614
NI ET AL., CURRENT OPINION IN DRUG DISCOVERY AND DEVELOPMENT, vol. 7, no. 4, 2004, pages 446
P. GOULD, INTERNATIONAL J. OF PHARMACEUTICS, vol. 33, 1986, pages 201 - 217
P. STAHL ET AL.: "Handbook of Pharmaceutical Salts. Properties, Selection and Use", 2002, ZURICH: WILEY-VCH
S. BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, pages 1 - 19
See also references of EP2753325A4
SIMMONDS ET AL., J GEN VIROL, vol. 74, no. 11, 1993, pages 2391 - 2399
SIMMONDS ET AL., J GEN VIROL, vol. 75, no. 5, 1994, pages 1053 - 1061
STEVEN S. CARROLL ET AL.: "Inhibition of Hepatitis C Virus RNA Replication by 2'-Modified Nucleoside Analogs", J. BIOLOGICAL CHEMISTRY, vol. 278, no. 14, 2003, pages 11979, XP002316770, DOI: doi:10.1074/jbc.M210914200
T. HIGUCHI; V. STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, 1987, A.C.S. SYMPOSIUM SERIES
T. W. GREENE ET AL.: "Protective Groups in Organic Synthesis", 1991, WILEY
TAN ET AL., NATURE REVIEWS, vol. 1, 2002, pages 867

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CA2847019A1 (en) 2013-03-14
IL231217A0 (en) 2014-04-30
RU2014113539A (en) 2015-10-20
KR20140059278A (en) 2014-05-15
EP2753325A4 (en) 2015-01-21
JP2014526445A (en) 2014-10-06
US20140213571A1 (en) 2014-07-31
TW201317241A (en) 2013-05-01
EP2753325A1 (en) 2014-07-16
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US9265773B2 (en) 2016-02-23
BR112014005407A2 (en) 2017-03-28

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